Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C)C=O>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([O:40][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)O)c2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Cesium carbonate (24.00 g, 73.67 mmol) and benzyl bromide (8.03 mL, 67.53 mmol) were added sequentially to a solution of of 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (22.31 g, 61.39 mmol) and dimethylformamide (100 mL) at ambient temperature. The resulting mixture was warmed to 60° C., stirred 1.5 h, cooled to ambient temperature and diluted with water (600 mL). The aqueous solution was extracted with diethyl ether (2×300 mL). The organic extracts were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultant oil was purified by flash column chromatography (7:1 hexanes/ethyl acetate) to provide 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:25])[NH:18][NH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[C:11]([CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]([O:30][CH2:31][C@H:32]1[O:37][C@H:36](Br)[C@H:35]([O:39][C:40]([CH3:42])=[O:41])[C@@H:34]([O:43][C:44]([CH3:46])=[O:45])[C@H:33]1[O:47][C:48]([CH3:50])=[O:49])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:40]([O:39][C@@H:35]1[C@@H:34]([O:43][C:44](=[O:45])[CH3:46])[C@@H:33]([O:47][C:48](=[O:49])[CH3:50])[C@@H:32]([CH2:31][O:30][C:28](=[O:29])[CH3:27])[O:37][C@H:36]1[O:25][C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:26])=[C:20]([C:21]([F:24])([F:23])[F:22])[NH:19][N:18]=1)(=[O:41])[CH3:42]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(F)(F)F)[nH][nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A suspension of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one (0.5 g), acetobromo-α-D-galactose (0.62 g) and potassium carbonate (0.29 g) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.66 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:34][CH:33]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(Cl)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-chloro-phenylboronic acid as starting materials in step D. MS (ES): 492.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21]([NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CC(N)C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(C)C(=O)c1ccccc1
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of triethylamine (15 g) in chloroform (15 ml) was added dropwise to a stirred mixture of 2-aminopropiophenone hydrochloride (12 g) and chloroform (65 ml) at ice bath temperature in 10 minutes. To the stirred mixture was added dropwise a solution of ethyl chloroformate (8 g) in chloroform (20 ml) under the same conditions and then stirring was continued for 4 hours at ice bath temperature. The solution was evaporated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, water, 5% hydrochloric acid, and water, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil containing the object compound. The above obtained product was purified by column chromatography on silica gel (200 g) using a mixture of diisopropyl ether and chloroform (1:4) as an eluent to give an oil of 2-ethoxycarbonylaminopropiophenone (10.48 g).
Reaction SMILES: [C:1](=[O:40])([O:9][C:10]1[C:11]([CH3:39])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:14][CH2:13]2)[O:2][CH2:3][CH:4]=[C:5]([CH3:8])[CH2:6][OH:7].ClC1C=CC=C(C(OO)=[O:49])C=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[C:1](=[O:40])([O:9][C:10]1[C:11]([CH3:39])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:14][CH2:13]2)[O:2][CH2:3][CH:4]1[O:49][C:5]1([CH3:8])[CH2:6][OH:7]
Reactant: CC(=CCOC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2)CO
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC1OC1(C)CO)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Yield: 95.3 %

Procedure:
4.1 g (0.0073 mol) of 4-hydroxy-3-methyl-2-butenyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate was dissolved in 80 ml of dichloromethane. To the obtained solution was added 2.6 g (0.012 mol) of m-chloroperbenzoic acid (purity: 80%) in small portions under ice-cooling and stirring. After the completion of the addition, the obtained mixture was further stirred at the same temperature for 1 hour. After filtering off the precipitate thus formed, the filtrate was poured into an aqueous solution of sodium hydrosulfite and extracted with dichloromethane. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, hexane/ethyl acetate). Thus 4.0 g of the title compound was obtained as a colorless viscous liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][CH2:16][O:17][CH:12]1[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: ClCC1OCCCO1
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC1OCCCO1

Procedure:
2,6-Dimethylaniline (75 grams), 2-chloromethyl-1,3-dioxane prepared in Example 1 (35 grams), potassium carbonate (30 grams) and dimethyl formamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was then heated at reflux for a period of about 16 hours. After this time the reaction mixture was filtered and the filtrate was distilled to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2,6-dimethylaniline as a residue which crystallized upon standing at room temperature.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]1.Cl[CH2:19][C:20](=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[C:13]2[C:14](=[O:16])[CH2:15][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH3:3])[CH2:11][C:12]=2[O:17][CH:19]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C1CC(=O)c2c(C)coc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.4 %

Procedure:
To 60% sodium hydride (0.21 g, washed with hexane thrice) was added ethanol (30 ml), and to the mixture was added 5-(2-methylphenyl)cyclohexane-1,3-dione (1.0 g) and then was added chloroacetone (0.45 g) at 0° C. The mixture was stirred at room temperature for 20 minutes and was refluxed for 24 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:71][NH:72][C:73]([NH2:75])=[O:74].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:71][NH:72][C:73]([NH:75][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:74]
Reactant: CNC(N)=O
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
0.5 ml of a 1,4-dioxane solution contained 20.8 mg (0.05 mmol) of the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step A of Example 114; 2.2 mg (0.0025 mmol) of tris(dibenzylideneacetone)dipalladium; 4.2 mg (0.0075 mmol) of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene; 22.8 mg (0.07 mmol) of cesium carbonate, and 4.44 mg (0.06 mmol) of methylurea, was stirred at 110° C. overnight. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto. The mixture was extracted with ethyl acetate, and the extract was then dried over anhydrous sodium sulfate. The extract was concentrated, and the obtained residue was then purified by thin-layer chromatography (methylene chloride:methanol=20:1), so as to obtain 1.7 mg (9%) of 1-methyl-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]urea in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:27][OH:28])=[C:23]([Cl:26])[CH:24]=3)[CH:19]=[CH:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH:27]=[O:28])=[C:23]([Cl:26])[CH:24]=3)[CH:19]=[CH:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2ccc3cc(CO)c(Cl)cc32)CC1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCCn2ccc3cc(C=O)c(Cl)cc32)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(6-chloro-5-hydroxymethyl-indol-1-yl)-propyl]-piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.35 mmol) and MnO2 (0.59 mg, 6.77 mmol) in toluene (10 mL) was heated at 100° C. for 30 min. The mixture was cooled to rt and filtered through diatomaceous earth. The filtrate was concentrated and used without further purification. MS: mass calcd. for C22H29ClN2O3, 404.19; m/z found, 405.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=3)[C:12]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:24][CH:25]=3)[C:12]2=[O:26])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCN(c3ccc(C(C)(C)C)cc3)C2=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCN(c3ccc(CO)cc3)C2=O)cc1
Reaction time: 2 h

Procedure:
A solution of methyl 4-(3-(4-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzoate (270 mg, 0.77 mmol) in dichloromethane (50 ml) at −78° C. was treated with ml of 1.0 M DIBAL solution in dichloromethane. The resulting solution was stirred cold for 2 hour, then quenched with ml of sat's Rochelle salt solution. The mixture was partitioned between 100 ml dichloromethane and 50 ml of 1 N NaOH. The organic layer was separated, dried and concentrated. The residue was purified on ISCO system (5% methanol in dichloromethane) to give a pure product as a white crystalline (113 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 7.60 (d, 2H), 7.50 (d, 2H), 7.10 (m, 4H), 4.64 (s, 2H), 4.00 (s, 4H), 1.58 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([NH2:12])[CH3:11]>>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:12][CH2:10][CH3:11])[CH:7]=1
Reactant: CCN
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: CCNc1cc(Cl)nc(N)n1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In a 50 mL flask under argon were combined 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) and ethylamine (2.0 M in CH3OH) (15.24 mL, 30.5 mmol) and the reaction mixture was stirred at 50° C. for 3 hours. The mixture was cooled to room temperature and concentrated. The resulting yellow solid was dissolved in EtOAc and the solution was washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound (368 mg, 69%) as a yellow solid. LC-MS (ES) m/z=173 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[Cl:11]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 290.5 %

Procedure:
2-Methoxybenzyl alcohol (1.01 g, 7.31 mmol) and triphosgene (757 mg, 2.55 mmol) were dissolved in tetrahydrofuran (5 ml). The solution was added with pyridine (1.18 ml, 14.6 mmol) under ice cooling, and then warmed to room temperature. After 20 minutes, insoluble solids were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting oil was diluted with ethyl acetate and insoluble solids were further removed. The solvent was evaporated under reduced pressure to obtain the title compound as pale yellow oil (1.16 g, yield: 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N:10]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:8]([Br:29])[S:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.CO>[Br:29][C:8]1[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]=1[N:10]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1csc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)csc2Br)cc1
Yield: 93.3 %

Procedure:
To a solution of 0.40 g (0.860 mmol) of the product of Example 24 in 9.0 mL of THF-MeOH (1:1) was added 0.072 g (1.72 mmol) of lithium hydroxide monohydrate. The reaction mix was heated to reflux for 18 h and then concentrated in vacuo. The residue was was washed with THF and filtered. The filtrate was concentrated in vacuo to provide 0.388 g (100%) of the desired product as a white foam. Electrospray Mass Spec: 483 (M+H).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]([C:35]#[N:36])[C:20]3[C:25]([C:26]=2[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=3)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:16])[N:18]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 1-{[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-cyclopentanecarboxylic acid tert-butyl ester (164 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (143 mg). LC MS ESI+: 432 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:19])=[O:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Amino-5-bromo-2-chloropyridine (767 mg) in dry pyridine (8 ml) was treated with 2-methylbenzenesulfonyl chloride (641 μl) then stirred at RT overnight. The reaction was purified by prep-HPLC. Desired fractions were combined, diluted with saturated sodium bicarbonate (aq) and brine and extracted into EtOAc. The solvent was dried over sodium sulfate and evaporated to give title compound (500 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.6 g, 0.0554 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the residue was triturated in 100 ml of water, the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature, and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water, and dried under high vacuum at 42° C. overnight to give 2.22 g (34%) of title compound, mp. 135°-136° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([NH2:11])=[S:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15]>>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:13]([CH3:20])([CH3:19])[C:14](=[O:15])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: NC(=S)NCC1CCCCC1
Product: CC1(C)SC(NCC2CCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-(cyclohexylmethyl)thiourea and ethyl 2-bromoisobutyrate according to Method C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[C:5](=[CH:12]/[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)/[CH2:6][C:7]([O:9][CH2:10][CH3:11])=O)[CH3:2].C([O-])(=[O:23])C.[Na+]>C(OC(=O)C)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([O:9][C:10](=[O:23])[CH3:11])[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH:12]=1)=[O:20])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C/C(=C\c1cccc(C)c1)C(=O)OCC
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(OC(C)=O)c2ccc(C)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 2 g of 2-[1-m-Tolyl-meth-(E)-ylidene]-succinic acid diethyl ester in 10 ml of acetic acid anhydride, 594 mg sodium acetate was added and the reaction mixture was heated to reflux for 5 h. After cooling to RT the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: C([Mg]Cl)(C)C.[Li]CCCC.I[C:12]1[C:16]([CH2:17][N:18]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:14]([CH2:39][O:40][CH3:41])[N:13]=1.[F:42][C:43]1[CH:50]=[CH:49][C:46]([CH:47]=[O:48])=[CH:45][CH:44]=1>C1COCC1>[F:42][C:43]1[CH:50]=[CH:49][C:46]([CH:47]([OH:48])[C:12]2[C:16]([CH2:17][N:18]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:14]([CH2:39][O:40][CH3:41])[N:13]=2)=[CH:45][CH:44]=1
Reactant: COCn1cc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1cc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a flame-dried flask under nitrogen was added THF (3 mL) followed by isopropylmagnesium chloride (2M THF, 0.708 mL) and the mixture cooled to −10° C. n-BuLi (1.6M Hexane, 1.77 mL) was added dropwise and stirred for 30 minutes. The reaction was cooled to −78° C. and tert-butyl (3-iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (43) (815 mg, 1.42 mmol) in THF (3 mL) was added dropwise and stirred for 30 minutes. 4-Fluorobenzaldehyde (0.91 mL, 8.52 mmol) was added neat and stirred for 1 hr before quenching with aq. ammonium chloride (5 mL). The aqueous layer was discarded and the reaction was concentrated in vacuo. The resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield tert-butyl (3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl(4-(trifluoromethyl)phenylsulfonyl)carbamate (44) (447 mg, 55%) as a clear oil.