Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[CH2:16][CH:17]2[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C1(C=O)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:27]([NH:26][C:22]1[CH:21]=[C:20]([N:15]([CH2:16][CH:17]2[CH2:18][CH2:19]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CC2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(=O)Nc1cccc(N(CC2CC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclopropylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopropanecarboxaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:48]1(B(O)O)[CH2:50][CH2:49]1.O>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH:48]4[CH2:50][CH2:49]4)=[CH:30][CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(Br)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(C4CC4)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
Compound 41-4 (500 mg) was dissolved in tetrahydrofuran (1.6 ml), tripotassium phosphate (430 mg), palladium acetate (9.0 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (17 mg), cyclopropylboronic acid (85 mg) and water (40 μl) were added, and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (440 mg) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc(CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc1
Temperature: 4 °C
Yield: 89.9 %

Procedure:
N-Methylglucamine (9.76 g, 50 mmol) was dissolved in hot methanol (200 mL), whereupon 4-vinylbenzylchloride (7.63 g, 50 mmol) and sodium carbonate (6 g) were added to the reaction. The mixture was allowed to reflux overnight. The solution was filtered, the methanol was removed, the residue taken up in hot chloroform and filtered. A precipitate formed in the eluent, which was heated until all solids dissolved and the solution was allowed to cool to 4° C. Filtration gave 14 g (90% yield) of white powder. 1H-NMR (90 MHz, DMSO-d6, δ): 7.33-7.28 (d, 4H); 6.86-6.83 (dd, 1H); 5.85-5.64 (d, 1H); 5.25-5.12 (d, 1H); 2.11 (s, 3h).
Reaction SMILES: S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Mg+2].[O:12]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:34][CH3:35])=[C:19]([C:23]([CH2:26][S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:13]1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(C)(C)C>[O:12]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]([O:34][CH3:35])=[C:19]([C:23]([CH2:26][S:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:25]=2)[C:20]([O:22][C:14]([CH3:17])([CH3:15])[CH3:13])=[O:21])=[CH:13]1
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 119.8 %

Procedure:
Concentrated sulphuric acid (0.31 g) was added to a stirred suspension of magnesium sulphate (1.31 g) in DCM (10 ml) in a sealed vial and the mixture was stirred for 5 minutes before addition of a solution of 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoic acid (Intermediate 223, 0.96 g) in DCM (8 ml) and t-butanol (1.03 g). The mixture was stirred in a sealed tube for 48 hours. DCM and saturated aqueous sodium hydrogen carbonate were added to the mixture and the organic layer was separated, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100%, to give t-butyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoate (0.67 g) as a colourless gum.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:7]=2[CH:22]=1.[C:25]([O:30][CH3:31])(=[O:29])[C:26]([CH3:28])=O>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([C:25]([O:30][CH3:31])=[O:29])[CH3:28])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:7]=2[CH:22]=1
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl)-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-(trifluoromethyl)-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[N:7]=1.[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCOC(=O)Cn1ccc2cnc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1ccc2cnc(Cl)nc21
Temperature: 25 °C
Yield: 54.2 %

Procedure:
To a solution of ethyl 2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (1.25 g, 5.23 mmol) in EtOH/H2O (100 mL) was added NaOH (1.1 g, 26.15 mmol). The reaction mixture was stirred at room temperature until TLC showed completion. The reaction mixture was concentrated and the residue taken up in water (15 mL) and treated with 2M HCl until pH=3 then extracted with EA (2×25 ml). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated to yield the title product (600 mg, Yield 50%). The crude product was used in next step without further purification. LCMS (m/z): 212.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester (4.2 g, 11.6 mmol) in THF (24 ml) was added a 1 M solution of tetrabutylammonium fluoride in THF (11.6 ml, 11.6 mmol) within 15 min. The reaction mixture was stirred for 1 h at ambient temperature, poured onto 1 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 3.4 g (quant.) of the title compound as brown oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:19][C:14]1[C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1cccnc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1c1cccnc1Cl
Temperature: 30 °C
Yield: 99 %

Procedure:
A stirred slurry containing 15 grams of phthalic anhydride, 13 grams of 3-amino-2-chloropyridine, one gram of toluenesulfonic acid and 200 ml. of o-dichlorobenzene was heated at reflux for 6 hours. During this heating period 100 ml. of solvent and 1.8 ml. of water were removed. After cooling to 30° C., 50 ml. of heptane and 10 ml. of water were added and stirring was continued. The solid was collected by filtration and air dried. A 99 percent yield of N-(2-chloro-3-pyridyl) phthalimide, m.p. 156°-7° C., was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=[CH2:13])=[C:10]([C:14]([OH:16])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+](=[CH2:19])=[N-].C(O)(=O)C>CO.C(OCC)C>[CH3:19][O:15][C:14]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[C:11]=1[CH:12]=[CH2:13])=[O:16]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1c(C(=O)O)c2ccccc2[nH]c1=O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O

Procedure:
To a solution of 4.4 g (20 mmol) 2-Oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylic acid 4 in 200 mL methanol was added etheral diazomethane at ambient temperature until the vigorous evolution of nitrogen subsided and the starting material was used up. Then 10 mL acetic acid were added, the mixture was diluted with 200 mL diethylether and washed with a solution of sodium bicarbonate (5%) and brine. The organic layer was separated, dried over sodium sulfate and filtered. After evaporation the crude product was purified by chromatography on silica gel eluting with toluene/ethyl acetate/methanol 4:1:1, to give 2.6 g of 5 as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H:77]([N:79]3[CH:83]=[C:82](CO)[CH:81]=[N:80]3)[C@@H](O)[C@H]2O)C=CC=CC=1.N[C@@H]1CCNC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:80][C@@H:81]1[CH2:82][CH2:83][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH2:77]1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: N[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing the 1-(2-aminoethyl)piperidine with (3R)-(+)-3-amino pyrrolidine. MS (ES+) m/e 596 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])(=[O:5])=[O:4].[Li+].[OH-]>O1CCOCC1>[CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])=[O:4]
Reactant: COC(=O)c1ccccc1OS(=O)(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Oc1ccccc1C(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
Methyl 2-{[(dimethylamino)sulfonyl]oxy}benzoate (325.0 mg, 1.253 mmol) was dissolved in 2 ml of 1,4-dioxane and 2 ml of 1M LiOH was added. The resulting solution was shaken overnight at 45° C. The reaction mixture was washed with DCE and separated using a hydrophobic frit. The aqueous layer was acidified to give a white solid which was filtered and dried to afford 244.4 mg (80% yield) of 2-{[(dimethyl-amino)sulfonyl]oxy}benzoic acid.
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH2:31][C:32]2[C:33](=[O:43])[N:34]([CH3:42])[C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:10][CH:11]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH3:42][N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[C:32]([CH2:31][N:9]([CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:8])[C:33]1=[O:43]
Reactant: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C2CCCCC2)cc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1c(=O)c(CN(CC(c2ccccc2)C2CCNCC2)C(=O)C2CCCCC2)cc2ccccc21
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(2-{(cyclohexylcarbonyl) [(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-phenylethyl)piperidine-1-carboxylate (1.63 g, 2.78 mmol) in CH2Cl2 (5 ml) was added to 4 M HCl in dioxane (20 mL, 80 mmol) at 0° C. and the reaction stirred for 1.5 hours before being poured into satd. bicarb. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. 1.35 g, 100%.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate (92.9 mg, 0.22 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (44 mg, 1.10 mmol, 5.00 equiv) in water (1.5 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 85 mg (93%) of 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH:10]2[OH:13])[C:4](=[O:5])[C:3]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:23]3[CH:24]=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[O:29][N:30]=2)[CH2:18][CH2:17]1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:31][C:26]1[CH:25]=[CH:24][C:23]2[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:3]4[C:4](=[O:5])[N:6]5[CH2:7][CH2:8][CH2:9][CH:10]([O:13][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:11]5=[N:12][C:2]=4[CH3:1])[CH2:17][CH2:18]3)=[N:30][O:29][C:28]=2[CH:27]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OC(=O)CCC(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Paliperidone (10 g, 23.45 mmol) was dissolved in pyridine (100 mL) together with N,N-dimethyl-4-pyridinamine (0.5 g; 4.09 mmol) and succinic anhydride (18.3 g; 182.86 mmol). The mixture was stirred under an argon atmosphere for 4 h at 60° C. and for 48 h at room temperature. The reaction mixture was evaporated and dissolved in dichloromethane/methanol (100 mL/10 mL) and water (100 mL). The aqueous phase was extracted five times with dichloromethane/methanol (100 mL/10 mL). The organic layers were combined, dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography (gradient elution with chloroform/ethanol 80/20 to 70/30). The product was dissolved in isopropanol (50 mL) and the resulting precipitate was filtered and washed with isopropanol (10 mL). The precipitate was dried in vacuo to give the title compound as a white solid. ESI-MS (M+1) 528. 1H NMR: (DMSO-d6, 360 MHz): δ ppm 1.75-2.75 (m, 23H), δ 3.5-4.0 (m, 3H), δ 5.74 (m, 1H), δ 7.28 (td, J=9.15, 2.20 Hz, 1H), δ 7.69 (dd, J=8.96, 2.01 Hz, 1H), δ 8.02 (dd, J=8.78, 5.12 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 50 °C

Procedure:
To a suspension of 150 g of methyl p-toluate and 195.5 g of NBS in CCl4 (1.67 L) under N2 at 50° C. was added portion wise over 30 min, solid benzoyl peroxide (5.0 g). No exothermic reaction was observed. After heating for 2 hours at 50° C., the yellow solution was heated up at 65° C. for 1 d. After cooling down to rt, the precipitate formed was filtered off and washed with 150 mL of CCl4 and the filtrate was concentrated to afford a yellow oil that solidified on standing. The title compound, containing a small fraction of starting material was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (4-fluorophenyl)methanol (74.3 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was washed with toluene, and recrystallized from IPA-IPE to give the title compound (49.6 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[NH:16][C:17]2[CH:23]=[C:22]([C:24]([NH:35][NH:34][C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:37][CH:36]=3)=[O:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Reactant: NNC(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)NNC(=O)c3ccc(Cl)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl -phenyl)-3H-benzoimidazole-5-carboxylic acid in 10 ml of DMF was added 900 mg of 4-chlorobenzoic acid hydrazide, 1.1 g of EDCI and 700 mg of HOBT. The reaction was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture was diluted with water and the resulting precipitates were colleced by filtration and purified by column chromatography (DCM:MeOH=20:1) to give the title compound. LCMS ret T=1.19 min, m/z=504.1, Method 10.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][OH:47])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[CH:41]=[C:42]([CH:43]=[CH:44][CH:45]=1)[CH:46]=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
Manganese dioxide (20.4 g) was added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[3-(hydroxymethyl)phenyl]-D-glucitol (6.8 g) obtained in Reference Example 24 in chloroform (100 ml) and the mixture was refluxed with stirring for 1.5 hours. After separating the insoluble matter from the reaction mixture by filtration through celite at room temperature, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzaldehyde (6.8 g).