Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>ClCCl.CO>[Br:1][CH2:15][C:14]([C:10]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)C1(c2cccc(Cl)c2)CCC1
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)C1(c2cccc(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of bromine (9.9 ml) in dichloromethane (50 ml) was added dropwise at 10°-15° C. over 3 hours to a stirred solution of 1-[1-(3-chlorophenyl)cyclobutyl]-ethanone (38 g) in a mixture of methanol (75 ml) and dichloromethane (15 ml). When the addition was complete, the mixture was stirred at ambient temperature for 2.5 hours, then poured onto an excess of ice-water. The aqueous layer was separated and the product extracted into dichloromethane (3×90 ml). The combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 ml) and water (100 ml), dried over calcium chloride and the solvent removed in vacuo to leave 2-bromo-1-[1-(3-chlorophenyl)cyclobutyl]ethanone as an oil (47 g).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH3:17][C:18]#[N:19].Cl>C1(C)C=CC=CC=1>[CH:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3](=[O:14])[CH2:17][C:18]#[N:19])=[CH:9][CH:8]=1)([CH3:12])[CH3:13]
Reactant: COC(=O)c1ccc(OC(C)C)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(C(=O)CC#N)cc1
Temperature: 80 °C

Procedure:
To a solution of 4-Isopropoxy-benzoic acid methyl ester (2.2 g, 11.2 mmol, 1.0 eq) in dry toluene (15 mL) under N2, NaH (50-60% dispersion in mineral oil, 1.1 g, 22.4 mmol, 2.0 eq) was added. The mixture was heated at 80° C. and then dry CH3CN was added dropwise (2.8 mL, 56.0 mmol, 5.0 eq). The reaction was heated for 18 hours, then was allowed to cool down to room temperature and acidified with HCl 2N. The organic phase was recovered and 2.0 g of crude were obtained and it was used for cyclization without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:37]([NH:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH3:39]>>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:43][CH2:42][CH2:41][NH:40][CH2:37][CH2:38][CH3:39])[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCCNCCN
Product: CCCNCCNc1nc(-c2cc(C(=O)NC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound is prepared from N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and N-propyl-1,2-ethanediamine following the General Procedure for Sulfoxide/Sulfone Displacement, disclosed above. The concentrated reaction mixture is purified via reversed-phase HPLC. The desired product is obtained as a yellow solid (m.p. 120-134)>95% pure by HPLC (65 mg, 61%): LC-MS m/z 533 (M+H)+, 1.84 min (ret time).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[N-]=C=O>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[O:15])[N:17]([CH3:16])[NH2:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNN
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Agent: [N-]=C=O
Solvent: CCCCC
Product: CN(N)C(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 8.2 grams (0.0392 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask and cooled to 5° C. was added 1.82 grams (0.0392 moles) of methylhydrazine. The reaction was very rapid and exothermic and became quite viscous. The reaction mixture was diluted with pentane and stirred for an additional 60 minutes at room temperature. The pentane was evaporated under reduced pressure leaving 9.0 grams (90% crude yield) of a yellow solid. The product melted at 169°-171° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1660 cm-1 and a moderate NH band at 3320 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[F:11][C:12]([F:23])([F:22])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:11][C:12]([F:22])([F:23])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 102.6 %

Procedure:
A stirred mixture of 4-hydroxyacetophenone (0.9 g, 6.6 mmol), 4-(trifluoromethoxy)benzyl bromide (2.0 g, 7.8 mmol) and potassium carbonate (1.4 g, 10 mmol) in acetone (25 mL) was heated at reflux for 7 hours. The mixture was then cooled, diluted with H2O (50 mL) and extracted with EtOAc (2×100 mL). The organic portions were combined, washed with brine and dried (Na2SO4). Filtration and removal of solvent in vacuo afforded 2.1 g of a crude yellow semi-solid which was used without further purification.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([NH:30][C:31]2[C:36]([NH2:37])=[CH:35][N:34]=[C:33]([N:38]3[C:42]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]3)[N:32]=2)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:53](N2C=NC=C2)=[O:54])C=1>C1COCC1>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[C@H:22]([N:30]2[C:53](=[O:54])[NH:37][C:36]3[C:31]2=[N:32][C:33]([N:38]2[C:42]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:41]=4[N:40]=[CH:39]2)=[N:34][CH:35]=3)[CH2:21][CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2N)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](n2c(=O)[nH]c3cnc(-n4cnc5ccc(F)cc54)nc32)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
N4-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)pyrimidine-4,5-diamine (490 mg, 0.751 mmol, 1 equiv) was dissolved in anhydrous THF (15 mL) and CDI (737 mg, 4.54 mmol, 7 equiv) was added. The reaction was stirred at RT under argon overnight. The solvent was removed by evaporation. The residue was dissolved in EtOAc (30 mL) and washed with saturated NaHCO3, water and brine, dried (Na2SO4). The organic layer was evaporated to dryness. The residue was applied to ISCO (12 g column, MeOH—CH2Cl2 0-2%) to give a white solid product (420 mg, 82%). MS (ESI): 673.3
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (712 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as white powder (505 mg, yield 57%).
Reaction SMILES: C([O:8][C:9](=[O:44])[CH:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:35])[NH:26][O:27]CC3C=CC=CC=3)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:40]([O:39][C:37]([NH:36][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:35])[NH:26][OH:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)O
Yield: 71.6 %

Procedure:
Palladium on carbon (5%, 0.3 g) was added to a degassed solution of the benzyl hydroxamate 7 (0.4 g) in MeOH (25 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 8 (0.2 g, 72%). 1H NMR (DMSO-d6): 11.20 (s, 1H), 9.02 (br, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.10 (ddd, J=12.8 10.0, and 4.4 Hz, 1H), 3.03 (dd, J=13.6 and 4.4 Hz, 1H), 2.82 (dd, J=13.6 and 10.4 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:28])[C:19]([NH:21][C:22]3[CH2:23][O:24][C:25](=[O:27])[CH:26]=3)=[O:20])=[CH:10]2)=[CH:6][CH:5]=1.[CH3:31]I>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18](=[O:28])[C:19]([N:21]([CH3:31])[C:22]3[CH2:23][O:24][C:25](=[O:27])[CH:26]=3)=[O:20])=[CH:10]2)=[CH:29][CH:30]=1
Reactant: CI
Reactant: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12)C1=CC(=O)OC1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, sodium hydride (10 mg of a 60% wt/wt suspension in mineral oil) is added to a solution of 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-furanyl)acetamide (100 mg) in dry DMF (2 ml). After 20′, methyl iodide (0.016 ml) is added. After 3 h the solvent is removed by roto-evaporation and the obtained residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The obtained residue is suspended in boiling MeOH/i-PrOH 1/1. After cooling to room temperature the insoluble material is collected by filtration and oven-dried at 60° C. for 3 h, to give 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-methyl-2-oxo-N-(5-oxo-2,5-dihydro 3-furanyl)acetamide (52 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3cnco3)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 123 mg of (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.63 (s, 3H), 7.33 (m, 2H), 7.37 (s, 1H), 7.56 (m, 3H), 7.67-7.3 (m, 3H), 7.94 (m, 1H), 7.97 (s, 1H), 8.52 (b, 1H), 9.45 (s, 1H). MS: m/z 454.1 (M++1).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:7])=[O:6].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][CH:2]([CH3:23])[CH2:3][N:4]([CH2:9][C@@H:10]1[N:15]([C:25]2[N:26]=[CH:27][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:29][N:30]=2)[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]1)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 100 °C
Yield: 77.7 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1-piperazinecarboxylate (0.498 g, 1.42 mmol, step 1), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.479 g, 1.71 mmol, Intermediate D), DIPEA (0.75 mL, 4.3 mmol) and 1,4-dioxane (5 mL). The mixture was heated at 100° C. for 12 h and then cooled to room temperature and partitioned between water (50 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL) and the combined organic extracts were washed with saturated aqueous NaCl (60 mL) dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.655 g) as a light-yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[N+:9]([C:12]1[C:17]([CH:18]=O)=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)([O-:11])=[O:10]>C(O)C>[N+:9]([C:12]1[C:17]([CH:18]=[C:8]2[CH2:7][CH2:6][CH2:5][O:4][CH:3]2[CH2:2][NH2:1])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)([O-:11])=[O:10]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NCC1CCCCO1
Solvent: CCO
Product: COc1cc(C=C2CCCOC2CN)c([N+](=O)[O-])cc1OC

Procedure:
A solution of 2-aminomethyltetrahydropyran (51 g, 0.44 mole) and ethanol (50 ml) was slowly added to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (600 ml). The resulting solution was refluxed for 1.5 hrs and cooled overnight. The solution was concentrated to dryness and the oil was disolved in chloroform and washed with water. The chloroform extract was concentrated leaving a dark oil which crystallized upon standing. The solid was suspended in hexane and filtered (117 g. 95%), m.p. 89°-96°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: BrCCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
4-Fluorophenol (500 mg) and benzyl 4-bromobutyl ether (1.1 g) were dissolved in DMF (20 mL), and potassium carbonate (1.0 g) was added thereto at room temperature, followed by stirring at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 1-[4-(benzyloxy)butoxy]-4-fluorobenzene (851 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[S:9][C:10]([CH:31]=[O:32])=[CH:11][C:12]=1[S:13](=[O:30])(=[O:29])[N:14]([CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[O:18][CH2:19][O:20][CH3:21])[CH3:15])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)[C:44]2C=CC=[CH:40][C:39]1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[S:9][C:10]([C:31](=[O:32])[CH:39]([CH3:40])[CH3:44])=[CH:11][C:12]=1[S:13](=[O:30])(=[O:29])[N:14]([CH2:16][CH:17]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[O:18][CH2:19][O:20][CH3:21])[CH3:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: COCOC(CN(C)S(=O)(=O)c1cc(C=O)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCOC(CN(C)S(=O)(=O)c1cc(C(=O)C(C)C)sc1NC(=O)OC(C)(C)C)c1ccc(F)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Using (3-{[2-(4-fluorophenyl)-2-methoxymethoxyethyl]methylsulfamoyl}-5-formylthiophene-2-yl)carbamic acid t-butyl ester (200 mg), isopropyl group was introduced in the same way as Preparation Example 87, and a crude alcohol was obtained. Dess-Martin reagent (204 mg) was added to a solution of this compound in dichloromethane (2 mL). After stirring for 1 hour, an aqueous solution of saturated sodium bicarbonate and an aqueous solution of sodium thiosulfate were added, and the solution was extracted with ethyl acetate. After washing with saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. The solution was filtered through a small amount of silica gel, and the title compound (180 mg) was obtained as an orange oily substance.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH3:25])[CH:16]=2)=[N:11][CH:12]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH3:25])[CH:16]=3)=[N:11][CH:12]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(C#Cc2ccc(Br)cn2)ccc1OCCO
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
40 mL of 2 N aqueous sodium bicarbonate solution was added to a suspension of 13.20 g (39.74 mmol) of 2-[4-(5-bromopyridin-2-ylethynyl)-2-methylphenoxy]ethanol, 9.32 g (59.60 mmol) of 4-chlorophenylboric acid, and 2.30 g (1.99 mmol) of tetrakis(triphenylphosphane)palladium in 400 mL of 1,4-dioxane and the mixture was refluxed for 12 hours. Another 4.66 g of 4-chlorophenylboric acid and 1.14 g of tetrakis(triphenylphosphane)palladium were added and the mixture was refluxed for 8 hours. The reaction mixture was evaporated down in vacuo and the residue was stirred with EtOAc and water. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo. Yield: 10.70 g (74% of theoretical); C22H18ClNO2 (M=363.837); calc.: molpeak (M+H)+: 364/366 (Cl); found: molpeak (M+H)+: 364/366 (Cl); Rf value: 0.47 (silica gel, DCM/EtOAc 2:1).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12]([O:16][C:17]([N:19]1[C@@H:27]2[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:21][C@H:20]1[CH2:28][NH2:29])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[C@@H:27]2[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:21][C@H:20]1[CH2:28][NH:29][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCCC[C@@H]21
Reactant: O=Cc1cc2ccccc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3s2)C[C@@H]2CCCC[C@@H]21

Procedure:
Experimental conditions analogous to Example 1, from 0.1 g (0.63 mmol) of benzo[b]thiophene-2-carbaldehyde, 0.16 g (0.63 mmol) of (2S,3aS,7aS)-2-aminomethyl-octahydro-indole-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, and 0.2 g (0.94 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (ethyl acetate in hexane), yield 130 mg of the free base as colorless oil. LC-MSD, m/z for C23H32N2O2S [M+H]+: 401.6, [M+H-isobutylene]+: 345.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12](=O)[CH3:13])[C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.O>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:12]([CH3:13])=[CH:11]2
Reactant: Nc1cccnc1
Reactant: CC(=O)Cc1cccc(F)c1C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2cccc(F)c2c(=O)n1-c1cccnc1
Yield: 16.3 %

Procedure:
2-Fluoro-6-(2-oxo-propyl)-benzoic acid (12.33 g, 31.43 mmol) and 3-aminopyridine (5.12 g, 54.4 mmol) in 25 mL dioxane were refluxed overnight. The reaction mixture was poured into water (250 mL). The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over MgSO4 and filtered through a pad of silica gel. The silica gel pad was washed with 250 mL ethyl acetate. The organic fractions were combined and rotavaped. The crude product was flash chromatographed on silica gel (eluent: 50% heptane/ethyl acetate to ethyl acetate) to obtain the product as a pale pink solid (1.3 g, yield 16.3%). LC-MS (m/z) 255.5 (MH+); tR=0.64. 1H NMR (500 MHz, CDCl3): 1.99 (s, 3H, Me), 6.43 (s, 1H), 7.07 (dd, J=8.12 Hz, J=11.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.49 (dd, J=4.9 Hz, J=8.1 Hz, 1H), 7.58 (td, J(d)=4.8 Hz, J(t)=8 Hz, 1H), 7.64 (unresolved dt, J(d)=8.1 Hz, J(t)=ca. 1.5 Hz, 1H), 8.53 (d, J=2 Hz, 1H), 8.71 (d, J=4.8 Hz, J=0.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:15]3[CH:37]=[CH:38][CH:39]=[CH:40][C:14]=3[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1ccc(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(4-n-butoxyphenyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.