Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[OH-].[K+].O>C(O)CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1C(F)(F)F)NC=O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(C)(N)Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
5.70 g (20 mmol) N-[2-(4-chloro-2-trifluoromethyl-phenyl)-1,1-dimethyl-ethyl]-formamide and 3.00 g potassium hydroxide are stirred overnight at 140° C. in 20 mL ethyleneglycol. The reaction mixture is combined with water and repeatedly extracted with dichloromethane. The combined organic phases are washed with water, dried with sodium sulphate and evaporated down. The residue is filtered through a short column containing silica gel (eluant: dichloromethane/methanol/ammonia=9:1:0.1).
Reaction SMILES: C(C1C=CN=C(C=O)C=1)#N.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:16]=[CH:15][N:14]=1>>[N:20]1([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([CH:12]=[O:11])[CH:18]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: OCc1cc(CN2CCOCC2)ccn1
Agent: N#Cc1ccnc(C=O)c1
Product: O=Cc1cc(CN2CCOCC2)ccn1
Yield: 45.4 %

Procedure:
In a manner similar to that reported for the preparation of 4-cyano-2-pyridine-carboxaldehyde, 2-hydroxymethyl-4-(4-morpholinyl)methylpyridine (2.29 g, 11.01 mmol) gave 1.03 g (45%) of 4-(4-morpholinyl)methyl-2-pyridine carboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:17]([O:18][CH2:19][CH3:20])=[O:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(F)c(F)c1

Procedure:
A mixture of ethyl (3,4-difluorophenyl)acetate (11.3 g) in THF (50 mL) was added to a mixture of sodium hydride (60%, 4.74 g), diethyl carbonate (34.2 mL) and THF (250 mL) at room temperature, and the mixture was heated under reflux for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccncc3)ccc2OCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccncc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
To a solution of 7-(4-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (0.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(4-pyridyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 147) (0.07 g) as pale brown crystals.
Reaction SMILES: [BrH:1].C(O)(=O)C.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1>C(OCC)C>[BrH:1].[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 70 ml of a 25% hydrogen bromide-acetic acid solution was suspended 8.02 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane, and 2.96 g of dimethylsulfoxide sulfoxide was added thereto under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Then, 140 ml of diethyl ether was added to the reaction mixture, and crystals precipitated were collected by filtration and recrystallized from methanol to obtain 8.55 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane hydrobromide
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:27]([F:30])([F:29])[F:28])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:27]([F:28])([F:30])[F:29])=[N+:22]([O-:26])[CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2ncnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A portion of 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide (1.269 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours and then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Recrystallisation from a dichloromethane-ethanol mixture gave 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide as a yellow solid, 1.07 g (90%).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH:5]1[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][CH3:16])=[O:14].[Na].[OH2:20]>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(Cl)Cl.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:20])=[O:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O
Reactant: COC(=O)N1CCC(CO)CC1CCC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)N1CCC(C(=O)O)CC1CCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
Methyl 2-(3,3-dimethylbutyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.44 g, 9.49 mmol) was dissolved in CCl4 (20 mL) and acetonitrile (20 mL). Sodium periodiate (6.09 g, 28.5 mmol) was added followed by water (30 mL) and ruthenium (III) chloride (43 mg, 0.21 mmol). The resulting suspension was stirred at room temperature for 3 h 50 min. The reaction mixture was diluted with DCM (100 mL) and water (100 mL). The aqueous layer was extracted with DCM (×3) and the combined organic phase passed through a phase separator and evaporated to yield crude 2-(3,3-dimethylbutyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.42 g, 94%) as a black solid. MS m/z 272 (M+H)+
Reaction SMILES: C(O[C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9])C=C.O.C(OCC)(=O)C.CN1C[CH2:28][CH2:27][C:26]1=O>>[CH2:28]([C:14]1[C:5]2[O:10][C:8]([CH3:9])=[N:7][C:6]=2[CH:11]=[CH:12][C:13]=1[O:15][CH3:16])[CH:27]=[CH2:26]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1cc(OC)ccc1NC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(OC)ccc2nc(C)oc12
Temperature: 190 °C

Procedure:
1.04 g of 2′-allyloxy-4′-methoxyacetanilide was dissolved in 20 ml of 1-methyl-2-pyrrolidone. The reaction solution was then stirred while heating at 190° C. under nitrogen atmosphere. Eight hours later, the reaction solution was stood to cool. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain a product (1.01 g). The obtained product was dissolved in 20 ml of acetic acid without purification, and the obtained solution was stirred while heating at 135° C. After completion of the reaction, the reaction solution was stood to cool. Thereafter, the solvent was concentrated under a reduced pressure. 5 N NaOH and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 371 mg of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1>[NH2:13][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:12])[C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)c(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)c(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of methyl 4-amino-5-chloro-3-nitrobenzoate (429 g, 18.6 mmol) in ethanol (115 mL), water (250 mL) and tetrahydrofuran (200 mL) was added sodium hydrosulfite (80 g, 391 mmol). The reaction was stirred at ambient temperature for two hours. To the reaction was added water (55 mL). After stirring for an additional hour saturated aqueous sodium bicarbonate (140 mL) was added to the reaction. The reaction mixture was filtered and the filtrate was extracted twice with ethyl acetate (200 mL each). The organic extracts were combined and washed with saturated aqueous sodium bicarbonate (100 mL) followed by saturated aqueous sodium chloride (100 mL). The organic layer was concentrated in vacuo to a final volume of 100 mL and then allowed to sit at ambient temperature overnight to give a precipitate. The mixture was filtered and dried under a stream of nitrogen to give methyl 3,4-diamino-5-chlorobenzoate (973 mg, 26%). The filtrate was concentrated in vacuo to give methyl 3,4-diamino-5-chlorobenzoate (2.45 g, 66%), 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d, J=1.95 Hz, 1H) 7.08 (d, J=1.95 Hz, 1H) 5.44 (s, 2H) 5.08 (s, 2H) 3.70 (s, 3H),
Reaction SMILES: C([O:8][N:9]1[C:13]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[C:24]([F:27])([F:26])[F:25])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]3=[O:34])=[CH:12][CH:11]=[N:10]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:13]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[C:24]([F:27])([F:25])[F:26])[NH:20][C:19](=[O:28])[N:18]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:17]3=[O:34])=[CH:12][CH:11]=[N:10]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3ccnn3OCc3ccccc3)cc2c1=O
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3ccnn3O)cc2c1=O
Yield: 80.6 %

Procedure:
N-[6-(2-Benzyloxy-2H-pyrazol-3-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (100 mg, 0.202 mmol) was hydrogenated over 10% Pd/C in MeOH (5 mL) for 16 h at r.t. The catalyst was removed by filtration over Celite. The solution was concentrated in vacuo and the resulting resin was dissolved in DCM (1 mL). Hexanes (4 mL) was added and the precipitate was filtered off, washed with hexanes and dried to afford the title compound as a grey powder (66 mg, 81% yield). ES-MS: m/z 447.3 [M+CH3CN+H]+, rt 4.90 min. 1H-NMR (DMSO-d6, 400 MHz) 8.00 (s, H), 7.63 (s, 1H), 7.26 (d, J=2.34 Hz, 1H), 6.30 (d, J=1.89 Hz, 1H), 3.17 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.CC1N=C(N2CCN(C3C=CC(N)=CC=3)CC2)C=CC=1>>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(Cl)nc1
Agent: Cc1cccc(N2CCN(c3ccc(N)cc3)CC2)n1
Product: Cc1ccc(N2CCN(c3ccc(N)cc3)CC2)nc1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloro-5-methylpyridine, in the same manner as the preparation of 4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2CO)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCCC1>O>[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:20][Cl:24])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 60 h
Yield: 84.8 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol), carbon tetrachloride (7.0 mL, 73 mmol), (2-benzenesulfonyl-phenyl)-methanol (1.90 g, 7.65 mmol) and tetrahydrofuran (40 mL) were combined and heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, then stirred at room temperature for 60 hours. The reaction mixture was diluted with water, then extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (0%-15% ethyl acetate in hexanes) afforded 1.73 g (85%) of 2-(benzenesulfonyl)benzyl chloride as an off-white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (d, J=7.8 Hz, 1 H), 7.93 (d, J=7.2 Hz, 2 H), 7.56-7.82 (m, 6 H), 5.07 (s, 2 H). HRMS (EI+) cald. for C13H11ClO2S [M+] 266.0168, obsd. 266.0168.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.CO.O.O[Li].O>C1COCC1>[C:12]1([NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:7]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(Nc2ccccc2)nc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of 6-chloronicotinic acid ethyl ester (0.2 g, 0.00108 mole) and aniline (0.119 g, 0.00129 mole) in ethoxyethanol (10 mL) was heated to reflux for overnight. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) to afford 0.23 g (88%) of 6-phenylamino-nicotinic acid ethyl ester. To a stirred solution 6-phenylamino-nicotinic acid ethyl ester (0.23 g, 0.00095 mol) in a mixture of THF (4 mL), methanol (4 mL) and H2O (2 mL) was added LiOH.H2O (0.159 g, 0.0038 mol) at ambient temperature and the resulting mixture was stirred overnight. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous citric acid solution. The resulting precipitate was isolated by filtration and dried to afford 0.174 g (85%) of 6-Phenylamino-nicotinic acid.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)[CH3:21].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:20]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([CH2:3][C:4]2[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[C:24]([OH:36])[N:23]=1)[CH3:21]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 (323 mg, 1.07 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 94:6) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided, after evaporation, 60 mg of 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.04 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 43 as a yellow solid (69 mg, 12% yield).
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([O:16][CH3:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CSC(C)=O)C1
Agent: N
Product: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)CS)C1

Procedure:
Hydrolysis of (cis)-1-(2-acetylthio-1-oxoethyl)-4-methoxy-L-proline with an aqueous ammonia solution yields 1-(2-mercapto-1-oxoethyl)-cis-4-methoxy-L-proline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12](OC)=[O:13])[CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][SH:11])[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CS
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl N-(tert-butoxycarbonyl)-L-cysteinate (2.6 g, 11.0 mmol) in THF (10 ml) stirred at 0° C. under N2 was treated with slow addition of a 1M solution of LiAlH4 in THF (20 mL, 20 mmol). The reaction mixture was slowly warmed up to room temperature and further stirred for 2 h, cooled to 0° C. and quenched with slow addition of water, then poured on a 15% solution of K2CO3 in water (25 mL), shaken well and extracted with DCM (3×100 mL), the organic layers were combined and dried over MgSO4, filtered and concentrated to afford the title compound as colorless oil, kept under N2 atmosphere all the times and used fresh without further purification. Assumed quantitative yield. MS: m/z=230.1 (MNa+).
Reaction SMILES: [O:1]=[C:2]([N:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8][C@@H:9]1[CH2:14][O:13][CH2:12][CH2:11][N:10]1CC1C=CC=CC=1)[C:3](OC)=[O:4]>CO.[Pd]>[C:23]1([CH2:22][N:7]2[C:2](=[O:1])[C:3](=[O:4])[N:10]3[C@@H:9]([CH2:14][O:13][CH2:12][CH2:11]3)[CH2:8]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(=O)N(Cc1ccccc1)C[C@@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(=O)N2CCOC[C@H]2CN1Cc1ccccc1
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To a solution of crude methyl oxo((phenylmethyl){[(3R)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate (assumed 4.3583 g, 11.40 mmol) in MeOH (114 mL) was added 10% Pd/C (50% water, 870 mg). The mixture was hydrogenated under balloon pressure for 16 h, and then filtered through a 0.2 μm membrane. The solution was concentrated in vacuo, and the residue was triturated with 20% EtOAc-hexanes. The resulting solid was collected by vacuum filtration and washed with hexanes to provide (9aR)-8-(phenylmethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,7-dione (2.5610 g, 86% for 2 steps) as a light yellow solid. LCMS: (M+H)+: 261.1.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=O)[CH2:11]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>O1CCCC1>[CH3:17][N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[CH:16][CH:15]=2)[CH2:11][C:12]1=[S:20]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc2c(c1)CC(=O)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(=S)N2C
Temperature: 50 °C

Procedure:
18.5 g (0.22 mol) of sodium bicarbonate are added to a solution of 19.5 g (0.11 mol) of 5-methoxy-1-methyl-2-indolinone prepared according to A. H. BECKETT, R. W. DAISLEY and J. WALKER (Tetrahedron 1968, 24 6093) and 16.5 g (0.037 mol) of phosphorus pentasulfide in 200 ml of tetrahydrofuran. The reaction medium is heated to a temperature of 50° C. for 1 h 30 min and then filtered and concentrated on a water bath under vacuum. The residue is taken up with ice-cold water and the mixture is extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue is used in the next stage without further treatment.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(2-methoxy-ethoxy)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example A26) (7.90 g, 20.8 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (7.00 g, 96%).