Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:18](=[O:29])[N:17]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[C:16]3=[O:41])[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[O:37][CH3:38])[CH2:30][N:17]1[C:16](=[O:41])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)[CH:14]=2)[N:19]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:18]1=[O:29]
Reactant: COc1ccc(Cn2c(=O)c3cc(N4CC(OCc5ccccc5)C4)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(N4CC(O)C4)ccc3n(C3CCOCC3)c2=O)cc1OC
Yield: 50.7 %

Procedure:
A mixture of 0.04 g of the compound obtained in Step 10.1, 0.007 g of ammonium formate and 0.008 g of Pd/C (10%) in 7.2 ml of EtOH is irradiated in a microwave field for 1 hour at 120° C. The reaction mixture is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (95/5, v/v) to give 0.017 g of the expected product.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[CH:18]=[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[N:12][CH:13]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[NH:56]1[CH2:59][CH2:58][CH2:57]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:56]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=3)[CH:18]=[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:12][CH:13]=2)[CH2:59][CH2:58][CH2:57]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(Br)cn3)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCC4)cn3)c2)CC1
Temperature: 0 °C
Yield: 23.9 %

Procedure:
To a mixture of sodium-tert-butoxide (0.18 g, 1.87 mmol) in toluene (2 mL) cooled to 0° C. under an inert atmosphere was added tert-butyl 4-(3-(5-bromopyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.34 mmol). The mixture was degassed for 20 min. Palladium acetate (0.02 g, 0.089 mmol) and (2-biphenyl)di-tert-butylphosphine (0.06 g, 0.2 mmol) was added and the mixture was degassed for 10 min. Azetidine (0.092 g, 1.6 mmol) was added and the reaction was heated at 85° C. for 15 h. The reaction was cooled and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title compound (0.135 g, 23.7%). 1H NMR (500 MHz, DMSO-d6): δ 7.49 (s, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.81 (m, 3H), 6.80 (d, J=8.65 Hz, 1H), 6.31 (s, 1H), 3.88 (t, J=7.15 Hz, 4H), 3.48 (m, 2H), 3.38 (m, 2H), 2.40 (m, 4H), 2.30 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 62.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-4-fluoro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (26 mg).
Reaction SMILES: O[C@H]1CCN(C(OC(C)(C)C)=O)C1.[O:14]([C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:14]([C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccccc2)C1
Yield: 51 %

Procedure:
tert-Butyl (3R)-3-phenoxypyrrolidine-1-carboxylate was prepared from tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (0.43 g, 2.286 mmol) according to the method described for Intermediate 270 to afford the title compound (0.312 g, 51% yield). Method B HPLC-MS: MH+ requires m/z=208 Found: m/z=208, Rt=2.20 min (100%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)CCCOc1ccc(CC(C)=O)cc1
Product: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-(3-carbomethoxypropoxy)phenyl] propan-2-one (6.0 g) and 2-hydroxy-2-phenyl ethanamine (3.29 g) and crystallised from hexane m.p. 60°-76° as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)C)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:10][C:2]=2[CH3:1])=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: Cc1cc(C(C)N2CCCCC2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCCCC3)cc2C)c(O)n1
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A solution of 2-methyl-4-(1-(piperidin-1-yl)ethyl)benzoic acid (100 mg, 0.40 mmol) in dichloromethane (50 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (35 mg, 0.1 mmol) and triethylamine (32 mg, 0.3 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was washed with water (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative-TLC (silica gel, methanol/dichloromethane=1:15, 1% NH4OH) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(piperidin-1-ylmethyl)benzamide as a white solid (35 mg, 23%). LRMS (M+H+) m/z: calcd 381.51. found 381. HPLC purity (214 nm): 93%. 1H NMR (300 MHz, CD3OD): δ 7.42-7.32 (m, 3H), 6.11 (s, 1H), 4.85 (s, 2H), 4.79-4.72 (m, 1H), 2.94-2.79 (m, 4H), 2.40 (s, 3H), 2.34 (s, 3H), 2.24 (s, 3H), 1.83-1.63 (m, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[CH3:17][N:18]=[C:19]=[S:20].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][NH:18][C:19]([C:9]1[C:8]2[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][C:11]([CH3:13])([CH3:14])[C:10]=1[OH:15])=[S:20]
Reactant: CN=C=S
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
To a mixture of 3.2 g of 6-nitro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 1.2 g of methyl isothiocyanate, and 40 ml of dried N,N-dimethylformamide was added 1.9 g of potassium t-butoxide while stirring under cooling with ice. The mixture was stirred for 3 hours under ice-cooling and then allowed to stand for 12 hours. Ice-water was added thereto, and the mixture was made acidic with hydrochloric acid and then extracted with methylene chloride. The organic layer was re-extracted with 2N NaOH. The aqueous layer was made acidic with hydrochloric acid and re-extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solution: n-hexane:ethyl acetate =10:1) and recrystallized from a mixed solvent of methylene chloride and n-hexane to obtain 2.33 g of N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ncc(C(F)(F)F)cc1CO
Solvent: ClCCl
Product: COc1ncc(C(F)(F)F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methanol (14) (0.4 g, 1.93 mmol) dissolved in DCM was added thionyl chloride (0.38 ml, 3.86 mmol). The reaction mixture was stirred for 2 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield 3-(chloromethyl)-2-methoxy-5-(trifluoromethyl)pyridine (15) as a liquid. (Yield 0.3 g, 69.76%)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][S:7]([NH:10][CH2:11][C:12]([NH2:14])=O)(=[O:9])=[O:8].[OH-].[Na+].[CH2:22](OS(OCC)(=O)=O)[CH3:23]>ClCCl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:22]([N:10]([CH2:11][C:12]#[N:14])[S:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=1)(=[O:9])=[O:8])[CH3:23]
Reactant: CCOS(=O)(=O)OCC
Reactant: NC(=O)CNS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN(CC#N)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In this example 2 g of 3-trifluoromethylbenzylsulfonamidoacetamide was dissolved in 30 ml of dichloromethane. To this was added 0.32 g of sodium hydroxide dissolved in a minimum amount of water and 0.46 of benzyltriethylammonium chloride. A solution of 1.1 ml of diethylsulfate in 5 ml of dichloromethane was added dropwise. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the dichloromethane layer was separated. The water phase is extracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and stripped. Trituration of the resulting solid residue yielded 1.4 g of title compound as a white solid; m.p. 67° to 68.5° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([OH:36])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([O:36][C:9]([O:11][CH3:12])=[O:10])=[C:23]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[CH3:35])[C:24](=[O:26])[N:25]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(-c2c(O)sc(-c3ccc(F)cc3)nc2=O)c(C)c1
Reactant: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1sc(-c2ccc(F)cc2)nc(=O)c1-c1c(C)cc(C)cc1C
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
1.0 g (10 mmol) of triethylamine and then 0.94 g (10 mmol) of methyl chloroformate in 10 ml of ethyl acetate are added dropwise at 0° C. to 3.4 g (10 mmol) of 2-(4-fluorophenyl)-6-hydroxy-5-(2,4,6-trimethyl-phenyl)-1,3-thiazin-4-one in 50 ml of ethyl acetate. The mixture is stirred for 8 hours at 20° C. and filtered, the organic phase is washed using half-concentrated sodium chloride elusion and dried over sodium sulphate, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (35 to 70 μm) using toluene/acetone (20:1 parts by volume). 3.1 g of 2-(4-fluorophenyl)-6-methoxycarbonyloxy-5-(2,4,6-trimethylphenyl)-1,3-thiazin-4-one are obtained (yield: 78% of theory). M.p.=129° to 131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:28]([F:39])[CH:27]=2)[CH:19]=1.[OH-].[Na+].[ClH:42].C(OCC)(=O)C.Cl>C(OCC)(=O)C.O1CCCC1.CO>[ClH:42].[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:39])[CH:27]=2)[CH:19]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCc4cccc(C)n4)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(COc2cc(C)c(-c3cccc(COc4ccc(CCC(=O)O)c(F)c4)c3)c(C)c2)n1
Yield: 86 %

Procedure:
To a mixture of ethyl 3-[4-({2′,6′-dimethyl-4′-[(6-methylpyridin-2-yl)methoxy]biphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (1.30 g, 2.46 mmol), methanol (6 mL) and tetrahydrofuran (10 mL) was added 1 N sodium hydroxide aqueous solution (4.9 mL) at room temperature with stirring, and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) to give an oil. The oil was dissolved in ethyl acetate and 4 N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, washed and dried to give the title compound (1.14 g, yield 86%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH2:24]>>[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH:24][C:14]([C:3]1[N:4]=[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]2[C:7](=[O:8])[C:2]=1[OH:1])=[O:16]
Reactant: Cc1ccc(CN)cc1C
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Product: Cc1ccc(CNC(=O)c2nc3n(c(=O)c2O)CC(=O)N3C)cc1C
Yield: 43.8 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.070 g, 0.28 mmol) with 3,4-dimethylbenzylamine (0.15 g, 1.12 mmol) as described in the preparation of example 1 gave 0.042 g (58% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.18 (3H, s, CH3), 2.20 (3H, s, CH3), 3.14 (3H, s, NCH3), 4.42 (2H, d, J=6.3 Hz, NCH2), 4.47 (2H, s, CH2), 7.0–7.1 (3H, m, aromatics), 9.40 (1H, broad t, NH), 12.35 (1H, s, OH). MS (ESI+) m/z 343 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)[C@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 70.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.45 g), S-trityl-D-cysteine methyl ester hydrochloride (0.46 g), 1H-1,2,3-benzotriazol-1-ol (0.26 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.32 g), triethylamine (0.19 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 64 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.60 g, yield 72%) as a colorless amorphous solid.
Reaction SMILES: B(O)(O)O.C1N2CN3CN(C2)CN1C3.[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1O)([CH3:18])[CH3:17].OS(O)(=O)=O.CC(C1C=C(C=C)C=C(C(C)(C)C)[C:40]=1[OH:51])(C)C>C(O)CO>[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)[CH:40]=[O:51])([CH3:18])[CH3:17]
Reactant: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: OCCO
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Temperature: 149 °C
Reaction time: 0.5 h

Procedure:
3.5 g of boric acid was heated in 150 ml of ethylene glycol at 150° C. for 30 minutes, in a 500 cc flask equipped with a reflux condenser. 25 g of hexamethylenetetramine and 21 g of 2,6-bis (1,1-dimethylethyl)phenol were then added and the solution maintained at 148-150° C. for 15 minutes. After cooling to 125° C. at which stage the first crystals appeared, 150 ml of H2SO4 (30% 0 was added and stirring was continued for another 30 minutes. The resulting slurry was filtered and washed with warm water. After drying, 22 g of 3,5-bis (1,1-dimethylethyl)benzaldehyde was obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:50])[N:32]4[CH2:37][CH2:36][N:35]([C:38]5[CH:43]=[CH:42][C:41]([C:44]6[N:49]=[CH:48][CH:47]=[CH:46][N:45]=6)=[CH:40][CH:39]=5)[CH2:34][CH2:33]4)[CH2:26]3)=[O:24])[CH:20]=2)[NH:15][N:14]=1>C(O)C.O.NN>[NH2:3][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:50])[N:32]4[CH2:33][CH2:34][N:35]([C:38]5[CH:43]=[CH:42][C:41]([C:44]6[N:49]=[CH:48][CH:47]=[CH:46][N:45]=6)=[CH:40][CH:39]=5)[CH2:36][CH2:37]4)[CH2:26]3)=[O:24])[CH:20]=2)[NH:15][N:14]=1
Reactant: O=C(Nc1ccc2[nH]nc(CN3C(=O)c4ccccc4C3=O)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1n[nH]c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Yield: 29.3 %

Procedure:
1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1H-indazol-5-yl]-amide (compound 50 from Example 78, 424 mg, 0.633 mmol) was dissolved in ethanol and 0.31 ml of hydrazine hydrate. The mixture was heated at 80 C for 20 hrs and then evaporated to dryness. The mixture was chromatographed on silica gel to obtain 100 mg of title product.
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][C@@H:34]([CH3:37])[CH2:35][OH:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][C@@H:34]([CH3:37])[CH2:35][OH:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Reactant: C[C@H](N)CO
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)N[C@@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.23 (d, J=6.72 Hz, 3 H), 1.85 (s, 3 H), 2.95 (s, 2 H), 3.50-3.55 (m, 5 H), 4.07-4.12 (m, 1 H), 4.18 (s, 2 H), 4.36 (d, J=4.80 Hz, 2 H), 4.70 (t, J=5.63 Hz, 1 H), 7.12 (t, J=8.78 Hz, 2 H), 7.37-7.41 (m, 2 H), 8.08 (s, 1 H), 8.55 (s, 1 H), 10.27 (s, 1 H), 17.14 (s, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:15]=12.[CH3:28][C:29]1[N:30]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=[C:32]([CH:34]=[O:35])[N:33]=1.C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[OH:35][CH:34]([C:32]1[N:33]=[C:29]([CH3:28])[N:30]([C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:31]=1)[CH:24]1[C:23](=[O:27])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1nc(C=O)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c2n(c3ccccc13)C(=O)CCC2
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n1)CC2
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
To a solution of diisopropylamine (557 mg) in tetrahydrofuran (7.5 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (3.35 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (995 mg) in tetrahydrofuran (10 ml) over 15 minutes. The mixture was stirred at -70° C. for 40 minutes, and a solution of 2-methyl-1-trityl-1H-imidazole-4-carbaldehyde (1.76 g) in tetrahydrofuran (20 ml) was added dropwise over 15 minutes. After the mixture was stirred at -70° C. for 1 hour and at ambient temperature for 1 hour, it was diluted with water and neutralized with a aqueous solution of oxalic acid. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated in vacuo, the residue was subjected to a column chromatography on silica gel (20% ethyl acetate-chloroform). The fractions containing the product were combined and evaporated in vacuo. The residue was crystallized from n-hexane-ether to give 8,9-dihydro-7-[(hydroxy)(2-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (2.06 g).