Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([C:42](=[O:44])[CH3:43])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:9][C@@H:8]1[CH3:35])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(n1)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O)C[C@H](C)N2C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
Cool to 0° C. a suspension of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) and pyridine (0.203 mL, 2.52 mmol) in dichloromethane (3 mL) under nitrogen. Add acetic anhydride (0.117 mL, 1. 247 mmol) dropwise. After the addition is complete, remove the cooling bath and warm the reaction to room temperature with stirring for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with saturated aqueous sodium bicarbonate (25 mL). Dry the organic layer over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue using silica gel chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-30% ethyl acetate in hexane), to afford the title compound (0.196 g, 88%). MS (ES+): 548 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[C:3]([CH3:11])=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Cc1cc2nccn2nc1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2ncc(Br)n2nc1Cl
Yield: 69.8 %

Procedure:
The 6-chloro-7-methylimidazo[1,2-b]pyridazine 8 (0.230 g, 1.372 mmol) was taken in glacial acetic acid (10 ml) and bromine (0.070 ml, 1.372 mmol) was added slowly at room temperature. After 20 mins the solvents were evaporated the obtained brown solid was washed with ether (3×15 ml) and dried under air to furnish compound 9 (0.236 g, yield 69.8%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[C:12]([CH3:21])[CH:11]=1.CCN(C(C)C)C(C)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH:46]1[CH2:48][CH2:47]1)[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:35])([CH3:34])[CH3:33]>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:43]2[CH2:42][CH2:41][CH:40]([CH2:39][N:38]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])[CH:46]3[CH2:48][CH2:47]3)[CH2:45][CH2:44]2)=[O:20])=[C:12]([CH3:21])[CH:11]=1
Reactant: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)N(CC1CCNCC1)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)C3CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Oxalyl chloride (1.26 ml, 14.4 mmol) was added to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (1.60 g, 7.2 mmol) in dichloromethane (50 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (50 ml) and DIEA (2.5 ml, 14.4 mmol) and cyclopropyl-piperidin-4-ylmethyl-carbamic acid tert-butyl ester from Example E38 (1.83 g, 7.2 mmol) in dichloromethane (5 ml) was added. The mixture was stirred for 2 h at room temperature, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (1.42 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:14].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]([N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)[CH3:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of tert-butyl 4-[1-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-ethyl]piperazine-1-carboxylate (0.091 g, 0.24 mmol) in methanol (3.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.039 g, 0.27 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (100:0→97:3)) to obtain tert-butyl (Z)-4-(1-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperazine-1-carboxylate (0.10 g, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:34]=1[CH2:35]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C.C(OCC)C>[CH3:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:34]=1[CH2:35][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cccc(C)c1CO
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 3-hydroxybenzoate (12.21 g, 73.47 mmol) and triphenylphosphine (21.01 g, 80.13 mmol) in dry THF (100 ml) was added dropwise a solution of 2,6-Dimethylbenzyl alcohol (10 g, 73.5 mmol) and diisopropyl azodicarboxylate (16.19 g, 80.13 mmol) in dry THF (35 ml) and dry DMF (15 ml) at ambient temperature. After three hours of stirring at room temperature, the reaction mixture was diluted with diethyl ether and washed twice with water and brine. The combined organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography using ethyl acetate:hexane (1:3) as elutent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[O:17][C:18]1[C:23]2[C:24]([O:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]4([OH:42])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:31][CH2:30]3)=[N:25][O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl.O>[OH:42][C:36]1([CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([CH2:28][O:27][C:24]3[C:23]4[C:18]([O:17][CH:13]5[CH2:14][CH2:15][CH2:16][C:12]5=[O:11])=[CH:19][CH:20]=[CH:21][C:22]=4[O:26][N:25]=3)[CH2:30][CH2:31]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: O[C@@H]1CCC[C@H]1Oc1cccc2onc(OCC3CCN(CC4(O)CCOCC4)CC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCC1Oc1cccc2onc(OCC3CCN(CC4(O)CCOCC4)CC3)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of oxalyl chloride (9 μL, 0.1 mmol) in dichloromethane (0.5 mL) was added dimethylsulfoxide (9 μM, 0.12 mmol) at −78° C. under nitrogen. The mixture was stirred for 5 min, a solution of 4-({4-[({4-[(trans-2-Hydroxycyclopentyl)oxy]-1,2-benzisoxazol-3-yl}oxy)methyl]-piperidin-1-yl}methyl)tetrahydro-2H-pyran-4-ol (EXAMPLE 32) in dichloromethane (1.5 mL) was added to the mixture. After being stirred for 5 min, triethylamine (45 μL, 0.33 mmol) was added to the mixture. The mixture was allowed to warmed to room temperature and stirred for 3 h. Water was added to the mixture and the mixture was extracted with ethyl acetate and washed with brine. The extract was dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (dichloromethane/methanol 20:1) to give 13 mg (45%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[F:16])=[O:6]
Reactant: Nc1ccccc1F
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1F
Yield: 33.9 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.1 mmol) in benzene (60 mL), followed by 2-fluoroaniline (2.3 mL, 23.4 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 1.05 g of a yellow solid (34%). 1H NMR (CDCl3) δ: 8.45 (t, J=8.0 Hz, 1H); 8.01 (br s, 1H); 7.02-7.22 (m, 4H); 6.78 (dd, J=0.5, 7.9 Hz, 1H); 6.64 (dd, J=0.8, 8.2 Hz, 1H); 4.73 (br s, 2H). MS (ES): m/z 265.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1F.[F:26][C:27]([F:33])([F:32])[C:28]([CH3:31])([OH:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:23]([F:24])=[CH:22][C:14]([C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])=[C:13]([F:25])[CH:12]=2)[CH:5]=[N:6][C:7]=1[O:30][C:28]([CH3:31])([CH3:29])[C:27]([F:33])([F:32])[F:26]
Reactant: CC(C)(O)C(F)(F)F
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(COc2cnc(F)c(Cl)c2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(Oc1ncc(OCc2cc(F)c(C(=O)NS(C)(=O)=O)cc2F)cc1Cl)C(F)(F)F
Temperature: 100 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 4-{[(5-chloro-6-fluoropyridin-3-yl)oxy]methyl}-2,5-difluoro-N-(methylsulfonyl)benzamide (Example 23, 0.092 g, 0.233 mmol) in DMSO (1.0 mL) were added 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) and caesium carbonate (0.305 g, 0.936 mmol). The mixture was stirred at 100° C. in a pressure vial for 16 hours. Then 1,1,1-trifluoro-2-methylpropan-2-ol (0.120 g, 0.937 mmol) was added to the mixture and heated at 125° C. for another 24 hours. The reaction mixture was diluted with EtOAc (15.0 mL), washed with water (10.0 mL), aqueous citric solution (10%, 10.0 mL) and water (2×10.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was suspended in a mixture of heptane and acetone (8:2, 5.0 mL) and sonicated for 2 minutes. The mixture was filtered to yield the title compound as an off-white solid (0.023 g, 20%).
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([CH2:17][CH3:18])=[C:11](C)[N:10]=1.O>CN(C)C=O>[C:1]([S:5][C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S
Reactant: CCc1cc(C#N)c(Cl)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(SC(C)(C)C)c(C#N)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
t-Butylmercaptan (0.40 mL, 3.55 mmol) was added to a suspension of 60% sodium hydride in mineral oil (158 mg, 3.85 mmol) in dry dimethylformamide (5 mL). After 10 minutes, when gas evolution ceased, 2-chloro-3-cyano-5-ethyl-6-methylpyridine (542 mg, 3.0 mmol) was added. After stirring for one hour, water was added and product extracted into diethyl ether. This extract was dried (Na2SO4), filtered and the solvent removed to give 648 mg (92%) of crystalline product, m.p. 63°-66° C.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COP(=O)(CCC(N)C(=O)O)Oc1cccc(CC(=O)O)c1
Yield: 51.2 %

Procedure:
Next, 0.72 g (1.12 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(benzyloxycarbonylmethyl)phenyl](methyl)phosphono}butanoate was dissolved in 24 mL of a solvent mixture of methanol and water at 5:1 and mixed with 200 mg of 5% palladium-carbon, and hydrogen gas was introduced at room temperature for 2.5 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated and the residue was freeze-dried from water to obtain 2-amino-4-{[3-(carboxymethyl)phenyl] (methyl)phosphono}butanoic acid (0.19 g, yield 51%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C1C(=O)N([Cl:20])C(=O)C1.CN(C=O)C.C(Cl)Cl>CCOC(C)=O.CCCCCC>[Cl:20][C:7]1[C:2]([OH:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][C:6]=1[CH2:8][O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1cc(O)nc(SC)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COCc1nc(SC)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of 4-hydroxy-6-methoxymethyl-2-(methylthio) pyrimidine (10.0 g, 53.7 mmol), NCS (14.34 g, 107 mmol), DMF (10 mL) and CH2Cl2 (200 mL) was stirred at room temperature for 4 h. TLC (EtOAc/hexane 40:60) showed no starting material left. The solvent was removed. The final product was recrystallized from EtOAc. The mother liquid was purified by column chromatography on silica gel using EtOAc/hexane=40:60 as the eluent.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:8]2=[N:9][C:10]([CH3:17])=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4]1.[CH2:18]1COCC1.[H-].[Na+].CI>C(OCC)(=O)C.O.CN(C)C=O>[CH3:18][O:1][N:2]=[C:3]1[C:8]2=[N:9][C:10]([CH3:17])=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=[C:7]2[CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1cc2c(nc1C)C(=NO)CCC2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CON=C1CCCc2cc(C(=O)OC)c(C)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
In an atmosphere of argon, methyl 8-hydroxyimino-2-methyl-5,6,7,8-tetrahydrocyclohexa[b]pyridine-3-carboxylate (1.01 g, 4.33 mmol) was suspended in a mixed solution of THF (5.0 ml) and dimethylformamide (DMF) (1.5 ml) at 0° C., and the suspension was mixed with sodium hydride (192.0 mg, 4.80 mmol) and stirred at room temperature for 1.5 hours. To this was added dropwise methyl iodide (192.0 mg, 4.80 mmol) at room temperature, followed by 2 hours of stirring. The reaction solution was diluted with ethyl acetate, mixed with water and then extracted with ethyl acetate. The thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain the title compound (801.4 mg, 74.5%) as pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[Br:25]N1C(=O)CCC1=O>O1CCCC1>[Br:25][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[N:13]([S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cn1
Solvent: C1CCOC1
Product: Cn1cc(-c2cnc3c(c2)c(Br)cn3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.832 g, 2.46 mmol) in tetrahydrofuran (12.3 ml) was added N-bromosuccinimide (0.875 g, 4.92 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 10% aqueous sodium thiosulfate solution (50 mL), then extracted with EtOAc (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was adsorbed on to silica gel and purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a white solid. LRMS (ESI) calculated for C17H13BrN4O2S [M+H]+, 417.0; found 417.0.
Reaction SMILES: [Mg].[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Cl)[NH:5][N:4]=1.C(Br)(C)C.O=O.C(=O)=[O:20].S(=O)(=O)(O)O>O.C(OCC)C>[NH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:20])[NH:5][N:4]=1
Reactant: O=C=O
Reactant: Nc1n[nH]c2cccc(Cl)c12
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CC(C)Br
Solvent: CCOCC
Product: Nc1n[nH]c2cccc(O)c12
Reaction time: 12 h
Yield: 42 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 1.68 g of 3-amino-4-chloroindazole prepared by the method as described in Beck. Gunkther et al., Justus Liebigs Ann. Chem., 716, 47(1968), 2.06 g of isopropyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 0.626 g of 3-amino-4-hydroxyindazole having the following analytical values in a yield of 42%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:3]=1.CCN(CC)CC.[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:3]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])([CH3:19])[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cncc(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cncc(C#C[Si](C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A solution of 2-chloro-6-(4-isopropylsulfonylphenyl)pyrazine (320 mg, 1.078 mmol) in anhydrous toluene (5 mL) was degassed and placed under an atmosphere of nitrogen. Pd(PPh3)2Cl2 (60.53 mg, 0.08624 mmol) and CuI (16.42 mg, 0.08624 mmol) were added and the reaction was again degassed under nitrogen. Et3N (109.1 mg, 150.3 μL, 1.078 mmol) as added followed by the quick addition of TMS-acetylene (116.5 mg, 167.6 μL, 1.186 mmol). After an initial exotherm the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 20% EtOAc/Petroleum Ether) to give the sub-title product as an off-white solid (192 mg, 50% Yield). 1H NMR (400.0 MHz, DMSO) δ 9.21 (s, 1H), 8.67 (s, 1H), 8.25 (d, 2H), 7.86 (d, 2H), 3.35 (sept, 1H), 1.03 (d, 6H) and 0.15 (s, 9H) ppm; MS (ES+) 359.1
Reaction SMILES: Cl[CH2:2][S:3]([NH:6][C:7]1[C:28]([OH:29])=[CH:27][C:10]2[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[OH-].[Na+].[Cl-].[NH4+]>CO>[CH3:15][C:13]1([CH3:16])[CH:12]([OH:17])[CH:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:9](=[CH:8][C:7]3[NH:6][S:3](=[O:5])(=[O:4])[CH2:2][O:29][C:28]=3[CH:27]=2)[O:14]1
Reactant: CC1(C)Oc2cc(NS(=O)(=O)CCl)c(O)cc2[C@H](NCCc2ccccc2)[C@H]1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc3c(cc2C(NCCc2ccccc2)C1O)OCS(=O)(=O)N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 1-Chloro-N-{(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl}methanesulfonamide (220 mg, 0.50 mmol) in methanol (2.2 mL), 1 mol/L sodium hydroxide aqueous solution (1.00 mL, 1.00 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. Then, the temperature was raised to 50° C., and the mixture was further stirred for 2 hours. Upon the completion of the reaction, the solution was cooled on standing, neutralized with saturated ammonium chloride aqueous solution, extracted 4 times with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off and the aimed product was obtained (yield: 37%).
Reaction SMILES: II.[Mg].Br[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](C#N)([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C(OCC)C.C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]([N:23]([CH3:25])[CH3:24])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cccs1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A little iodine was added to a mixture of 5.6 g (3 eq.) magnesium and 20 ml dry diethyl ether, followed over a period of 10 min by 5 g 2-bromothiophene, and the mixture was stirred for a further 10 min. Once the reaction had started, 33.5 g (2.6 eq.) 2-bromothiophene dissolved in 80 ml diethyl ether were added dropwise and the mixture was stirred for a period of 2 h at room temperature. The Grignard reagent prepared in the preceding step was added dropwise to a solution of 20 g (1 eq.) tert-butyloxycarbonyl-4-cyano-4-(dimethylamino)piperidine dissolved in 200 ml THF and stirred overnight at room temperature. Once the conversion was complete, the reaction solution was cooled to 0° C., mixed with saturated NH4Cl solution, extracted with ethyl acetate (3×100 ml) and the combined organic phases were dried with Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (alox neutral; 30% EtOAc/hexane). 6.1 g (25%) of product were obtained in the form of a white solid.