Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[CH:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41]([OH:43])=[O:42])=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[C:38]([CH:46]=[CH:45][CH:44]=1)[CH2:36][N:18]1[CH2:17][CH2:16][S:15][C@H:14]1[C:12]([O:11][C@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[CH2:9][C:8]1[C:7]([Cl:34])=[CH:6][N+:5]([O-:35])=[CH:4][C:3]=1[Cl:2])=[O:13])([OH:43])=[O:42]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CN2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 570 mg, 1.0 mmol) in DCM (5 mL) was added 3-formylbenzoic acid (180 mg, 1.2 mmol) followed by glacial AcOH (0.17 mL, 3.3 mmol). The reaction was stirred at room temperature for 18 h. Sodium triacetoxyborohydride (690 mg, 3.12 mmol) was added and the reaction was stirred at room temperature for 1.5 h. Additional 3-formylbenzoic acid (180 mg, 1.2 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. DCM (25 mL) and 1 N HCl (15 mL) were added to quench the reaction and the mixture was passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O[CH2:13][CH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[NH:16]1>C(Cl)Cl>[S:1]([CH2:13][CH2:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[NH:16]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NC(CCO)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCC2NC(=O)c3ccccc32)cc1
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Tosyl chloride (3.4 g, 17.7 mmol) is added to a solution of TEA (5.1 g, 50.8 mmol) and 1,3-dihydro-3-(2-hydroxyethyl)-2H-isoindol-1-one (3.0 g, 16.9 mmol) in 50 mL of CH2Cl2 at room temperature under argon. After 12 hours, the reaction mixture is extracted with H2O (2×100 mL) and dried over Na2SO4. Evaporation of the solvent gives 4.2 g (75% yield) of 1,3-dihydro-3-(2-tosylethyl)-2H-isoindol-1-one; mp=146-149° C. (dec) after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]1[CH:11]2[C:12]3[C:17]([C:18](=[O:19])[N:10]2[CH2:9][CH2:8][NH:7]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([CH:6]1[CH:11]2[C:12]3[C:17]([C:18](=[O:19])[N:10]2[CH2:9][CH2:8][NH:7]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4]
Reactant: O=C1c2ccccc2C2CNCCN12
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)C1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of chloroacetyl chloride (657 mg, 0.0058 mol) in 30 ml of benzene is added dropwise to a stirring solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-6-one (described in Example 8, 1.0 g, 0.0053 mol) and triethylamine (650 mg, 0.0064 mol) in 90 ml of benzene. The reaction is stirred at room temperature for 30 min and evaporated. A mixture of chloroform and water is added and the chloroform phase is collected, washed with water, dried and evaporated to afford 2-chloroacetyl-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-6-one, (1.2 g), nmr (CDCl3) δ 3.0-3.5(m), 4.2-4.8(m) and 7.3-7.9(m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29].O1CCOCC1>CO>[ClH:29].[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 206d (1.46 g, 3.2 mmol) and HCl/1,4-dioxane (3.2 mL, 4M, 12.8 mmol) in methanol (20 mL) was heated at 80° C. for 1 h. The mixture was then concentrated under reduced pressure to afford 206e (1.24 g, 99%). MS-ESI: [M+H]+ 351.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH2:18][CH:19]=[CH2:20])=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:21][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[C:5]=1[CH2:18][CH:19]=[CH2:20])=[C:9]([O:17][CH2:18][C:5]1[CH:6]=[CH:15][CH:2]=[CH:3][CH:4]=1)[CH:10]=[CH:11][CH:12]=3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)cc(O)c2c(=O)c3cccc(O)c3oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 110 °C
Yield: 160.7 %

Procedure:
To a solution of xanthone 5 (48 g, 168 mmol) in dry DMF was added potassium carbonate (46 g, 336 mmol) and benzyl bromide (90 g, 526 mmol) and the mixture was heated to 110° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.4L) and the remaining potassium carbonate was destroyed with 2M Sulfuric acid. The organic layer was washed with brine (2×500 mL), dried over magnesium sulfate and concentrated in vacuo to afford the xanthone 6 as a solid (63 g, 135 mmol, 81%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16]CC)(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](=[O:22])[CH2:14][C:13]([OH:16])=[O:15]
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:21]([NH:20][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][N+:17]([O-:32])=[CH:16][CH:15]=2)=[C:9]([C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:10]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2cc[n+]([O-])cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a suspension of N-[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]acetamide (1.0 g) in chloroform (30 mL), was added 70% m-chloroperbenzoic acid (0.80 g), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was treated with an aqueous saturated solution of sodium hydrogen carbonate. The formed crystalline residue was washed with water, dried and recrystallized from ethanol to obtain the title compound (0.55 g, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N+:9]([O-])=[CH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2cc(-c3ccccc3)[n+]([O-])cc2c1
Product: COc1ccc2cc(-c3ccccc3)nc(Cl)c2c1

Procedure:
7-Methoxy-3-phenylisoquinoline-2-oxide (0.30 g) was reacted with phosphorus oxychloride (3 ml) at 110° C. for 2 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and an aqueous solution of saturated sodium bicarbonate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.20 g of the title compound was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO.O1CCCC1>[C:11]1([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
1-Phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.1 g) synthesized in Reference Example 16 was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL), aqueous sodium hydroxide solution (1 mol/L, 40 mL) was added, and the mixture was stirred at 60° C. for one hour. The reaction mixture was concentrated under reduced pressure, aqueous hydrochloric acid solution (1 mol/L, 50 mL) was added, and the precipitated solid was filtrated. The solid was dissolved in ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1-phenyl-1H-pyrazole-4-carboxylic acid (2.5 g) as a white solid. This carboxylic acid (8.72 g) and 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (14 g) synthesized in Example 7 were dissolved in N,N-dimethylformamide (225 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (10.65 g) and 1-hydroxybenztriazole (HOBt) monohydrate (10.62 g) were successively added thereto, and the mixture was stirred at room temperature for 6 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 dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (16.2 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Br)cc(F)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(Br)cc(F)cc1Br
Temperature: 10 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of 104k (20 g, 71 mmol) in EtOH (500 mL) was added NaBH4 (10 g, 284 mmol). The mixture was stirred at room temperature (10° C.) for 4 h and TLC showed the starting material had disappeared. The reaction was quenched by aqueous HCl solution (150 mL, 1M) and evaporated in vacuo until most of EtOH was distilled. The residue was extracted by ethyl acetate (500 mL×3). The organic layers were combined, dried with Na2SO4, and evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 104l as a white solid (15g, 75%). MS: [M-OH]+ 267. 1H NMR (500 MHz, DMSO-d6) δ 7.68 (d, J=8.5, 2H), 5.23 (s, 1H), 4.71 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][C:11]([CH3:15])([OH:14])[CH2:12][OH:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.C1C=CC=CC=1>O>[CH2:2]([O:9][CH2:10][C:11]1([CH3:15])[CH2:12][O:13][C:17]([CH3:19])([C:16]([O:21][CH2:22][CH3:23])=[O:20])[O:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(O)(CO)COCc1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C)OCC(C)(COCc2ccccc2)O1
Temperature: 90 °C

Procedure:
Dry hydrogen chloride gas was passed into a mixture of 3-benzyloxy-2-methylpropane-1,2-diol (14.9 grams) and ethyl pyruvate (9.15 grams) for 1 hour. The mixture was heated at 90° C for a further 1 hour and then cooled to 50° C. Benzene (100 milliliters) was added to the mixture and the water formed in the reaction was removed azeotropically. The cooled solution was washed with potassium carbonate solution and dried. The solvent was removed under reduced pressure and the residue was fractionally distilled to yield the desired product boiling point 124-126° C at 0.3 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+]>Cl.O>[ClH:9].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)ccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 248.8 %

Procedure:
A suspension of 5-bromo-2-chloroaniline (23 g, 0.11 mol) in concentrated hydrochloric acid (150 mL) and water (90 mL) was cooled in an ice/salt bath. A solution of sodium nitrite (8 g, 0.11 mol) in water (50 mL) was added dropwise to the reaction mixture while maintaining the temperature below 4° C. After stirring for 30 minutes the suspension was transferred via cannula to a solution of SnCl2 dihydrate in concentrated hydrochloric acid (170 mL) and cooled to 5° C. The resulting thick suspension was stirred for 2 h at 5° C. and the solid was isolated via filtration. The solid was air dried and then further dried by adding chlorobutane (500 mL) and refluxing using a Dean-Stark condenser. After cooling, the solid was isolated by filtration to afford the title compound as an off-white solid (35.3 g).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].[I-].[Li+].N1C(C)=CC(C)=CC=1C.Cl>>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([OH:16])=[O:15])=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCC(C)(C)C(=O)OC)ccc(C(C)=O)c1O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CCCc1c(OCCCCC(C)(C)C(=O)O)ccc(C(C)=O)c1O

Procedure:
A solution of 1.1 g. of methyl 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-2,2-dimethylhexanoate and 2.6 g. of lithium iodide in 50 ml. of collidine was heated to 100° C. under a nitrogen blanket for about 46 hours. The reaction mixture was then added to ice. After making the solution acidic with hydrochloric acid, the solution was extracted with ether. The ether phase was washed three times with a 10% sodium bicarbonate solution. The ether solution was then further washed with a dilute hydrochloric acid solution, water, and a saturated sodium chloride solution. Evaporating the ether layer to dryness gave 1.03 g. of the title product, M+ =336; NMR.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)=[N:9][C:7]=2[N:8]=1.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[N:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[NH:36][N:35]=2)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:28]4[CH2:33][CH2:32][CH:31]([C:34]5[NH:38][C:37]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[N:36][N:35]=5)[CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[N:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)nc2n1
Reaction time: 3 h

Procedure:
A mixture of 4-[2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (1-4) (0.200 g, 0.56 mmol), 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine HCl salt (A [see synthesis below]; 0.193 g, 0.727 mmol), and TEA (0.074 g, 0.727 mmol) were stirred in 5% AcOH in DMF for 0.5 hr. Sodium triacetoxyborohydride (0.178 g, 0.0.839 mmol) was then added and the reaction was stirred for 3 hr. The reaction was quenched with 3N NaOH and extracted 3×w/CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silicon gel chromatography (6% MeOH in CH2Cl2) to give the titled compound. 1H-NMR (500 MHz, d6 DMSO) δ 9.50 (s, 1H), 8.64-8.72 (m, 2H), 8.58 (s, 1H), 7.88-8.07 (m, 3H), 7.28-7.56 (m, 9H), 3.52 (s, 2H), 2.84 (m, 2H), 2.66 (s, 3H), 2.11 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H). LRMS m/z (M+H) calcd: 571.7, found: 571.2.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([OH:20])(=O)=[O:18])=[CH:9]1.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:24])(=[O:20])=[O:18])=[CH:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)c1cn(CC2=NCCN2)c2ccccc12
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1cn(CC2=NCCN2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid hydrochloride (1.52 g, 4.814 mmol) from Step 3 was dissolved/suspended in methylene chloride (25 mL) and stirred at room temperature. Oxalyl chloride (2 mL) was added dropwise to the mixture, after which stirring was continued for 3 hours. The mixture was then evaporated to dryness, and excess oxyalyl chloride was azeotroped off with methylene chloride (3×) to provide 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonyl chloride as a hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH:15]1([CH2:21][C:22](OC)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)C.[H-].[Na+]>O>[CH:15]1([CH2:21][C:22]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Reactant: COC(=O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(CC2CCCCC2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 75 mg (0.39 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbox-amide and 183 mg (1.16 mmol, 3 equiv.) of methyl cyclohexylacetate are introduced into 1.5 ml of absolute ethanol. At 0° C., 54 mg of sodium hydride (60% dispersion in mineral oil; 1.35 mmol, 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly heated and stirred under reflux for 18 h. For workup, 20 ml of water are added, and the mixture is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(F)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b), the reaction is carried out with 5.6 g (20 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester, 5 g (50 mmol) of triethylamine, 150 cc. of toluene and 4 g (25 mmol) of 4-fluorobenzoic acid chloride. Reaction time: 5 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) was diluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate (0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15 minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol). The reaction was maintained at 100° C. for 5 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The dark brown oil was purified by flash chromatography on silica gel, eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was obtained as a light pink solid (0.50 g, 30%). 1H NMR (300 M, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H) 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.42 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:10][S:11][CH2:12][CH2:13][CH2:14]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:14][CH2:13][CH2:12][S:11][CH3:10]
Reactant: CSCCCO
Reactant: Cc1c(O)cccc1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CSCCCOc1cccc(Br)c1C

Procedure:
3-Bromo-2-methylphenol (0.10 g), 3-(methylthio)propanol (0.055 mL), tri-n-butyl phosphine (0.12 g) and 1,1′-(azodicarbonyl)dipiperidine (0.15 g) are stirred in tetrahydrofurane for 16 hours. Water is added and the mixture extracted with diethyl ether. The organic layer is washed with brine, dried (Na2SO4) and volatiles removed under reduced pressure. The product (80 mg) is obtained after column chromatography (silica gel, n-hexane/ethyl acetate gradient 100:0 to 50:50).