Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[OH:24])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])[CH3:5].[Na+].Cl[CH2:27][C:28]([O-:30])=[O:29].Cl>O1CCCC1.O>[CH3:16][C:13]([C:11]1[CH:10]=[C:9]([S:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[O:24][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[CH:12]=1)([CH3:14])[CH3:15]
Reactant: O=C([O-])CCl
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
Sodium hydride (0.33 g, 0.0138 mole) was added to a solution of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol (3.4 g, 0.0106 mole) in tetrahydrofuran (50 ml) at 0° C. After stirring the reaction mixture for 1.5 hours, the tetrahydrofuran was removed by rotary evaporation. Dimethyl sulfoxide (75 ml) was added followed by chloroacetic acid sodium salt (1.48 g, 0.0127 mole), and the reaction mixture was stirred at room temperature for 10 days. Water (100 ml) was added dropwise to the mixture followed by 10% hydrochloric acid (10 ml). The product was extracted twice with 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 200 ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by chromatography on silica gel. The structure was supported by NMR and elemental analysis (378.6+1/4 mole H2O).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22]Cl>CN(C)C=O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22][N:3]1[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH2:22][C:21]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=3[CH3:19])=[O:11])[CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COC(=O)c1ccc2ncn(Cc3c(C)cccc3C)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.7 %

Procedure:
To a solution of 5-benzoimidazole carboxylic acid (1.1 g) in N,N-dimethylformamide (15 mL) were added potassium carbonate (2.7 g) and 2,6-dimethylbenzyl chloride (2.3 g) at room temperature, and then the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (1.1 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:24]=[C:23]([CH3:32])[CH:22]=1)=[O:4].[OH-].[Li+]>>[Cl:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:21]2[N:25]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:24]=[C:23]([CH3:32])[CH:22]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:12])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)O)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow foam which was used in the next step without further purification. MS (ESI): m/z=472.1 [M+H]+.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=[O:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([S:4]([NH:7][C:8](=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)NS(=O)(=O)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of ethyl 3-(cyclopropanesulfonamido)-3-oxopropanoate (0.48 g, 2.04 mmol) and lithium hydroxide monohydrate (0.17 g, 4.08 mmol) in THF (5 mL) and water (3 mL) was stirred at rt overnight. The pH of the reaction solution was adjusted to ˜6 by using 1N HCl and extracted with EtOAc (3×). Aq. layer was then saturated using ammonium sulfate and extracted with EtOAc (3×), dried (MgSO4), and concentrated to give 3-(cyclopropanesulfonamido)-3-oxopropanoic acid (0.4 g, 1.93 mmol, 95% yield) as a light brown solid. LCMS Anal. Calc'd for C6H9NO5S 207.02. found [M+H] 207.9.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccn1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=C(NCc1ccccn1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (300 mg, 0.95 mmol) dissolved in pyridine (4 mL) was added 2-aminomethyl pyridine (106 μl, 1.02 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. Solvent was removed and water was added to the flask. A solid crashed out of solution that was collected by filtration. The product was purified by column chromatography (SiO2, 5% methanol in dichloromethane). The solid was taken up in 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with Ethyl Acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (106 mg, 32% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.3 (t, 1H), 8.65 (s, 1H), 8.5 (d, 1H), 8.1 (m, 2H), 8.0 (d, 1H), 7.75 (t, 1H), 7.65 (d, 1H), 7.4 (m, 3H), 7.25 (t, 1H), 4.6 (d, 2H), ES-MS m/z 368 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][C:3]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:2]=2[NH:1][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:10]1)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2N)C1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A mixture of 5-(2-amino-5-chlorophenoxy)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (2.92 g, 7.8 mmols), ethyl 4-bromobutyrate (2.2 ml, 15.6 mmols), potassium carbonate (1.08 g, 10 mmols) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 3 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy]-4-chlorophenyl]aminobutyrate (2.47 g, 64.8%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]=[CH:22]3)[CH:6]=1.C(O)(=O)C>CO.[Pt](=O)=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)[CH:6]=1
Reactant: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3cnccc23)cn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cn(-c2cc(C(F)(F)F)ccc2-c2cccc3c2CCNC3)cn1
Reaction time: 3 h
Yield: 55.7 %

Procedure:
A solution of 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)isoquinoline (1.435 g, 4.06 mmol) in 15 mL MeOH was treated with platinum(IV) oxide (0.092 g, 0.406 mmol) and acetic acid (0.697 ml, 12.18 mmol) and was placed under 45 psi (4559.6 kpa) H2 for 3 hours. The reaction mixture was filtered through a plug of diatomaceous earth eluting with EtOAc. The filtrate was concentrated then purified directly be reverse phase column chromatography [RediSep Gold C18 150 g, 5 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielding 5-(2-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.808 g, 2.261 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7](Cl)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH2:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: ClCC=Cc1ccccc1
Solvent: CC(C)O
Product: C(=Cc1ccccc1)CN1CCNCC1
Temperature: 70 °C
Yield: 56 %

Procedure:
Absolute piperazine (217 g, 2.5 moles) was dissolved in 1 liter of isopropanol and 72.6 g of cinnamyl chloride (0.5 moles) were added dropwise gradually at room temperature without mixing. After the completion of dropwise addition, it was heated at 70° C for 3 hrs. with mixing. After the solvent was distilled away, the reaction mixture was dissolved in 500 ml of chloroform and then washed with sodium hydroxide and water. Subsequently, it was dried over potassium carbonate and then was filtered. Chloroform was distilled away in vacuo. By Subliming the mixture obtained, piperazine was removed and then the residues were distiled to obtain N-cinnamyl piperazine. The product was crystallized and then was recrystallized from n-hexane. Boiling point of the product was 162°-165° C (4 mmHg). Melting point was 31°-33° C and the yield was 56%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:18]1[CH:23]=[CH:22][C:21]([S:26]([Cl:25])(=[O:28])=[O:27])=[CH:20][CH:19]=1)[CH3:24]
Reactant: O=S(=O)(O)Cl
Reactant: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Product: CC1(c2ccc(S(=O)(=O)Cl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (0.50 g., 0.0014 mole) is added portionwise with stirring to chlorosulfonic acid (5 ml.) in an ice-water bath. The reaction mixture is stirred at 0° C. for 2 hours, left to come to ambient temperature for 2 hours, then slowly added to crushed ice to precipitate 0.51 g. of [1-oxo-2-(b 4-chlorosulfonylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 209°-210° C. after crystallization from acetic acid:water, 3:2.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[OH:30][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1nnc(O)nc1N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 200 mg (0.67 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile in 10 ml of dichloromethane was cooled to 0° C. and treated with 332 mg (1.35 mmol) of 3-chloro-perbenzoic acid (70%). The reaction mixture was warmed up to room temperature and stirred overnight. For the working-up, the reaction mixture was diluted with 10 ml of dichloromethane and extracted twice with 10 ml of a saturated solution of sodium hydrogencarbonate. The combined organic phases were dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue, 170 mg of a yellow powder, was purified by chromatograhy on silica gel with a 98:2 mixture of dichloromethane and methanol as eluent. There were obtained 154 mg (86% of theory) of 3-hydroxy-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a yellowish solid; MS: 266 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
A mixture of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (582 mg, 1.21 mmol) and 10% palladium on activated carbon (0.6 g) in methanol (200 mL) was heated at 50° C. under hydrogen (5 atm) for 5 h. After cooling, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to give {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (584 mg) which was used in the next step without purification: LC/MS m/e calcd for C26H33N3O4S [M+H]+ 484.63, observed 484.2.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][S-:45].[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][S:45][CH3:44])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
N-(4-((4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (100 mg, 0.17 mmol) was added portionwise to a stirred mixture of sodium thiomethoxide (35 mg, 0.50 mmol) in MeOH (5.0 mL) and the resulting mixture was stirred for 1 hr at RT. The mixture was evaporated in vacuo and partitioned between brine (20 mL) and DCM (30 mL). The organic layer was concentrated in vacuo, the residue pre-adsorbed on silica and purified by column chromatography (12 g, 10-100% EtOAc in iso-hexane, gradient elution). Product fractions were evaporated in vacuo to give N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(methylthio) acetamide (Example 6) as a light yellow solid (28 mg, 26%): m/z 610 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.26 (1H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.78 (1H, s), 10.60 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]#[N:11].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11]
Reactant: N#CC=Cc1ccccc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N#CCCc1ccccc1F
Yield: 96 %

Procedure:
A solution of the cis/trans mixture of 3-(2-fluorophenyl)acrylonitrile (9.36 g) in ethanol (100 mL) was treated with Pearlman's catalyst (palladium hydroxide, 1 g, 20% Pd by wt. dry) and the mixture shook vigorously under 60 p.s.i. hydrogen for 30 minutes. The mixture was filtered and the filtrate concentrated to afford 3-(2-fluorophenyl) propionitrile (9.11 g). GC/MS gave: m/z (rel.int.) 149 (M+, 19), 109 (100) and 83 (15).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15]CC2C=CC(OC)=CC=2)[CH2:12][N:11]1[S:25]([CH3:28])(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH2:1]([NH:8][CH2:9][C@H:10]1[N:11]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:12][C@H:13]([SH:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CNCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1CNCc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
(Method 2): 100 mg (0.24 mmol) of (2S,4R)-benzyl-[1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl]-amine was dissolved in 8.5 ml TFA and treated at 0° C. with 0.38 ml (2.38 mmol) triethylsilane. The reaction was warmed up over night, heated 1.5 h at 80° C. and evaporated, partitioned between water (10 ml)/Et2O (2×10 ml). The water was lyophilized to give 90 mg (91%) of (3R,5S)-5-(benzylamino-methyl)-1-methanesulfonyl-pyrrolidine-3-thiol trifluoro-acetate, MS: 301 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([Br:26])[CH:24]=5)[N:19]=[CH:18][C:17]4=[O:27])[CH2:12][CH2:13]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Br)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(Br)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To 20 mL of a chloroform solution containing 0.47 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-bromo-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 280 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-bromoquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[C:4]2[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH:18][CH:19]4[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)=[N:3][C:4]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCC(=O)CC1
Reactant: Clc1cccc(-c2cnn3ccc(Cl)nc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(Nc2ccn3ncc(-c4cccc(Cl)c4)c3n2)CC1
Yield: 23.2 %

Procedure:
A mixture of 5-chloro-3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.379 mmol), 4-aminocyclohexanone (43 mg, 0.379 mmol), and DIEA (0.158 ml, 1.515 mmol) in 2-propanol (3 ml) was irradiated to 150° C. for 14 h in a Biotage microwave. After cooling, the mixture was diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. After absorbing on celite, the compound was purified by chromatography (12 g silica, 0-15% methanol/DCM) to give 4-((3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexanone (30 mg, 24% yield) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]([O:52][CH3:53])=[O:51])[C:43]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]([O:52][CH3:53])=[O:51])[C:43]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COC(=O)CN1CCCC[C@H](N)C1=O
Product: COC(=O)CN1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(=O)OC)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(2-methoxy-2-oxoethyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 28 (5.0 mg, 0.025 mmol) to give a white solid (2.8 mg, 29% yield). Anal. Calcd. for C40H52N4O8S m/z 748.5. found: 749.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.28-7.08 (m, 10H), 5.53 (dd, J=6.3, 3.0 Hz, 1H), 5.03-4.95 (m, 2H), 4.65-4.55 (m, 1H), 4.25-4.15 (m, 1H), 4.08-4.01 (m, 1H), 3.72 (dd, J=15.4, 10.4 Hz, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.35 (d, J=2.7 Hz, 1H), 3.11-3.01 (m, 1H), 2.83 (ddd, J=14.3, 6.9, 3.0 Hz, 1H), 2.80-2.62 (m, 6H), 2.34 (d, J=13.7 Hz, 1H), 2.15-2.04 (m, 1H), 2.03-1.94 (m, 1H), 1.90-1.82 (m, 1H), 1.79-1.51 (m, 13H), 1.35-1.25 (m, 2H).