Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.C([BH3-])#N.[Na+].[F:15][C:16]1[C:17]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:18]([CH:26]=[C:27]([CH:30]=O)[C:28]=1[F:29])[C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20]>O1CCCC1>[F:15][C:16]1[C:17]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=2[F:40])=[C:18]([CH:26]=[C:27]([CH2:30][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[C:28]=1[F:29])[C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: COC(=O)CCCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NOCCO)c1cc(CN2CCCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
Methyl 5-amino-pentanoate hydrochloride {see J. Org. Chem. (1968) 1581} (128 mg, 0.178 mmol) and sodium cyanoborohydride (45 mg, 0.718 mmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (115 mg, 0.239 mmol) obtained in Step F of Example 1 in tetrahydrofuran (anhydrous, 4.0 mL). The mixture was stirred at room temperature for 1.5 hours. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was heated at 60° C. for 2 days. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 4% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-piperidin-1-ylmethyl)-benzamide (Compound H-4, 42.7 mg, 37%) as a white solid.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCC[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A 4M hydrochloric acid-dioxane solution (15 ml) was added to tert-butyl 3-(R)-benzyloxycarbonyloctanoate (983 mg), prepared in Referential Example 6, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 30:1 mixture of chloroform and methanol as an eluent, to give 838 mg of the desired compound as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33].[OH-].[Na+]>O1CCOCC1>[Cl:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:33])[C:26]=1[NH:25][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=2)=[CH:10][C:5]=1[CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)Cc1cc(Cc2cccc(Oc3ccccc3)c2)ccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(Cc2cccc(Oc3ccccc3)c2)ccc1Nc1c(Cl)cccc1Cl
Yield: 43.3 %

Procedure:
A solution of the ester (2.2 g, 4.3 mmol) of Step A in dioxane (20 mL) containing 1N NaOH (7 mL) is heated at reflux under nitrogen for 4 hrs. The solvent is removed and the residue is partitioned between dilute HCl and ether (30 mL each). The organic phase is washed with brine, dried (Na2SO4) and filtered. The filtrate is treated with tris(hydroxymethyl)aminomethane (0.485 g) in methanol (20 mL). The solvent is evaporated to a syrup in vacuo and diluted with ethyl acetate. The crystalline solid is collected (white solid, 1.6 g, 60%) and recrystallized from methanol-water to provide the pure title compound (0.89 g, m.p. 137°-138° C.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:26]=[C:27]([CH2:34][OH:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(#N)C>[OH:35][CH2:34][C:27]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH2:7][CH2:8]2)[CH:26]=1
Reactant: CC(C)C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C(=O)N[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a suspension of N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride (200 mg, 0.906 mmol) and DIPEA (0.432 mL, 2.471 mmol) in ACN (2 mL) was added (3-fluoro-4-nitrophenyl)methanol (141 mg, 0.824 mmol). The reaction was stirred overnight at 80° C. After 16 hours, the reaction mixture was concentrated and the residue purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide N-(cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)isobutyramide as an orange foam (176 mg, 63.7% yield). MS, m/z (C17H25N3O4): calcd, 335.2. found, 336.0 [M+H].
Reaction SMILES: F[C:2]1([N+:12]([O-:14])=[O:13])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:4]=[CH:3][C:2]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])C1(F)C=C(C(F)(F)F)C=CC1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:13])[CH2:7][NH:8]C(C)(C)C)=[CH:4][C:3]=1[Cl:17].CO.Cl.[CH:21]([OH:24])(C)C>CCO>[ClH:13].[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([O:24][CH3:21])[CH2:7][NH2:8])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(C)O
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(CN)c1cc(Cl)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2 atmosphere, 11 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0° C. After 20 minutes, the cooling bath is removed and the reaction mixture is stirred at ambient temperature. After the reaction is completed, the mixture is evaporated to dryness in vacuo. The residue is stirred in 75 ml of H2O and the mixture is made alkaline with 6N NaOH solution and extracted with CH2Cl2 (3×50 ml). The organic phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtOH and acidified with HCl/isopropyl alcohol solution to pH 2. The solution is evaporated to dryness and the residue is stirred in 75 ml of ethyl acetate. After cooling, this affords a pale yellow solid which is collected to give 6.97 g of the title compound, m.p. 195°-198° C. dec.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:18].O>O1CCCC1>[CH3:18][NH:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Nc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 8-nitroquinolin-7-amine (1.89 g, 10 mmol) in tetrahydrofuran (THF) (10 mL) was added sodium hydride (60% wt in mineral oil, 800 mg, 20 mmol). The mixture was stirred at room temperature for 30 minutes, then iodomethane (1.42 g, 10 mmol) was added. The mixture was stirred at room temperature for 5 h. Then water (10 mL) was added. The mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give N-methyl-8-nitroquinolin-7-amine as a yellow solid (1.6 g, yield 79%). ESI MS: m/z 204 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:30][CH2:31][N:32]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:33][CH2:34]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCNCC6)c5)cc4c3C2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCN(S(C)(=O)=O)CC6)c5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
To a stirred solution of methyl-2-{8-[3-(piperazin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (800 mg, 1.65 mmol) in dry DCM (50 mL) was added 4-dimethylaminopyridine (1.012 g, 8.29 mmol), then methanesulfonyl chloride (0.155 mL, 1.99 mmol) was added at 0° C. and stirred for 10 min. The reaction mass was maintained at room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC and after completion the reaction mass was diluted with water and extracted with DCM. The DCM layer dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl-2-{8-[3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (900 mg, 95.40%) with HPLC purity 95.40%. 1HNMR (200 MHz, CD3OD) δ: 2.62 (t, 4H, 2×CH2), 2.85 (s, 3H, CH3) 3.0 (t, 2H, CH2), 3.22 (t, 4H, 2×CH2), 3.7 (s, 2H, CH2) 3.95 (s, 3H, OCH3), 4.4 (t, 2H, CH2), 5.18 (s, 2H, CH2), 7.2-7.8 (m, 7H, Ar—H), 8.9 (s, 2H, Pyrimidine-H); m/e=561 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[C:8](=[O:19])[O:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=2)C.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:33](O)=[O:34]>>[CH:33]([C:11]1[C:12]([OH:18])=[CH:13][CH:14]=[C:15]2[C:10]=1[O:9][C:8](=[O:19])[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:20])=[C:16]2[CH3:17])=[O:34]
Reactant: CCOC(=O)CCc1c(C)c2ccc(O)cc2oc1=O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1c(CCC(=O)O)c(=O)oc2c(C=O)c(O)ccc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
A mixture of 3-(7-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester (100 mg, 0.36 mmol) and hexamethylenetetramine (203 mg, 1.44 mmol) in trifluoroacetic acid (3.6 mL) was stirred in a closed vial under argon at 110° C. for 2 h. The reaction was poured onto crushed ice (15 mL), warmed to room temperature, and the solid precipitate was filtered off. This mixture of formylated ester and corresponding carboxylic acid was dissolved in dioxane-1N NaOH (1:1) and was stirred at room temperature. After 2 h, 15 mL of dichloromethane was added. The aqueous layer was separated and acidified by portionwise addition of 1N HCl. The precipitate was collected, washed with water, and dried to afford title compound (15 mg, 0.043 mmol, 13%) as a light brown powder.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][CH:33]1[C:38](=O)[CH2:37][CH2:36][O:35][CH2:34]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][CH:33]1[C@H:38]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:37][CH2:36][O:35][CH2:34]1
Reactant: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methyltetrahydro-4H-pyran-4-one (52.1 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (9.1 mg, 12%). MS calculated for C26H37F3N4O3; (M+H) 511.3; found 511.3.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.P(Cl)(Cl)([Cl:23])=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1
Reactant: CCCCc1ccc2nc(C(=O)OCC)cc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCc1ccc2nc(C(=O)OCC)cc(Cl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
126 parts of ethyl 4-hydroxy-6-n-butylquinoline-2-carboxylate, prepared as described in Example 2, and 213 parts of phosphorus oxychloride were stirred together. After the exothermic reaction had subsided the dark-coloured mixture was stored for 1 hour at room temperature then cooled to 0°C, diluted with 75 parts of ethanol to improve its mobility and subsequently added dropwise to 500 parts of ice and 1500 parts of water. The aqueous mixture was neutralised to pH 7 - 8 by addition of sodium carbonate when 133.2 parts of a light brown coloured crystalline solid separated out and were collected by filtration and dried. This material was purified by recrystillisation from about 380 parts of acetone (with carbon treatment) and yielded 100.8 gm. of ethyl 4-chloro-6-n-butylquinoline-2-carboxylate which was isolated as pale grey needles, m.pt. 58°- 58.5°C. An additional 27.5 parts of less pure product, m.pt. 54.5°-56°C, was obtained by dilution of the acetone mother-liquor with water.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([O:21]C(C)(C)C)=O)[CH:17]=[CH:18][C:12]=2[NH:11][C@H:10]([CH2:26][OH:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH2:39][NH:40][CH3:41].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]([N:40]([CH3:41])[CH2:39][C:31]3[N:30]([CH3:29])[C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:21])[CH:17]=[CH:18][C:12]=2[NH:11][C@H:10]([CH2:26][OH:27])[C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C(=O)[C@@H](CO)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(Cc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 82.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-4-benzyl-2-hydroxymethyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.39 g, 1.0 mmole), 1-methyl-2-(methylaminomethyl)indole (0.18 g, 1.1 mmole), Et3N (0.31 mL, 2.2 mmole), HOBt.H2O (0.15 g, 1.1 mmole), and EDC.HCl (0.21 g, 1.1 mmole), the title compound (0.40 g, 83%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 483.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[C:14]1[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=1
Reactant: COc1ccc(F)c(Br)c1
Reactant: O=Cc1cc(F)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(-c2cc(F)cc(C=O)c2)c1
Temperature: 90 °C
Yield: 28.6 %

Procedure:
To a RBF was added 2-bromo-1-fluoro-4-methoxybenzene (1.850 mL, 9.02 mmol, Oakwood), 3-fluoro-5-formylphenylboronic acid (1667 mg, 9.93 mmol, Combi-blocks), tetrakis(triphenylphosphine)palladium (521 mg, 0.451 mmol) and potassium carbonate (3741 mg, 27.1 mmol). A condenser and septum was attached and 1,4-dioxane (24.100 mL) and water (6.03 mL) were added. The mixture was heated at 90° C. for 2 h, at which time the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with brine (20 mL) and dried over MgSO4. The solution was filtered and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a 50 g silica column, eluting with a gradient of 0% to 30% EtOAc in Heptane, to provide 2′,5-difluoro-5′-methoxy-[1,1′-biphenyl]-3-carbaldehyde (640 mg, 2.58 mmol, 28.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.01-10.14 (m, 1H), 8.01 (q, J=1.56 Hz, 1H), 7.82 (tdd, J=1.41, 2.59, 9.76 Hz, 1H), 7.67-7.78 (m, 1H), 7.32 (dd, J=9.65, 10.42 Hz, 1H), 7.18 (dd, J=3.23, 6.46 Hz, 1H), 7.05 (td, J=3.57, 9.00 Hz, 1H) 3.83 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[CH:10][C:11]=1[CH3:12]>CCOCC>[Cl:3][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:6]([F:5])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cc1F
Solvent: CCOCC
Product: Cc1ccc(CCl)cc1F
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.892 g, 7.5 mmol) was added to a solution of the product of STEP 1 (1.0 g, 6.4 mmol) in 10 ml ether dropwise at 0° C. After 30 min, the reaction was quenched with crushed ice carefully, and diluted with H2O. The product was extracted with ether. The organic layer was washed with saturated NaHCO3 solution, brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to give a colorless liquid in 10.5 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:20])[CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[O:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[OH:20][CH:9]([CH2:10][N:11]1[CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19]1)[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC(O)CN1Cc2ccccc2C1)c1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 3-amino-N-(2-hydroxy-3-(isoindolin-2-yl)propyl)benzamide (120 mg, 0.39 mmol) in MeOH (10 mL) was added dihydro-2H-pyran-4(3H)-one (78 mg, 0.78 mmol) and AcOH (0.05 mL). The mixture was stirred at 25° C. for 2 h. NaBH3CN (123 mg, 1.95 mmol) was added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated, and the residue was dissolved in water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC purification. (22 mg, yield 14%) MS (ESI+) e/z: 396.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.62-7.53 (m, 2H), 7.53-7.36 (m, 5H), 7.30-7.21 (m, 1H), 4.76-4.57 (m, 2H), 4.34-4.24 (m, 1H), 4.08-3.96 (m, 2H), 3.74-3.65 (m, 1H), 3.65-3.57 (m, 2H), 3.57-3.43 (m, 4H), 3.36-3.32 (m, 2H), 2.03-1.91 (m, 2H), 1.72-1.57 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([CH2:11][S:12][C:13](=O)[CH3:14])=[CH:8][C:6]=2[N:7]=1.C[O-].[Na+].[CH3:25][O:26][CH2:27]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO>[CH3:25][O:26][CH2:27][CH2:14][CH2:13][S:12][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:3][C:2]([CH3:1])=[N:7][C:6]=2[CH:8]=1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)SCc1cc2nc(C)nc(N3CCOCC3)c2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCSCc1cc2nc(C)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of thioacetic acid S-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl) ester (200 mg) in methanol (10 mL) at 0° C. was added a solution of sodium methoxide (35 mg) in methanol (2 mL). The reaction mixture was stirred at 0° C. for 30 min and then a solution of toluene-4-sulfonic acid 3-methoxy-propyl ester (156 mg) in methanol (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 6-(3-methoxy-propylsulfanylmethyl)-2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a white solid (170 mg).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32]C(O)C[CH:15]3[C:14]=2[CH:13]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:15]3[C:14]=2[CH:13]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Yield: 82.7 %

Procedure:
Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200 mg, 0.52 mmol), Et3 N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol) in CH2Cl2 (5 mL) and stir the reaction at room temperature for 1 hour. Dilute the solution with EtOAc and wash with H2O, saturated aqueous sodium bicarbonate and brine. Dry (Na2SO4), filter and concentrate the solution in vacuo. Purify the product by flash chromatography (10 g SiO2, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40% EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol, 83%) as a yellow oil. HRMS(FAB+) calcd for C24H28O7: 428.1835; found: 428.1833 (M+).