Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]=[O:14].Cl>CS(C)=O.C[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][OH:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) and paraformaldehyde (6.27 g, 209 mmol) were dissolved/suspended in DMSO (400 mL) and treated with NaOMe (537 mg, 9.94 mmol). The mixture was allowed to stir at room temperature for 2 hours, at which time the reaction was complete as determined by TLC analysis of the crude. The reaction was poured into ice-cold water (700 mL; emulsion) and neutralized with the addition of 1M HCl solution. The aqueous layer was extracted with ethyl acetate (3×), and the organics were combined. The organic layer was washed with water (2×), brine (1×), separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as an oil. The residue was loaded onto a large fitted filtered with silica gel and eluted with 9:1 hexanes:ethyl acetate and then with 1:1 hexane:ethyl acetate to give Methyl 2-(4-chlorophenyl)-3-hydroxypropanoate as an oil (39.4 g, 92%).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:7]([N:6]1[C:2]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(Cl)cc1
Yield: 38 %

Procedure:
A mixed solution of 2-[2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl]-N-[(tetrahydro-2H-pyran-4-yl)methyl]acetamide (44.1 mg, 100 μmol), 4-chlorophenylboronic acid (15.6 mg, 100 μmol), potassium carbonate (27.6 mg, 200 μmol) and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.08 mg, 10.00 μmol) in 1,2-dimethoxyethane (0.5 mL) and water (0.5 mL) was stirred at 150° C. for 30 min under ultrasonic irradiation. To the reaction solution was added water (1 mL), the mixture was extracted with ethyl acetate (2 mL), and the organic layer was concentrated. The residue was purified by preparative HPLC to give the title compound (17.9 mg, 0.038 mmol, 38%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O-:19])=[O:18])=[C:15]([OH:20])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:10])=[O:18])=[C:15]([O:20][CH2:27][C:28](=[O:29])[NH2:30])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: NC(=O)CBr
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC(N)=O

Procedure:
6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 120) and 2-bromoacetamide.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[S:17]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)C#N>C1COCC1>[C:1]1([S:17][C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CSc1ccc[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: Brc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Sc2ccc[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of phenyl magnesium bromide (prepared from bromobenzene (0.75 ml) and magnesium chips (0.19 g, 7.8 mmol) in anhydrous THF (20 ml), cooled to 0° C., was slowly added a solution of 2-thiocyanopyrrole 11 (0.5 g, 4.0 mmol) in anhydrous THF (20 ml). After stirring at 0° C. for 30 min, the mixture was poured into crushed ice and extracted with ethyl acetate. The organic phase was washed with 20% NH4Cl, anhydrified and evaporated. The residue was purified by chromatography (35% hexane in chloroform) to give 0.6 g (93% yield) of 12 as colourless prisms: melting point 86-87° C. (hexane); IR (CHCl3) 3420 cm−1; 1H NMR (CDCl3) δ8.20 (br s, 1H), 7.25-6.85 (m, 5H), 6.92 (m, 1H), 6.55 (m, 1H), 6.31 (m, 1H). Anal. (C9H9NS): C, H, N.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:30][NH2:31]>O>[CH3:30][NH:31][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Temperature: 70 °C

Procedure:
A mixture of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (2.0 g, 6.1 mmol), THF (10 mL), and methylamine (available as a 40% solution in water, 4 mL, 52 mmol) was sealed in a high-pressure vessel and heated at 70° C. overnight. An analysis by TLC indicated the presence of starting material, and the reaction was sealed and heated at 80° C. for nine hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with 5% aqueous sodium hydroxide (2×25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 1.83 g of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:31])(=[O:30])[CH:22]([C:24]1C=CC=CC=1)[OH:23].[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:31])(=[O:30])[C@H:22]([CH3:24])[OH:23]
Reactant: O=C([O-])C(O)c1ccccc1
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](O)C(=O)[O-]
Temperature: 15 °C
Reaction time: 20 h

Procedure:
Sertraline mandelate (750 grams) was slurried in a mixture of water (3.9 L) and ethyl acetate (3.9 L). The slurry was cooled to 15° C. NaOH (25% aqueous, 250 mL) was added, resulting in a solution with pH 9.6. The free base of sertraline was partitioned into the ethyl acetate layer which was separated. The aqueous layer was extracted with an additional 3.4 liters of ethyl acetate. The combined ethyl acetate layers were washed with 3.9 liters of water. The ethyl acetate layer containing sertraline base was concentrated under vacuum and filtered to clarify the solution. To this solution was added L-lactic acid (155 g). The reaction mixture was granulated hr 20 hours at room temperature. The solids were filtered, washed 4 times with ethyl acetate(400 mL each time). The crystals were dried overnight under vacuum at 40° C. The yield was calculated to be 84%. mp 153° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
164 a) A suspension of o-Nitrobenzylbromide (5.71 g, 26.4 mmol) and sodium methanesulfinate (4.0 g, 40.0 mmol) in ethanol (70 mL) was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. To the residue was added water (50 mL) and stirred for 30 minutes. The suspension was filtered, rinsed with water and air dried. 1-Methanesulfonylmethyl-2-nitro-benzene was isolated as a yellow solid (5.36 g, 94%). MP=115-117° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.10 (d, J=8.1 Hz, 1H), 7.74-7.65 (m, 2H), 7.62-7.58 (m, 1H), 4.80 (s, 2H), 2.91 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[C:27](O)[CH:26]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].IC.O.CN(C)[CH:54]=[O:55]>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[C:27]([O:55][CH3:54])[CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN(C)C=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)cc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-hydroxy-3-(2-phenylethyl)benzofuran (25 mg) and potassium carbonate (18 mg) in N,N-dimethylformamide (1 mL) was added iodomethane (0.007 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (8 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2].[F:16][CH:17]([F:21])[C:18](O)=[O:19].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([O:15][C:18](=[O:19])[CH:17]([F:21])[F:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=C(O)C(F)F
Reactant: CCC1CCC(C2CCC(O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
In 30 ml of dichloromethane were dissolved 2.2 g (11 mmol) of 4-(4-ethylcyclohexyl)cyclohexanol, 1.9 g (20 mmol) of difluoroacetic acid, and 0.8 g (8 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 15 ml of solution of 2.4 g (12 mmol) of dicyclohexylcarbodiimide (DCC) in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization to give 1.4 g (4.9 mmol) of difluoro-acetic acid 4-(4-ethylcyclohexyl)-cyclohexyl ester. Yield of this compound based on 4-(4-ethylcyclohexyl)cyclohexanol was 45%.
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([N:15]1[C:19]2[C:20]([CH3:24])([CH3:23])[NH:21][CH2:22][C:18]=2[C:17]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[N:16]1)=O)C.[F:36][C:37]1([C:44](Cl)=[O:45])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[C:26]([NH:25][C:17]1[C:18]2[CH2:22][N:21]([C:44]([C:37]3([F:36])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:45])[C:20]([CH3:24])([CH3:23])[C:19]=2[NH:15][N:16]=1)=[O:35]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(Cl)c(Cl)c2)c2c1C(C)(C)NC2
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(F)(C(=O)N2Cc3c(NC(=O)c4ccc(Cl)c(Cl)c4)n[nH]c3C2(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA (0.220 mL, 1.66 mmol) and 3-(3,4-Dichloro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester (221 mg, 0.51 mmol) were added to a solution of 4-Fluoro-1-methyl-piperidine-4-carbonyl chloride (0.51 mmol) in CH2Cl2 (10 mL). The reaction was stirred at RT for 4 h. The mixture was quenched with H2O (30 mL), extracted with CHCl3 (2×30 mL). The organic layers were dried over MgSO4 and concentrated to give the title compound as brown color oil which was used without further purification. ESI (MNa+): 564.10.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cnc3ccccc32)nc1
Reaction time: 9 h
Yield: 65.2 %

Procedure:
To a mixture of ethyl 6-chloronicotinate (2.43 g), 1H-benzimidazole (1.7 g) and potassium carbonate (5.43 g) was added N,N-dimethylformamide (20 mL), and the mixture was stirred at 50° C.-60° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (2.28 g).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:15][C@H:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][N:21]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@@H]1NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3CCNC(=O)[C@@H]3C)nc12
Yield: 98.8 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:13][C:12](=[O:14])[CH2:11][N:10]1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>ClCCl>[NH:18]1[CH2:17][CH2:16][CH:15]([N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[O:8])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C2CCNCC2)C(=O)N1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (0.300 mL) was added to a solution of tert-butyl 4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (32 mg, 0.113 mmol) in dichloromethane (1 mL). After 4 h, the reaction was concentrated to give the title compound. MS184.04 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:12])=[O:11].[BH4-].[Li+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:15]([CH2:16][OH:17])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(CO)c2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (400 mg, 1.065 mmol) was dissolved in tetrahydrofuran (THF) (10 mL). To this solution was added lithium borohydride (2 M in THF) (0.932 mL, 1.864 mmol). The reaction was left to stir overnight, at room temperature. The reaction was quenched by the addition of 5% citric acid (10 mL), and the reaction allowed to stir under nitrogen, for 1 hour. The reaction mixture was then diluted with ethyl acetate (25 mL), and the product extracted to the organic phase. The organic phase was dried by passing it through a hydrophobic frit and then concentrated in vacuo to give the desired product, 378.7 mg. LCMS [LCMS1] Rt 1.23 min, m/z (ES+) 348 (M+H).
Reaction SMILES: [NH:1]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.CO.[Pd]>[NH:1]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 80 %

Procedure:
The Boc-Gly-Phe-Leu-OBzl (1.7 g) obtained in Example 19 was dissolved in a mixed solution of ethyl acetate (30 ml) and methanol (30 ml), and added with 5% Pd-C (1.5 g) to perform catalytic reduction. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give the title compound (1.15 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19](=[O:20])[C:18]([CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[NH:17][C:16]2=[CH:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[O:37])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:20]=[C:19]1[N:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16](=[CH:35][C:36]([C:38]2[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=2)=[O:37])[NH:17][C:18]1([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1

Procedure:
Using the same procedure as described in Example 3, the title compound of 40A (0.958 g, 1.58 mmol) was treated with TFA (3 ml) in CH2Cl2 to give the title compound of 40B (0.621 g, 1.23 mmol, 78% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([N:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1([N:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:18](=[O:21])[CH2:19][CH3:20])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1

Procedure:
A mixture of 52 parts of N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water, cooled and alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide as an oily residue.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29].O>N1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cccc([C@@H](C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
A suspension of 4-{[(1R)-1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (2.0 g, 6.51 mmol) in dry pyridine (50 mL) was treated with 3-fluoro-4-methoxybenzoyl chloride (1.51 g, 8.01 mmol, 1.23 eq), and the contents were stirred at room temp for 45 min. The clear-yellow solution was slowly added to water (1000 mL), and the white precipitate was filtered, washed with water (300 mL) and dried under vacuum at 35° C. to get the title compound in 98% yield (2.93 g).
Reaction SMILES: [CH:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C=O.[CH2:15](NCCCC)CCC.C(O)(=O)CCCCCCCCCCCCCCCCC>>[CH2:15]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:1]=[O:12]
Reactant: CCCCNCCCC
Reactant: CCCCCCCCCCC=O
Agent: C=O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: C=C(C=O)CCCCCCCCC
Temperature: 95 °C
Yield: 1583.3 %

Procedure:
A 3 L four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 1043 g (6.0 mol) of n-undecanal, 520 g (6.4 mol) of a 37% by mass formaldehyde aqueous solution, 47 g (0.36 mol) of dibutyl amine and 33 g (0.11 mol) of stearic acid, and the contents in the flask were stirred while heating at 95° C. After the elapse of 30 min. it was confirmed that no n-undecanal was present in the raw mixture, and then the mixture was cooled and separated into two layers. The thus separated organic layer was subjected to distillation treatment, thereby obtaining 1062 g (5.7 mol) of α-methylene undecanal (purity as measured by gas chromatography: 97%) (yield based on theoretical amount: 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.N.O1CCOCC1.CC[N:21](C(C)C)C(C)C>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:21])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CCOCC
Product: NC(=O)c1cc(Cl)nc(Cl)n1
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carbonyl chloride (26.13 g, 123.6 mmol) in Et2O (500 mL) was added a mixture of 0.5M ammonia in dioxane (250 mL, 125 mmol) and iPr2NEt (22 mL, 126 mmol) dropwise over approximately 50 minutes. After stirring overnight the reaction was concentrated in vacuo to a residue and chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo, and the resulting solid residue triturated with 10 mL 10% EtOAc/hexanes and filtered to give 2,6-dichloropyrimidine-4-carboxamide as an orange crystalline solid (9.743 g, 50.74 mmol, 41% yield). LC/MS: m/z=192.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): 8.40 (1H, br s), 8.16 (1H, br s), 8.10 (1H, s).