Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([F:14])[C:6]=1[NH:15]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:15][C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][C:7]=2[F:14])([CH3:22])([CH3:21])[CH3:1]
Reactant: CCCC(=O)Nc1c(F)cc([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(F)c2[nH]1
Temperature: 120 °C
Yield: 84.7 %

Procedure:
To a solution of N-[2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol) at room temperature. The mixture was heated at 120° C. for 2 g before being cooled down to room temperature. Water (50 mL) was added to the reaction mixture and the resulting mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 81%), which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 9.95 (brs, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.74 (dd, J=1.8, 11.1 Hz, 1H), 6.43 (dd, J=2.4, 3.3 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][C:3]=1[CH3:16].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.O.[OH-].[NH4+]>O1CCCC1>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH2:19])=[O:9])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC(C)(C)C(N)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propionic acid (500 mg) is dissolved in 10 mL of tetrahydrofurane, 1,1′-carbonyldimidazole (217 mg) and 30% ammonium hydroxide water solution are added and the reaction mixture is stirred at room temperature for 3 h. The reaction mixture is concentrated under vacuum, ethyl acetate is added and the organic solution is washed with a 10% HCl water solution. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound. Yield: 300 mg.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([CH:29]([O:39]CC1C=CC(OC)=CC=1)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][CH:33]=1)[C:22]([O:24]C(C)(C)C)=[O:23]>ClCCl>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([CH:29]([OH:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][CH:33]=1)[C:22]([OH:24])=[O:23]
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(I)cc1
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
Trifluoroacetic acid (5 mL) was added in one portion to a stirred solution of 1,1-dimethylethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (261 mg, 0.390 mmol) in dichloromethane (5 mL) at room temperature under nitrogen. The resulting solution was stirred for 45 min then the volatiles evaporated to give the title compound (192 mg, 100%) as a yellow solid which was a mixture of diastereomers. LC/MS: 3.32 min; z/e 493, calcd (M+1) 493. 1H NMR (400 MHz: CDCl3): 7.85 (4H), 7.55 (2H), 6.95 (2H), 4.90 (1H), 3.80-3.50 (3H), 2.70-2.20 (3H), 1.85 (2H), 1.55 (2H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(D) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: [C:1]([O:21][CH3:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[Si:27]([O:13][C@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:21][CH3:22])=[O:20])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:29]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:28]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCC[C@H](C/C=C\CCCCCCCC(=O)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 148.6 %

Procedure:
To a solution of methyl ricinoleate (8.0 g, 32 mmol) in anhydrous pyridine (90 mL) and anhydrous THF (45 mL) was added t-butylchlorodimethyl silane (8.5 mL, 33.3 mmol) and silver nitrate (5.65 g, 33.3 mmol). The solution was stirred at room temperature for 90 minutes under nitrogen. The solution was filtered through celite and the filter cake was rinsed with THF (400 mL). The filtrate was concentrated in vacuo and the residue was dissolved in dichloromethane (300 mL) and washed with 5% HCl (150 mL). The aqueous layer was separated and washed with dichloromethane (2×200 mL). The combined dichloromethane extracts were washed with brine (350 mL), dried on magnesium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (gradient: 100% hexanes to 10% ethyl acetate in hexanes) to afford the title compound as a colourless oil (13.1 g, 93%).
Reaction SMILES: C(OC(=O)[O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([F:15])=[CH:8][C:7]=1[Cl:16])C.C(=O)(O)[O-].[Na+]>CO.O>[Cl:16][C:7]1[CH:8]=[C:9]([F:15])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of the product from Example 47B (0.87 g, 3.30 mmol) in methanol (20 mL) and water (1 mL) was added sodium bicarbonate (2.22 g, 26.4 mmol) and the mixture stirred at room temperature for 16 hours. The methanol was then removed under vacuum, dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product (0.62 g, 98%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53](=[O:60])[N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:46][CH:45]=1>CN(C=O)C.O>[C:44]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:45]=[CH:46][C:47]([NH:50][C:51](=[O:61])[CH2:52][C:53]([N:54]2[CH2:55][CH2:56][N:57]([C:23](=[O:25])[C:22]3[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:21]=3[F:20])[CH2:58][CH2:59]2)=[O:60])=[CH:48][CH:49]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2,5-difluorobenzoic acid (34 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (70% ethyl acetate in hexane) to 36 mg (37%) of N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 464.17 (M+1)+, 97.6%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.34 (t, 1H), 7.12 (m, 3H), 3.85 (d, 3H), 3.7 (m, 3H), 3.55 (d, 2H), 3.4 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27]C(=O)OC(C)(C)C)[CH2:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[N:5][N:6]2[CH3:35].[F:41][C:42]([F:47])([F:46])[C:43](O)=[O:44].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:17]([NH:27][C:43](=[O:44])[C:42]([F:47])([F:46])[F:41])[CH2:18][C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[N:5][N:6]2[CH3:35]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cccnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To (S)-tert-butyl (1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (57A, 3.39 g, 5.73 mmol) in DCM (5 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2.5 hours. Upon complete removal of the Boc protecting group, trifluoroacetic anhydride (2.02 mL, 14.31 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Upon completion, the reaction mixture was filtered through celite, concentrated in vacuo, taken in EtOAc, and carefully neutralized with 1M aqueous NaHCO3 until the aqueous layer was at pH 10. The organic layer was collected and the aqueous layer extracted once more with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound. MS (m/z) 588.14 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C@@H:5]1[NH:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[C:23][Si](C)(C)C)=[CH:17][N:16]=1>CO.O>[CH3:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C@@H:5]1[NH:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([C:22]#[CH:23])=[CH:17][N:16]=1
Reactant: Cc1ccc2c(c1)[C@H](Nc1ncc(C#C[Si](C)(C)C)c(N)n1)[C@@H](C)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1cnc(N[C@H]2c3cc(C)ccc3C[C@@H]2C)nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
0.427 g of potassium hydroxide is added to a mixture of 0.47 g (1.34 mmol) of N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-5-[(trimethylsilyl)ethynyl]pyrimidine-2,4-diamine (Ex.: 1.98) in 3 ml of methanol and 1 ml of water, the mixture is stirred for one hour at 25° C., concentrated by evaporation and taken up in water. Then, extraction is carried out with ethyl acetate, and the organic phase is dried and concentrated by evaporation. Following purification of the crude mixture by column-chromatographic separation, 0.139 g of N2-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]-5-ethynylpyrimidine-2,4-diamine is obtained (yield 33% at 90% purity).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[OH:8]>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C:6]1[CH:5]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a stirred solution compound ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in dry methanol (100 mL) was added Pd(OH)2 under an atmosphere of nitrogen. The reaction mixture was stirred for 5 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite™, washed with methanol and concentrated to dryness under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%). 1H NMR (CDCl3, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs, 1H); 4.13 (q, 2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[NH:9][C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26].O>C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:10]1[NH:9][C:8]2[CH:22]=[CH:23][C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Product: NNC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Yield: 15 %

Procedure:
2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (20 mg, 0.057 mmol) and hydrazine hydrate 0.2 ml was heated to reflux until reaction completion, then put cool water, diluted with ethyl acetate. The organic phase was separated, washed with brine and water, dried over anhydrous MgSO4. The resultant crude was filtered and concentrated under reduced pressure to afford 2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid hydrazide as a solid (3 mg, 15% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:45])[CH:15]([N:22]2[C:26]3[CH:27]=[C:28]([C:31]#[N:32])[CH:29]=[CH:30][C:25]=3[N:24]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)(=[O:34])=[O:35])[C:23]2=[O:44])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC(=O)OC(C)(C)C)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)CC3)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
A solution of (1-{2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydrobenzoimidazol-1-yl]-2-phenyl-acetyl}piperidin-4-yl)-carbamic acid tert-butyl ester (254 mg, 0.39 mmol) in CH2Cl2 (5 mL) was treated with trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×). The residue was dissolved in CH2Cl2 (30 mL) and treated with solid K2CO3. The reaction mixture was stirred at room temperature for 1 hour, filtered and concentrated in vacuo to afford 3-[2-(4-amino-piperidin-1-yl)-2-oxo-1-phenyl-ethyl]-1-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbonitrile (179 mg, 83%) as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[C:5]=1[Cl:10].[C:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.CO>C1COCC1.O>[Cl:10][C:5]1[C:6]([CH3:9])=[N:7][O:8][C:4]=1[NH:3][S:17]([C:14]1[CH:13]=[CH:12][C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Sodium hydride (188 mg, 4.4 mmol) was suspended in dry THF (1 ml) and cooled to 0° C. A solution of 5-amino-4-chloro-3-methylisoxazole (mg, mmol) in dry THF (1 ml) was added with stirring. Once the addition was complete, the reaction mixture was warmed to room temperature for 10 min. The solution was recooled to 0° C., and 4-biphenylsulfonyl chloride (0.283 ml, 2.2 mmol) was added. Stirring was continued at 25° C. for 2 h. Excess sodium hydride was decomposed by the addition of methanol (0.4 ml) followed by water (0.5 ml). The THF was removed under reduced pressure and the residue was dissolved in water (20 ml) and basified by addition of sodium hydroxide (pH 9-10). Neutral impurities were removed by extraction with ethyl acetate (2×10 ml). The aqueous layer was acidified to pH 2-3 using concentrated HCl and extracted with ethyl acetate (3×10 ml). The combined organic layer was dried over magnesium sulfate. Removal of the solvent gave N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfonamide in 83% yield. This product was purified by recrystallization from ethyl acetate/hexanes as a white solid, m.p. 129-132° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].C(N(CC)CC)C>C(O)C>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH:14][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 37.5 °C

Procedure:
Ethyl acrylate (11.5 g, 0.115 mol) was added to a solution of glycine ethyl ester hydrochloride (107) (20 g, 0.144 mol) and triethylamine (17.6 mL, 0.127 mol) in ethanol (134 mL) and the mixture heated to 35-40° C. for 3.5 hrs. The mixture was concentrated and partitioned between water (100 mL) and ethyl acetate (1×300 mL). The organics were washed with 1×100 mL half saturated sodium bicarbonate, 1×50 mL saturated sodium chloride, and dried over Na2SO4. The dried organics were evaporated to 20.94 g of clear colorless oil that was used in the next step without further purification. MS (ESI) m/z 204 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: OCCOCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCOCC(F)(F)F
Reaction time: 2 h

Procedure:
Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol) and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give 2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether.
Reaction SMILES: C[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14]CCCC(O)CCCCCCC.CCCCCC(O)CCCCCC.CC(O)CCCCCCCCCCCC>>[CH3:2][CH2:3][CH:4]([OH:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:14]
Reactant: CCCCCCCCC(O)CCC
Reactant: CCCCCCCC(O)CCCC
Agent: CCCCCCC(O)CCCCC
Agent: CCCCCCCCCCCCC(C)O
Product: CCCCCCCCCC(O)CC

Procedure:
4-dodecanol; 5-dodecanol; 6-dodecanol; 2-tetradecanol;
Reaction SMILES: [C:1]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[N:16]=2)[NH:11][C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[C:1]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[N:16]=2)[N:11]([C:20]([NH2:21])=[O:26])[C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccccc2)c2nc(Cl)ccc21
Reaction time: 20 h

Procedure:
The title compound was prepared from 3-benzoyl-5-chloro-4-azaoxindole (Example 32) according to the procedure of Example 25, using 3-benzoyl-5-chloro-4-azaoxindole (2.73 g, 10.0 mmol), N-chlorosulfonyl isocyanate (1.3 mL, 15 mmol) and acetonitrile (80 mL). The reaction time was 20 hours. The crude N-chlorosulfonyl carboxamide was hydrolyzed by stirring in DMSO (15 mL) for 20 hours. The crude product was recrystallized from acetic acid and washed with methanol. Yield: 0.36 g (11%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:14]([O-])=O)[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[NH4+].[Cl-].O>C(O)C.[Fe]>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[NH2:14])(=[O:3])=[O:4]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1c(C)cc(N)cc1S(N)(=O)=O

Procedure:
The reduction of 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene (0.740 g, 3 mmol) using iron powder (0.81 g, 15 mmol), NH4Cl (0.81 g, 15 mmol) in ethanol (100 mL):water (25 mL) at 60° C. for 1 hour followed by filtration through a pad of Celite gave aqueous alcoholic solution. Concentration of it followed by dilution with water afforded a solid mass, which was isolated by filtration to give 3-aminosulfonyl-4-methoxy-5-methylaniline. 1H NMR (DMSO-d6): δ 6.90 (bs, 1H), 6.55 (bs, 1H), 5.1 (bs, 2H), 3.65 (s, 3H), 2.15 (s, 3H), LCMS: purity: 94%, MS (m/e): 217 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][N:12]1[CH:21]=[C:20]([CH2:22]O)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]3[CH:25]=[C:26]([CH:33]=[C:34]([F:37])[C:35]=3[CH3:36])[C:27]([NH:29][CH:30]3[CH2:32][CH2:31]3)=[O:28])[CH:18]=2)[C:13]1=[O:38])(C(C)(C)C)(C)C.CS([Cl:45])(=O)=O.[CH3:46][C@H:47]1[CH2:52][NH:51][CH2:50][CH2:49][N:48]1C(OC(C)(C)C)=O>>[ClH:45].[CH:30]1([NH:29][C:27](=[O:28])[C:26]2[CH:25]=[C:24]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:38])[N:12]([CH2:11][C:10]([CH3:39])([CH3:40])[CH2:9][OH:8])[CH:21]=[C:20]4[CH2:22][N:51]3[CH2:50][CH2:49][NH:48][C@@H:47]([CH3:46])[CH2:52]3)[C:35]([CH3:36])=[C:34]([F:37])[CH:33]=2)[CH2:32][CH2:31]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(CO)c2c1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCN[C@@H](C)C3)c2c1
Product: Cl

Procedure:
The subtitle product was made from 3-[2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-(hydroxymethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 26 g, 190 mg) by sequential reaction with methanesulfonyl chloride (57 μL) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (240 mg) using a similar method to Example 26 h, to afford the title compound (58 mg) as a white solid.