Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][CH2:31]C)=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:33](=O)(OC)OC.C1N2CCN(CC2)C1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:33])[C:21]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)OC
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Temperature: 25 °C

Procedure:
A solution of ethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D115) (112 mg), dimethyl carbonate (2.0 mL) and DABCO (33 mg) in N,N-dimethylformamide (2 mL) was stirred at 90° C. for 2 days. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford methyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D116) (72 mg). The crude product was used directly in the next step without further identification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@H:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C=CC1(C(=O)O)COCCOC1
Reactant: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@@H](O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (244 mg, 0.459 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid 57d (79 mg, 0.459 mmol), triethylamine (140 mg, 192 μL, 1.38 mmol) and tri(o-tolyl)phosphine (28 mg, 0.092 mmol) in 1,4-dioxane (9 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol) was added and the mixture was heated to 80° C. for 45 min and then allowed to cool. The suspension was filtered and evaporated to give crude title compound which was used in the next stage without further purification. LCMS (m/z) 624.2 [M+H], Tr=1.58 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([NH2:16])[C:14]#[CH:15]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH2:13][C:14]#[CH:15])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: C#CCN
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C#CCNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (3-47 g) in acetonitrile (16 mL) a solution of propargylamine (1.76 g) in acetonitrile (16 mL) was added dropwise at 0° C., the mixture warmed to r.t. and stirred at r.t. for 48 h. The suspension was diluted with ethyl acetate, washed with brine, dried (Na2SO4), and evaporated. Purification by flash chromatography on silica using hexane/methyl tert-butyl ether gave the title compound (1.97 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[C@@H:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O1CCCC1.C(OCC)(=O)C>[CH:22]([NH:26][C:4](=[O:7])[CH:3]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=1)[C:2]([CH3:21])([CH3:1])[CH2:6][OH:5])([CH2:24][CH3:25])[CH3:23]
Reactant: CC[C@H](C)N
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Reaction time: 192 h

Procedure:
To a stirring solution comprised of (+)-4-(4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile (1.345 g; 4.495 mmol) in tetrahydrofuran (5 mL) at ambient temperature under a nitrogen atmosphere is added (S)-(+)-sec-butylamine (0.4931 g; 6.742 mmol.) The reaction mixture is stirred for eight days. The reaction mixture is diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid and with a brine solution. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo to afford 1.633 of a white solid as a mixture of diastereomers; HPLC UV purity: 94% (two diastereomers.)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:8]3[C:9]2=[C:4]([CH2:5][CH2:6][N:7]3[CH2:33][CH3:34])[N:3]=1.[C:35]1([C@H:41]([NH:43][C:44]([NH2:46])=[O:45])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(Cl)Cl>[CH2:33]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([NH:46][C:44]([NH:43][C@@H:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:42])=[O:45])[CH:11]=[C:10]3[N:12]([C:14]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:13]=[C:8]1[C:9]=23)[CH3:34]
Reactant: CCN1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCN1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
7-chloro-3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine (35 mg, 0.075 mmol), (R)-1-(1-phenylethyl)urea (18.5 mg, 0.113 mmol), cesium carbonate (73.6 mg, 0.226 mmol) and BrettPhos pre-catalyst (6.8 mg) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (0.4 mL) and heated reaction at 100° C. for 1 hour. The reaction mixture was diluted with DCM, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-75% EtOAc-hexanes) gave (R)-1-(3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C38H36N6O [M+H]+ 593. found 593.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]3[CH2:21][C@H:20]3[C:22]([O:24]C)=[O:23])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]3[CH2:21][C@H:20]3[C:22]([OH:24])=[O:23])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@@H]1Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(C[C@H]1C[C@H]1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To the ester from Step 2 (145 mg, 0.33 mmol) in 3 mL THF and 3 mL MeOH was added 2N NaOH (1 mL, 2 mmol) and the reaction mixture was stirred at r.t. for 16 h. Excess 0.5N citric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Purification by flash chromatogrpahy on silicic acid (20% to 40% ethyl acetate in hexane) provided 99 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@H:51]1[NH2:56]>CN(C)C=O>[NH2:49][C@H:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@H:51]1[NH:56][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
2-Methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C, 590 mg, 2.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (646 mg, 5 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.05 g, 2.7 mmol) were added. After 5 minutes of stirring at room temperature cis-1,2-diaminocyclohexane (570 mg, 5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->140:10:1) yielded cis-N-(2-amino-cyclohexyl)-2-methylsulfanyl-4-trifluoromethyl-benzamide as a light yellow solid (282 mg, 34%), MS: m/e=3331.1 [(M+H)+].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncn4)cc(=O)n3C)CCO2)cc1
Yield: 90.4 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (0.30 g, 1.35 mmol), 2-chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (0.40 g, 1.75 mmol) and triethylamine (0.56 ml, 4.05 mmol) in tetrahydrofuran(6 ml) was refluxed for several hours. The reaction mixture was removed in vacuo. The residue was dissolved in 1N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate as the eluent to give the title compound (463 mg, 90%)
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].FC(F)(F)C(O)=O.[OH:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1)[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: O=C1CCC[C@H](CO)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Ethyl vinyl ether (1.68 mL, 17.5 mmol) and trifluoroacetic acid (0.1 mL) were added sequentially to a solution of (R)-6-hydroxymethylpiperidin-2-one (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485–3496, 1.62 g, 12.5 mmol) in CHCl3 (10 mL) at rt. The reaction mixture was stirred at rt for 18 h, then saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2Cl2 (3×75 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→4% MeOH/CH2Cl2, gradient) afforded 2.03 g (80%) of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([C:21]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[C:12]2[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>>[CH2:24]([O:23][C:21]([N:11]([C:12]1[C:17]([O:18][CH3:19])=[N:16][C:15]([CH3:20])=[CH:14][N:13]=1)[S:8]([C:7]1[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][CH:34]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[O:22])[CH:25]([CH3:27])[CH3:26]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1

Procedure:
reaction of 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide with 4-methoxycarbonylphenylboronic acid (or an anhydride or ester thereof) in the presence of a source of fluoride ion and under aqueous conditions to give N-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide;
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]([SH:19])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:15][C:16]1[S:19][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:9][CH:8]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 4-(trifluoromethyl)benzenecarboximidamide hydrochloride (2.60 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 770 mg (29.2%) of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]#[C:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(CC#C)C=CC=CC=1.C=O.CNC.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH3:13][N:2]([CH3:1])[CH:3]=[CH:4][C:5](=[O:33])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)CC#CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C#CCc1ccccc1
Agent: C=O
Agent: CNC
Solvent: ClCCl
Product: CN(C)C=CC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cold solution of 1-dimethylamino-4-phenyl-2-butyne (0.5 g; prepared by the Mannich reaction of 3-phenyl-1-propyne with formaldehyde and dimethylamine as per Mornet, et.al. Bull.Soc.Chim.Fr. 1974, 206) in dichloromethane (12 ml) was added in small portions 3-chloroperoxybenzoic acid (0.52 g). After the reaction was stirred at 0° C. for 20 minutes, the mixture was passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 10% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The residue was treated successively three times with small portions of methanol (ca. 10 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 25 mL by addition of methanol. The methanolic solution of the N-oxide was heated to reflux for approximately 4 hours and cooled. The solvent was evaporated to dryness in vacuo and the residue was chromatographed over silica gel (95:5 ethyl acetate-hexanes was used as the eluant) to give upon evaporation of the solvent in vacuo the desired product as an oil. MS(+ES) m/z: 190 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12](=[O:15])[O:13][CH3:14])[CH3:10])=[CH:4][CH:3]=1.C=O.S(=O)(=O)(O)O.[C:23](O)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([CH3:10])[N:11]([C:12]([O:13][CH3:14])=[O:15])[CH2:23]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COC(=O)NC(C)Cc1ccc(Br)cc1
Agent: C=O
Agent: O=S(=O)(O)O
Product: COC(=O)N1Cc2cc(Br)ccc2CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a mixture of methyl [2-(4-bromophenyl)-1-methylethyl]carbamate (465 mg, 1.71 mmol) and paraformaldehyde (82.1 mg, 2.73 mmol) was added a mixture of concentrated sulfuric acid (2.5 mL, 47 mmol) and glacial acetic acid (3.75 mL, 66.0 mmol). The resulting mixture was stirred at r.t. overnight. The reaction mixture was poured into ice-water, and extracted with CH2Cl2. The organic layer was washed with water, saturated NaCO3 aqueous solution and brine, dried with MgSO4. After filtration, the filtrate was concentrated to afford the desired compound (490 mg, 100%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=284.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]1
Reactant: COc1ccccc1N=C(Cl)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1-n1nnnc1C(F)(F)F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Four grams (16.8 mmol) of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 9, 1.98 g (30.2 mmol) of sodium azide, 1.16 g (8.42 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.01 g of 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.6%).
Reaction SMILES: [CH3:1]OC1C=C(O)C(Cl)=CC=1C(OC)=O.[C:15]1([CH3:22])[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N1CCCC1CN)C>CO>[C:15]1([CH3:1])([CH3:22])[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][CH:16]12
Reactant: COC(=O)c1cc(Cl)c(O)cc1OC
Reactant: Cc1ccccc1C
Agent: CCN1CCCC1CN
Solvent: CO
Product: CC1(C)C=CC=C2CC21

Procedure:
In a 500 ml flask with a 40 cm Vigreux column, there are put 32 g (0.15 mole) of methyl 2-methoxy-4-hydroxy-5-chlorobenzoate, 120 ml of xylene and 23 g of levo 1-ethyl-2-aminomethylpyrrolidine. It is heated gently. A solution is obtained. The methyl alcohol formed in the form of a methanol-xylene azeotrope is distilled at 60°-62° C in about an hour. At the end of the reaction, 10 ml of xylene is distilled at 135° C. In the distillate, 5 ml of alcohol are recuperated for 6 ml theoretical.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[OH:42][CH2:41][CH:40]([NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1)[CH2:43][OH:44]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 66.3 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 40 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 604 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2(O)[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].CCN(S(F)(F)[F:35])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2([F:35])[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(O)CCC4)C3=C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cn(C2=NCC(=O)N3CCc4c(cccc4C4(F)CCC4)C3=C2)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34.7 %

Procedure:
Example 113. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (120 mg, 0.32 mmol) in DCM was cooled to 0° C. under N2 and treated with DAST (0.42 mL, 3.19 mmol) dropwise. The mixture was stirred for 20 min at 0° C., and the allowed to warm to RT. The reaction mixture was then slowly poured onto a cooled saturated aq. solution of NaHCO3 and extracted with DCM. The combined org layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (42 mg) as a beige solid. UPLC-MS: MS 379.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.19 (m, 3 H); 1.46-1.64 (m, 1 H); 1.88-2.09 (m, 1 H); 2.47 (m, 2 H); 2.51-2.79 (m, 4 H); 2.95 (t, J=5.28 Hz, 2 H); 3.73 (t, J=6.06 Hz, 2 H); 4.22 (br. s., 2 H); 7.07 (s, 1 H); 7.33-7.48 (m, 2 H); 7.58-7.67 (m, 1 H); 7.95 (d, J=8.21 Hz, 1 H); 8.13 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl.C(O)C.N>[N:12]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Clc1ncc2ccccc2n1
Reactant: C1CNCCNC1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: c1ccc2nc(N3CCCNCC3)ncc2c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A reaction mixture of 2 g (12.1 mmol) of 2-chloroquinazoline and 3.65 g (36.45 mmol) of [1.4]diazepan is stirred for one hour at 140° C. The cooled reaction mixture is dissolved in dichloromethane/ethanol/ammonia. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=35:1:0.1).