Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH3:31][Zn]C>C1(C)C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH3:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:15][C@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc2c1C(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans tert-butyl 6-methyl-5-oxo-8-(trifluoromethylsulfonyloxy)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 91, Part A (225 mg, 0.5 mmol) was added dimethylzinc (0.75 mL of a 2.0 M solution in toluene, 1.5 mmol). The reaction mixture was degassed with a stream of argon and then there was added bis(diphenylphosphino)ferrocene]-dichloropalladium (II) (18 mg, 0.025 mmol). The reaction mixture was allowed to stir at 65° C. for 18 h. The reaction was allowed to cool to ambient temperature and was quenched with 1N HCl. The mixture was diluted with ethyl acetate and the organics were washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.18 g of the title compound as an off-white solid, which was sufficiently pure to be employed directly in Part B. LRMS (ESI): 317.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.B(Br)(Br)[Br:23]>ClCCl.C(=O)=O.CC(C)=O>[Br:23][CH2:20][C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([OH:2])[CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Benzyl Alcohol 3 (0.500 g, 1.759 mmole) was dissolved in dichloromethane (50 mL) and cooled to −78° C. in dry ice/acetone bath. To this solution, boron tribromide (1.0 M in dichloromethane), (7.04 mL, 7.05 mmole) was added drop wise over 15 minutes. After 30 minutes, the dark orange solution was allowed to come to room temperature and reacted for an additional 4 hours. The solution was concentrated and added to saturated sodium bicarbonate and extracted with ethyl acetate. Organic layers were combined and washed with water, brine, and dried over magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 7:3) to afford 0.495 g (88%) of benzyl bromide 4 as a white solid: Mp=337-339° C.; 1H NMR (DMSO-d6) δ 7.90 (s, 2 H),), 7.74 (d, 2 H, J=8.8 Hz), 7.06 (s, 1 H), 6.89 (d, 2 H, J=8.7 Hz), 6.86 (d, 1 H, J=2.5 Hz), 6.77 (d, 1 H, J=2.2 Hz); MS 317/319 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=2[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:10]1[C:9]([CH3:17])=[C:8]2[C:13](=[C:12]([F:14])[C:11]=1[F:15])[N:4]([CH:3]=[CH2:2])[CH:5]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:7]2=[O:18]
Reactant: CCOC(=O)c1cn(CCBr)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cn1cc(C(=O)OCC)c(=O)c2c(C)c(F)c(F)c(F)c21
Temperature: 80 °C
Yield: 96.1 %

Procedure:
A rapidly stirred suspension of 1.98 g (5.08 mmol) of ethyl 1-(2-bromoethyl)-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 3.50 g (25.3 mmol) of ground potassium carbonate, and 40 mL of DMF was heated at 80° C. under argon for 4 hours. The suspension was concentrated and the residue was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and concentrated to give 1.52 g of the title compound as a DMF complex, mp 150°-152° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CO.[Pd]>[CH3:11][O:10][CH2:9][CH2:8][O:7][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=1)(=[O:12])[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCCOC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCOP(=O)(Cc1ccc(N)c(OC)c1)OCCOC
Yield: 96.8 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitro-3-methoxybenzyl)phosphonate (Compound 217D, 4.5 g, 12.4 mmol) and 5% Pd/C (2 g, wet) in MeOH (100 mL) was hydrogenated under 50 psi hydrogen pressure at 50° C. for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (4 g, 97%). 1H NMR (DMSO-d6, 400 MHz): δ=3.11 (d, J=21.2 Hz, 2H), 3.34 (s, 6H), 3.49 (m, 4H), 3.81 (s, 3H), 4.05 (m, 4H), 6.12 (d, J=8.4 Hz, 2H), 6.20 (dd, J=8.4 Hz, 1H), 6.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (5.0 g) in CH2Cl2 (100 mL) at 0° C. was treated sequentially with N-methyl-N-(phenylmethyl)amine (3.0 mL), triethylamine (3.36 mL) and N,N-dimethylaminopyridine (0.26)). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (100 mL) and water (2×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (6.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=2)[CH:3]=1)=[O:16]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Product: Cc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3c2)cn1

Procedure:
The title compound was prepared in the same manner as described for example 76 from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (183 mg, 0.835 mmol). The title compound was collected as 75 mg (24%); 1H NMR (DMSO-d6, 400 MHz): 1.45 (d, J=6.4 Hz, 3H), 2.11 (s, 3H), 2.24 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 4.36-4.38 (m, 2H), 5.03-5.09 (m, 1H), 5.87 (s, 1H), 7.36 (s, 1H), 7.38 (s, 1H), 8.01 (s, 1H), 8.11 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.89 (s, 1H), 11.48 (s, 1H); LCMS (ES+) m/z: 444.21.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:13]2[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:34]=1)[CH:8]=C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:41]1([CH2:40][O:39][C:35]2[CH:34]=[C:33]([C:13]3[C:12]4[C:16](=[CH:8][CH:7]=[C:10]([CH2:18][CH:17]=[O:2])[CH:11]=4)[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:14]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH2:43][CH2:42]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1ccc2c(c1)c(-c1cccc(OCC3CC3)c1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
Sodium periodate (430 mg, 2.0 mmol) and osmium tetroxide (2.5 wt % solution in tert-butanol, 0.50 mL, 0.05 mmol) were added to a stirred solution of ethyl 5-allyl-3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 132, 385 mg, 0.777 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The reaction was stirred for 18 h and then diluted with water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and then the combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 15% ethyl acetate/hexane gave 183 mg (47%) of product containing impurities. The material was used in the next reaction without further purification. Mass spectroscopy gave MH+=498.1 (exact mass calc'd for C31H31NO5=497.22).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH2:28][OH:29])=[CH:23][CH:24]=3)[CH2:19]2)(=[O:17])=[O:16])=[C:10]([CH3:30])[CH:9]=1>C(Cl)Cl>[CH3:1][S:2]([O:29][CH2:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][N:18]([S:15]([C:11]3[C:12]([CH3:14])=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=3[CH3:30])(=[O:16])=[O:17])[CH2:19]2)=[CH:24][CH:23]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CO)cc3C2)c(C)c1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(COS(C)(=O)=O)cc3C2)c(C)c1
Reaction time: 1 h

Procedure:
MsCl (3.32 mmol, 1.5 equiv.) was added at 0° C. to a solution of (2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methanol (2.22 mmol, 1 equiv.) and TEA (2.5 equiv.) in DCM (16 ml), and the mixture was stirred for 1 h. The reaction mixture was diluted with DCM, extracted with sat. sodium hydrogen carbonate solution, water and sat. NaCl solution and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[S:10][C:11]([CH2:20][CH2:21][CH3:22])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:8]>O>[C:14]1([C:12]2[CH:13]=[C:9]([C:7](=[O:8])[CH3:1])[S:10][C:11]=2[CH2:20][CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[Mg]Br
Reactant: CCCc1sc(C(=O)N(C)OC)cc1-c1ccccc1
Solvent: O
Product: CCCc1sc(C(C)=O)cc1-c1ccccc1
Reaction time: 2 h

Procedure:
At 2° C. methylmagnesium bromide (1 mL, 1.7 M in THF) is added to a solution of 4-phenyl-5-propyl-thiophene-2-carboxylic acid methoxy-methyl-amide (900 mg, 3.11 mmol). The mixture stirred for 1 h before another portion (0.2 mL) of the Grignard reagent is added. Stirring is continued for 2 h. The mixture is diluted with water, extracted with EA and the organic extracts are dried over MgSO4 and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 5:4 to give 1-(4-phenyl-5-propyl-thiophen-2-yl)-ethanone (456 mg) as a yellow oil; LC-MS: tR=1.06 min, [M+1]+=245.14, 1H NMR (CDCl3): δ 7.59 (s, 1H), 7.47-7.32 (m, 5H), 2.87-2.81 (m, 2H), 2.54 (s, 3H), 1.76-1.63 (m, 2H), 0.95 (t, J=/.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[O-:14][CH2:15]C.[Na+]>O1CCCC1>[CH3:15][O:14][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC[O-]
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=CC(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
A solution of 2-chloro-1,4-naphthoquinone (10.3 g) in tetrahydrofuran (100 mL) was treated with a suspension of sodium ethoxide (3.20 g) in tetrahydrofuran (25 mL) at room temperature. After stirring overnight, the mixture was evaporated, and the residue was taken up in ether. The organic layer was washed with brine, dried, filtered and evaporated. Chromatography over silica gel gave 2-methoxy-1,4-naphthoquinone, m.p. 182°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][C@@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:28]=1)[C:6]([OH:8])=O.C(N(C(C)C)C(C)C)C.[NH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[N:25]([CH3:26])[C:24](=[O:27])[CH2:23][C@@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:28]=1)[C:6]([NH:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:8]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N1CCC[C@@H]1CC(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-benzoic acid (I-102a), 0.32 mL (0.0018 mole) of ethyldiisopropylamine and 0.082 g (0.00072 mole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.31 g (0.00072 mole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 3 hours, then diluted with saturated sodium carbonate. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (100:0-60:40) gave 0.060 g of 3-methoxy-4-((R)-6-methyl-5-oxo-2,3,3a,4,5,6-hexahydro-1H-6,8,10,10b-tetraaza-benzo[e]azulen-9-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-102).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14]([CH2:21][CH2:22][NH:23]C(=O)[O-])=[CH:13]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14]([CH2:21][CH2:22][NH2:23])=[CH:13]1)(=[O:11])=[O:10]
Reactant: O=C([O-])NCCc1cn(S(=O)(=O)c2ccc(F)cc2F)c2ccncc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1cn(S(=O)(=O)c2ccc(F)cc2F)c2ccncc12
Reaction time: 2 h

Procedure:
A solution of {2-{1-[(2,4-difluorophenyl)sulfonyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}ethyl}carbamate in CH2Cl2 is treated with trifluoroacetic acid, stirred for 2 h and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to afford the title product.
Reaction SMILES: CO.C1C[O:6][CH2:5]C1.[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]>CN(C=O)C>[CH3:5][O:6][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:14]=[C:13]([NH:23][S:24](=[O:36])(=[O:35])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:12]=1[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OC
Temperature: 80 °C

Procedure:
To a mixture of methanol (1 ml) and THF (2 ml) was added sodium hydride (100 mg, 60% dispersion in mineral oil) followed by the addition of 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg, Referential Example 1e)). DMF (0.5 ml) was added and the reaction mixture was heated to 80° C. for 20 h. The solvents were evaporated, water (14 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water to give 4-i-propyl-phenyl sulfamic acid-[6-methoxy-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (100 mg). tR=5.08 min, (LC); [M+H]+=522.45 (ES+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:26]([N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:27].CN1C(=O)CCC1>CO>[CH:23]1([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:4]2[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:36][CH3:37])[CH2:26][CH3:27])=[CH:34][CH:33]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Yield: 12.2 %

Procedure:
A microwave tube was charged with 1G (30 mg, 0.085 mmol), N1,N1-diethylbenzene-1,4-diamine (139 mg, 0.85 mmol), and NMP (1 mL). The mixture was irradiated in a microwave for three cycles of 15 min. (300W), 120° C. The crude reaction mixture was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 30 min. gradient, monitored at 220 nm) to afford 244A, (5 mg, 9.0% yield). HPLC: Rt=3.896 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=482.1 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CC1

Procedure:
The title compound, white solid (86 mg, 86%), MS (ISP) m/z=399.3 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclopropanecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:10]3[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]3[O:12]C(=O)C)[C:7]([Cl:9])=[N:8][C:4]=2[CH:3]=1>N.CO>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:10]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]3[OH:12])[C:7]([Cl:9])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(N)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A solution of 0.363 g (0.852 mmole) of 76 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature <40° C.), The residue was recrystallized from MeOH/Et2O to give 0.203 g (2 crops, 79%) of 78 as beige crystals. MP ~154° C. (dec.), MS (El) m/e 299.0675 (10%, M+ =299.0673), 1H NMR (DMSO-d6): d 7.56 (d, 1, 7-H, J7-6 =8.5 Hz), 6.73 (d, 1, 4-H, J4-6 =2.0 Hz), 6.57 (dd, 1, 6-H), 5.77 (d, 1, 1'-H, J1'-2' =7 5 Hz), 5.39 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.18 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 5.11 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 4.90 (s, 2, 5-NH2), 4.44 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.09 (m, 1, 3'-H, J3'-4' =2.5 Hz), 3.91 (m, 1, 4'-H, J4'-5' =3.5 Hz), 3.65 ("t", 2, 5'-H), 13C NMR (DMSO-d6): d 144.82 (C5), 142.77 (C3a), 138.25 (C2), 125.13 (C7a), 112.67 (C7), 112.22 (C6), 101.83 (C4), 88.81 (C1'), 85.48 (C4'), 70.89 (C2'), 69.61 (C3'), 61.31 (C5').
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:17]([O:19]C)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)([C:17]([OH:19])=[O:18])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(CC2CC2)CCN(C(=O)OC(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)O)C1
Yield: 104 %

Procedure:
The title compound was prepared according to general procedure B described in connection with Scheme 2. 1-t-Butyl 3-methyl 3-(cyclopropylmethyl)pyrrolidine-1,3-dicarboxylate (1.00 g, 3.5 mmol.) was dissolved in 2 mL MeOH and a solution KOH (0.59 g, 10.6 mmol.) in 2 mL H2O was added. The reaction mixture was microwaved at 130° C. for 30 min. The methanol was evaporated and 10 mL of 10% KHSO4 solution was added to the residue. The acid was extracted with EtOAc (2×20 mL). The combined organic fractions were dried over Na2SO4; evaporation of solvent gave 0.98 g of the desired product as orange oil which crystallized on standing (quantitative yield). 1H NMR (400 MHz, CDCl3): δ 3.81-3.93 (m, 1H), 3.36-3.44 (m, 2H), 2.28 (d, 1H), 2.33-2.46 (m, 1H), 1.83-1.91 (m, 1H), 1.60-1.70 (m, 2H), 1.45 (s, 9H), 0.62-0.75 (m, 1H), 0.42-0.50 (m, 2H), 0.05-0.12 (m, 2H); MS (ESI) m/z: Calculated for C14H23NO4: 269.2. found: 292 (M+Na)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]3[C:20]4[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH2:4][CH2:3]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a suspension of the bis HCl salt of 2-tert-butyl-1H-benzoimidazole-4-carboxylic acid (piperidin-4-ylmethyl)amide (4.28 g, 11.06 mmol) in dichloromethane (55 mL) at room temperature was added N,N-diisopropylethylamine (1.71 g, 2.31 mL), 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (2.58 g, 12.17 mmol) and sodium triacetoxyborohydride (3.28 g, 15.48 mmol) sequentially. The resulting mixture was stirred at room temperature for 2 h then extracted with 1M aqueous hydrochloric acid. The combined aqueous layers were basified to pH 12 with sodium hydroxide pellets, then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was dried under high vacuum to give a light brownish foam (4.9 g, 9.6 mmol, 87%) which was used without further purification. (m/z): [M+H]+ calcd for C29H45N5O3 512.35, found: 512.4.