Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[C:26]4=[N:27][C:28]([N:31]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]5)=[CH:29][N:30]=[C:25]4[N:24]=[N:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[C:26]4=[N:27][C:28]([N:31]5[CH2:35][CH2:34][C:33](=[O:36])[CH2:32]5)=[CH:29][N:30]=[C:25]4[N:24]=[N:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OC1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (1.5 mL, 17 mmol) in dichloromethane (15 mL) was added dimethyl sulfoxide (2.45 mL, 34.5 mmol) drop wise keeping T<−70° C. After 30 minutes, a suspension of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-ol (1.00 g, 2.88 mmol) in dichloromethane (35 mL) was added keeping T<−70° C. After 1 hour 15 minutes, triethylamine (3.61 mL, 25.9 mmol) was added slowly, the dry-ice bath was removed, and the reaction was stirred for 2 hours. The reaction was quenched with water (50 mL), diluted with dichloromethane (150 ml), and separated. The aqueous layer was extracted with dichloromethane (2×50 mL) and the organics were combined and concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 40M column eluting with chloroform/methanol (0.5-8%) to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-one (401 mg, 40%).
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12]([CH3:2])([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1
Reactant: C1CCOC1
Reactant: CC1Cc2ncc(Cl)cc2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Reaction time: 0.33 h

Procedure:
To a tetrahydrofuran solution (161 ml) of tert-butyl 4-(7-chloro-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (10.7 g) was added dropwise at −78° C. lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 31.0 ml). After stirring at the same temperature for 15 minutes and under ice cooling for 20 minutes, a tetrahydrofuran solution (54 ml) of methyl iodide (2.10 ml) was added dropwise. After stirring at the same temperature for 10 minutes and at room temperature for 30 minutes, ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (9.31 g).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Cl:13][C:14]1[N:19]=[C:18]2[S:20][N:21]=[C:22]([CH3:23])[C:17]2=[CH:16][CH:15]=1.[Br:24]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:23][C:22]1[C:17]2[C:18](=[N:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[S:20][N:21]=1
Reactant: Cc1nsc2nc(Cl)ccc12
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(CBr)nsc2n1
Temperature: 80 °C

Procedure:
AIBN (1.35 mmol) was added to a solution of 6-chloro-3-methylisothiazolo[5,4-b]pyridine (13.5 mmol) and N-bromosuccinamide (27.1 mmol) in carbon tetrachloride (25 mL). The reaction mixture was heated at 80° C. for 6 h, allowed to cool to rt, and the precipitated solids were removed by filtration. The filtrate was concentrated to provide crude 3-(bromomethyl)-6-chloroisothiazolo[5,4-b]pyridine as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][CH2:31][CH:32]1[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:33]1>ClCCl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH:32]2[O:37][CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH2:33]2)=[O:8])=[C:4]([O:12][CH2:13][CH3:14])[CH:3]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccc(F)cc2)CCO1
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-2-ethoxybenzoic acid (2.9 g) in dichloromethane (50 ml), triethylamine (1.6 g) is added at 25° C. The resulting mixture is cooled to -10° C., and isobutyl chloroformate (2.0 g) is added slowly. After the mixture is stirred at the same temperature for 1 hour, a solution of 2-aminomethyl-4-(4-fluorobenzyl)morpholine (3.0 g) in dichloromethane (10 ml) is added. The reaction mixture is stirred for 1 hour at a temperature of between -10° C. and -5° C. and then at 25° C. overnight. The mixture is washed successively with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue is recyrstallized from ethanol to give the title compound (4.1 g), mp 151°-153° C.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[SH:13][CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:18]([CH:14]1[CH2:15][CH2:16][O:17][C:4]2[C:5]3[C:10]([C:1](=[O:12])[C:2](=[O:11])[C:3]=2[S:13]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH3:20]
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: CCCC(S)CCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CCOC2=C(S1)C(=O)C(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of naphthalene-1,2-dione (1.5 g, 9.5 mmol) in acetonitrile (50 mL) was added 3-mercaptohexan-1-ol (1.6 g, 11.9 mmol) followed by the addition of diisopropylethylamine (1.65 mL, 9.5 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL). The organic layer was washed with water (30 mL), dried with sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (35 mL) and reacted with p-toluenesulfonic acid (1.9 g). The reaction mixture was stirred at room temperature for 40 min and solvent removed under reduced pressure. Crude product was purified by flash column (5% EtOAc in hexane to 15% EtOAc in hexanes) to give product as purple solid (0.170 g). M.p.=74-75° C. (decomposition); 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=7.2 Hz, 1H), 7.73 (m, 2H), 7.56 (m, 1H), 5.08 (m, 1H), 4.67 (m, 1H), 3.58 (m, 1H), 1.40-1.82 (m, 6H), 0.89 (brt, 3H); LCMS: 289 [M+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17](CC)[C:18](O)=O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([O-:26])(=O)[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:17][CH2:18][CH2:24][C:23]3=[O:26])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CCC(NS(=O)(=O)c1ccc(N2CCOCC2)cc1)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCN1S(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
6.2 g of product obtained in Stage A, 6.2 g of sodium acetate and 124 cm3 of acetic anhydride are heated to reflux for 4 hours. After cooling to ambient temperature and evaporating to dryness, the residue is taken up with 50 cm3 of water, filtered, washed with 10 cm3 of water and dried. 5.65 g of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]=[C:13]=[O:14])[CH:8]=[CH:7][CH:6]=2.[N:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C.CC#N>C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:13]([NH:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:28][CH:27]=1)=[O:14])[CH:8]=[CH:7][CH:6]=2
Reactant: O=C=Nc1cccc2cnc(Cl)cc12
Reactant: NCc1ccc(N2CCOCC2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(N2CCOCC2)cc1)Nc1cccc2cnc(Cl)cc12
Reaction time: 3 h

Procedure:
The product from Example 176A in diethyl ether (40 mL) was treated with the product from Example 172B (300 mg, 1.56 mmol) and triethylamine (3 mL) in 1:1 diethyl ether:CH3CN (10 mL). After stirring for 3 hours, the mixture was filtered, and the collected solid was washed with diethyl ether. The solid was purified by silica gel chromatography (95:5 CH2Cl2:MeOH) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.37 (d, 1H, J=6.7 Hz), 8.08 (s, 1H), 7.79 (d, 2H, J=8.2 Hz), 7.63 (t, 1H), J=8.0 Hz), 7.23 (d, 2H, J=8.7 Hz), 6.94 (d, 2H, J=8.4 Hz), 6.91 (t, 1H, 5.5 Hz), 4.26 (d, 2H, 5.7 Hz), 3.73 (m, 4H), 3.07 (m, 4H); MS (ESI+) m/z 397/399 (M+H, 35Cl/37Cl).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]1([CH2:14][N:15]2[CH:19]=[C:18]([C:20](OCC)=[O:21])[C:17]([C:25](OCC)=[O:26])=[CH:16]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>C(O)C>[CH3:1][N:2]1[C:25](=[O:26])[C:17]2=[CH:16][N:15]([CH2:14][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH:7]=[CH:6][CH:5]=3)[CH:19]=[C:18]2[C:20](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)OCC
Reactant: CNN
Solvent: CCO
Product: Cn1[nH]c(=O)c2cn(Cc3cccc4ccccc34)cc2c1=O
Temperature: 200 °C

Procedure:
Methyl hydrazine (0.55 ml) was added to a solution of diethyl 1-(1-naphthalenylmethyl)pyrrole-3,4-dicarboxylate (1.00 g) in ethanol (10 ml). The mixture was heated at 200° C. in a sealed tube for 3 days. The mixture was evaporated and the residue was purified by column chromatography, eluting with ethyl acetate:methanol (19:1). The resulting solid was suspended in ethyl acetate (25 ml), heated to reflux, and allowed to cool to ambient temperature. The title compound (0.105 g) was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:21])[CH:11]([OH:20])[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Bi]=O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:21])[C:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)C(O)c2ccc(SC)cc2)cc1F
Agent: O=[Bi]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=O)c2ccc(SC)cc2)cc1F
Temperature: 90 °C
Yield: 32.5 %

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-hydroxy-2-[4-(methylthio)phenyl]ethanone from step 2 (6.5 mmol, 2.00 g) was diluted with glacial acetic acid (30 mL). Bismuth oxide (11.4 mmol, 5.30 g) was added and the mixture was heated at 90° C. for 2 hours. The crude mixture was filtered through Celite® filter agent, lyophilized and subjected to chromatography, affording the title compound as a yellow solid (642 mg, 32%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][N:25]4[CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:12])([F:14])[F:13]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4CCC(N)=O)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(-c2nc(-c3cccc4c3ccn4CCC(N)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 46.5 %

Procedure:
To a solution of 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-indol-1-yl)propanamide (100 mg) in chloroform (1 ml) was added manganese dioxide (67.6 mg), followed by reflux for 15 hours. The reaction solution was left to be cooled to room temperature, and filtered through Celite to remove manganese dioxide. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain 3-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl) propanamide (46.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[C:24]2[S:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20].Br[C:31]1[N:32]=[C:33]([C@H:41]2[CH2:46][CH2:45][C@H:44]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)[CH2:43][CH2:42]2)[N:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=12>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:31]2[N:32]=[C:33]([C@H:41]3[CH2:42][CH2:43][C@H:44]([N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)[CH2:45][CH2:46]3)[N:34]3[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=23)[CH:6]=[CH:5][C:4]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[C:24]2[S:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccsc2n1C
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2ccsc2n1C

Procedure:
Reaction of N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (32 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (13 mg)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:24]C(=O)OCC2C=CC=CC=2)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:24][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)=[C:9]([OH:8])[CH:10]=1
Reactant: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2ccc(N)cc2O)cc1
Reaction time: 11 h
Yield: 76.6 %

Procedure:
To a solution of 3-benzyloxy-4-(4-ethylbenzyl)benzoic acid (1.4 g) and triethylamine (1.3 mL) in 1,4-dioxane (10 mL) was added diphenylphosphoryl azide (1.3 g) in 1,4-dioxane (10 mL), and the mixture was stirred at 100° C. for 1 hour. Benzyl alcohol (1.6 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 7 hours. The solvent of the reaction mixture was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give benzyl N-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]carbamate (1.4 g). To a solution of the obtained benzyl N-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]carbamate (1.4 g) in methanol (15 mL) was added 10% palladium-carbon powder (0.28 g), and the mixture was stirred under a hydrogen atmosphere for 11 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 5-amino-2-(4-ethylbenzyl)-phenol (0.54 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([C:2]2[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1cnc(N)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Temperature: 100 °C

Procedure:
3-Bromo-5-methylpyridin-2-amine (0.5 g, 2.7 mmol), 3,4-difluorophenylboronic acid (0.5 g, 3.2 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.1 g, 0.1 mmol) were dissolved in a mixture of dioxane (10 mL) and 1M aqueous sodium carbonate solution (8 mL) under argon and the mixture was heated to 100° C. for 1 hour. The reaction was diluted with ethyl acetate, separated and the organic layer was washed with brine, dried with sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-heptane/ethyl acetate (v/v 1:1) as eluent. The title compound was obtained as a light brown crystalline solid (0.6 g, quant.).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:19]=[CH:18][S:17][C:16]=1[CH:20]=[O:21]>CS(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=Cc1sccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1sccc1Sc1ccncc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A mixture of 4-mercaptopyridine (1.0 g), potassium carbonate (3.7 g) and dimethyl sulfoxide (10 mL) at 0° C. was treated with 3-chlorothiophene-2-carbaldehyde (1.3 g), and the resulting mixture was stirred at room temperature for 20 hours. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and petroleum ether (1:9 to 3:2 by volume) to afford the title compound as yellow oil (1.3 g).
Reaction SMILES: O[CH:2]([N:15]1[C@H:18]([S:19][CH2:20][C:21]([CH:23]2[CH:27]([CH3:28])[CH2:26][CH2:25][O:24]2)=[O:22])[C@H:17]([NH:29][C:30](=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:39])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[Cl-].S(Cl)(Cl)=O.N1C(C)=CC=CC=1C.[CH2:53]([P:57]([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:58][CH2:59][CH2:60][CH3:61])[CH2:54][CH2:55][CH3:56]>O1CCCC1.O1CCOCC1>[C:32]1([CH2:31][C:30]([NH:29][C@H:17]2[C@@H:18]([S:19][CH2:20][C:21]([CH:23]3[CH:27]([CH3:28])[CH2:26][CH2:25][O:24]3)=[O:22])[N:15]([C:2](=[P:57]([CH2:58][CH2:59][CH2:60][CH3:61])([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:53][CH2:54][CH2:55][CH3:56])[C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)=[O:4])[C:16]2=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCCCP(CCCC)CCCC
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2OCCC2C)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O=S(Cl)Cl
Product: CCCCP(CCCC)(CCCC)=C(C(=O)OCc1ccc(OC)cc1)N1C(=O)[C@@H](NC(=O)Cc2ccccc2)[C@H]1SCC(=O)C1OCCC1C
Yield: 47 %

Procedure:
4-Methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-3-phenylacetamido-4-[(2RS,3SR)-3-methyltetrahydrofuran-2-ylcarbonylmethylthio]azetidin-2-on-1-yl]acetate (10.406 g) was converted to it's chloride with thionyl chloride (3.34 g, 2.02 ml) and 2,6-lutidine (3.009, 3.25 ml) in tetrahydrofuran (100 ml) as described in Example 6(c). The crude chloride in dioxan (80 ml) was then converted to the product with tri-n-butylphosphine (6.98 ml) also described in 6(c). Flash chromatography on silica gel afforded the title compound as a foam (6.525 g, 47%). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (763)].
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)=[CH:25][CH:26]=1
Reactant: Nc1ncccc1Br
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (12.5 g) was added to a suspension of 3-bromopyridin-2-amine (31.2 g), 4,4,5,5-tetramethyl-2-[4-(4-methylphenoxy)phenyl]-1,3,2-dioxaborolane (72.8 g) and sodium carbonate (38.3 g) in 1,2-dimethoxyethane (500 mL) and water (250 mL) and the mixture was stirred at 100° C. under N2 for 16 hr. The mixture was diluted with water at room temperature and extracted with EtOAc-THF (3:1). The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give a crude product, which was washed with diisopropyl ether to give the title compound (35.2 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46](CN2C=CC(N)=N2)=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)=[CH:45][CH:44]=1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (117 mg, 74%) as a white solid: ESI-LRMS m/e calcd for C25H27C12N3O3S [M+] 519.1, found 520.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.40-1.93 (m, 8H, 4×CH2), 2.09-2.31 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.51-3.60 (m, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.06 (d, Jo=8.3 Hz, 2H, Ar), 7.26-7.33 (m, 3H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.88-8.36 (m, 2H, Ar and NH).