Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]([C:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH3:19])[C:13]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:12]=2[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)([CH2:7][CH2:8][CH3:9])[C:4]([O-:6])=[O:5])C.[OH-].[Na+]>CO.C(O)C>[O:16]=[C:15]1[N:14]([CH2:17][CH2:18][CH3:19])[C:13]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:12]=2[C:11]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[C:10]1[CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5]
Reactant: CCCn1c(=O)c(C(CC)(CCC)C(=O)[O-])c(-c2ccc(C)cc2)c2c3c(sc21)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(-c2ccc(C)cc2)c2c3c(sc2n(CCC)c1=O)CCCC3
Temperature: 90 °C
Yield: 22.6 %

Procedure:
To a suspension of ethyl[2-oxo-1-propyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.071 g; 0.152 mmol) in a mixture of methanol and ethanol (2:1) (4.5 mL) was added a 5% sodium hydroxide solution (3.66 mL; 4.57 mmol) and the reaction mixture was heated to 90° C. for 7 h. The organic volatiles were removed under reduced pressure and the remaining basic solution was acidified to pH 2 with a 1N hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organics were combined, dried over sodium sulfate, concentrated under reduced pressure. Purification by preparative HPLC (method 2) furnished 0.015 g (22.7%) of 2-[2-oxo-1-propyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoic acid as a white solid. ESI/APCI(+): 438 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[S:10][C:9]([CH:11]([N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH3:12])=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(c1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica yielded 300. NMR: (CDCl3): 1.44 (3H, d, J 7.1, Me), 2.52-2.64 (4H, m, CH2), 2.73 (3H, s, Me), 3.21-3.23 (4H, m, CH2), 3.80-3.83 (4H, m, CH2), 3.94-4.06 (5H, m), 5.16 (2H, s, NH2) and 9.20 (2H, s, Ar). MS: (ESI+): MH+=505.20
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([O:12][CH2:18][CH3:19])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCCC(=O)OCC
Temperature: 20 °C
Reaction time: 4 h

Procedure:
n-Decanoic acid (17.2 g), 36N aqueous sulphuric acid solution (3 cc) and ethanol (300 cc) are heated to boiling for 4 hours. After being cooled to a temperature in the region of 20° C., the solution is concentrated to dryness at 50° C. under vacuum (20 mm Hg; 2.7 kPa), and the residue is then taken up with dichloromethane (200 cc). The organic phase is washed with saturated aqueous sodium bicarbonate solution (2×100 cc), separated off after settling has taken place, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Ethyl n-decanoate (18 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: F[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].C(N(C(C)C)CC)(C)C.[CH:22]12[O:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][NH:24][CH2:23]2>CN1C(=O)CCC1>[CH:26]12[O:29][CH:22]([CH2:28][CH2:27]1)[CH2:23][N:24]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:25]2
Reactant: CCOC(=O)c1cccnc1F
Reactant: C1CC2CNCC1O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccnc1N1CC2CCC(C1)O2
Yield: 55.9 %

Procedure:
To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in NMP (0.5 mL) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3-azabicyclo[3.2.1]octane (0.17 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100° C.) for 1 h and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided methyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate as a clear oil (0.100 g, 42% yield). MS (ES) for C13H16N2O3: 249 (MH+).
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([C:6](=[O:30])[C:7]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])=[C:8]([OH:18])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[C:16]([F:17])=[C:15]2[C:5]([C:6](=[O:30])[C:7]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[C:8]([OH:18])[C:9]32[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(ccc(F)c2F)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)C2(CCOCC2)c2c(ccc(F)c2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A mixture of t-butyl N-((7,8-difluoro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (0.13 g, 0.3 mmol) in 3 mL TFA was stirred at room temperature for 1 hour. The mixture was diluted with 100 mL water and a white precipitate was formed to form a suspension. The suspension was stirred for 30 minutes at room temperature, filtered, and washed with 20 mL water. The solid was dried under vacuum at 45° C. for 15 hours to give 0.09 g of the title compound as a white solid. MS m/e: (M+H)+ 368.
Reaction SMILES: [C-:1]#[N:2].[K+].CS([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=1)(=O)=O.O>CN(C)C=O>[CH2:24]([NH:23][C:10]1[N:9]=[C:8]([C:1]#[N:2])[N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Reaction time: 70 h
Yield: 67.9 %

Procedure:
Potassium cyanide (5.6 g, 86.2 mmol) was added to a stirred solution of 2-(methylsulfonyl)-N-phenethyl-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (21.0 g, 43.1 mmol) (preparation 43) in N,N-dimethylformamide (100 ml). The reaction mixture was heated at 110° C. for 74 hr with extra potassium cyanide being added at 44 hr (3.3 g, 50.8 mmol) and 68 hr (1.2 g, 18.5 mmol). The reaction mixture was allowed to stand at room temperature for 70 hr, then poured into water (500 ml), extracted with diethyl ether (1000 ml) and the aqueous layer washed with diethyl ether (500 ml). The combined organic layers were washed with water (3×500 ml). The solvent was removed under reduced pressure from the combined organic layers to give a residue which was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) to give the title compound (10.2 g) as a brown solid. MS: 349 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:20]([CH3:30])([CH3:29])[C:21]([C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1)=[O:22].O>CS(C)=O>[CH3:29][C:20]([O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1)([CH3:30])[C:21]([C:23]1[CH:28]=[N:27][CH:26]=[N:25][CH:24]=1)=[O:22]
Reactant: CC(C)(Br)C(=O)c1cncnc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Oc1ccc(OC(F)(F)F)cc1)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.4 g (25.0 mmol) of 4-trifluoromethoxyphenol and 15.5 g (112.5 mmol) of potassium carbonate in 37.5 ml of dry dimethyl sulphoxide was stirred at room temperature for 2 h. The reaction mixture was subsequently warmed to 60° C., and 25.7 g (112.5 mmol) of 2-bromo-2-methyl-1-(pyrimidin-5-yl)propan-1-one, dissolved in 12.5 ml of dimethyl sulphoxide, were added. After the addition had ended, the reaction mixture was stirred overnight. The reaction mixture was poured into 250 ml of water and extracted with 250 ml of ethyl acetate. The organic phase was separated off and then washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The crude product was then purified by column chromatography. This gave 1.24 g (14%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:26]=2[CH:27]=1)=[O:22].C([O-])(O)=O.[Na+]>ClCCl>[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH:32][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:12])(=[O:10])=[O:9])=[CH:28][C:26]=2[CH:27]=1)=[O:22]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc2cc(NS(=O)(=O)c3cccc(Cl)c3C)ccc2o1
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (99 mg, 0.44 mmol) in dichloromethane (3 mL) was added pyridine (85 μL, 1.05 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-benzofuran-2-carboxylic acid methyl ester (80 mg, 0.42 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (122 mg, 77%), single spot at Rf 0.47 (2:1 hexane:ethyl acetate). mp 139.4-140.1° C., HPLC purity 99+% (tR 1.90 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.83 (1H, d, J=7.9 Hz), 7.55 (1H, d, J=7.9 Hz), 7.44 (1H, d, J=9.0 Hz), 7.42 (1H, s), 7.39 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=8.0 Hz), 7.05 (1H, dd, J8.7, 2.2 Hz), 6.65 (1H, s, N—H), 3.95 (3H, s), 2.72 (3H, s). LCMS: 378.16. FAB-MS (MH+, C17H14ClNO5S): calcd 379.0281, found 379.0281.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:31]=[N+:32]=[N-:33])=[O:19])=[CH:23][CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (8.7 g: 20 mmole) in dimethylformamide (60 ml), a solution of sodium azide (1.56 g) in water (6 ml) is added. The mixture is stirred at 80° C. overnight. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-azidomethylpyrrolidine (5.6 g). Yield: 92%.
Reaction SMILES: [OH-].[K+].[N+](C1C=CC(O[CH2:11][C:12]2O[N:15]=[C:14]([CH2:17][C:18]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[N:13]=2)=CC=1)([O-])=O.[N+:32]([C:35]1[CH:60]=CC(OCC(NC2CC(=O)N(C3C(Cl)=CC(Cl)=CC=3Cl)N=2)=O)=[CH:37][CH:36]=1)([O-:34])=[O:33]>CO>[N+:32]([C:35]1[CH:60]=[CH:11][C:12]([NH:13][C:14]2[CH2:17][C:18](=[O:19])[N:20]([C:21]3[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=3[Cl:27])[N:15]=2)=[CH:37][CH:36]=1)([O-:34])=[O:33]
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: O=C(Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1)Nc1c(Cl)cc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC(Nc2ccc([N+](=O)[O-])cc2)=NN1c1c(Cl)cc(Cl)cc1Cl

Procedure:
To a solution of 5 g of potassium hydroxide in 75 ml of anhydrous methanol was added 10 g of 2-[5-(p-nitrophenoxymethyl)-1,2,4-oxadiazol-3-yl]-2',4',6'-trichloroacetanilide. The mixture was heated under reflux for 2 hours. The reaction did not stop with 3-[(p-nitro-phenoxy)acetamido]-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one but proceeded further (Smiles rearrangement) to give 3-(p-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one. At the end of the reaction, the mixture was allowed to cool to room temperature, acidified with 10 ml of acetic acid, diluted with 70 ml of water, and then allowed to stand at room temperature overnight. The product was collected, washed with water and ethanol, and dried. There was obtained 3.8 g (43%) of 3-(p-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one as yellow crystals, mp 295°-298° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][N:22](C)C=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.[C-]#N.[Zn+2].[C-]#N>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C#N)cc2)C1
Temperature: 85 °C
Yield: 69 %

Procedure:
A mixture of (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (400 mg, 1.17 mmol), tetrakis(triphenylphosphine)palladium(0) (405 mg, 0.35 mmol) and zinc cyanide (206 mg, 1.75 mmol) in dimethylformamide (6 ml) was degassed with argon and heated in a closed tube at 85° C. on a Büchi shaker overnight. After cooling water (30 ml) was added, and the reaction mixture was extracted with ethyl acetate (50 ml). The aqueous phase was re-extracted with ethyl acetate (50 ml). The combined organic layers were re-extracted with conc. Sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (20 g silica gel, 10% ethyl acetate in heptane) to yield a white solid (233 mg, 69%). MS (ISP): 289.1 ([M+H]+), 306.2 ([M+NH4]+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[C:21]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:20]=2[OH:38])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:38][C:20]1[C:21]([CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)=CCc1c(OCc2ccccc2)ccc(C(=O)C=Cc2ccc(OCc3ccccc3)cc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(O)ccc(C(=O)CCc2ccc(O)cc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
Then, 21.03 g of the so-obtained 4,4'-dibenzyloxy2'-hydroxy-3'-(3-methyl-2-butenyl)chalcone was added to 200 ml of an ethyl acetate suspension of 7.01 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, and the mixture was stirred at room temperature for 6 hours and hydrogen was absorbed. After the reaction, the suspension was filtered to remove the palladium/carbon, and the solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from benzene to obtain 11.85 g (yield=86.6%) of 1-(2,4-dihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless needle.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>C1COCC1.[Ag]=O>[CH:24]1([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1
Reactant: BrC1C=CCCC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: O=[Ag]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(OC2C=CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-(benzyloxycarbonyl)piperidine (5.0 g) in THF (50 ml) were added 3-bromocyclohexene (3.67 ml) and silver oxide (7.4 g). The mixture was stirred at ambient temperature overnight. To the solution were added 3-bromocyclohexene (4.0 ml) and silver oxide (5.0 g), and the mixture was stirred at 40° C. for 6 hours. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(2-cyclohexenyloxy)-N-(benzyloxycarbonyl)piperidine (3.83 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[H-].[Na+].Cl[S:19]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=2[C:23]=1[CH3:32])(=[O:21])=[O:20]>C1COCC1>[F:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([S:19]([NH:1][C:2]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[S:12]([CH3:15])(=[O:14])=[O:13])(=[O:20])=[O:21])=[C:23]([CH3:32])[C:24]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(F)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Into 300 mL of THF was dissolved 14.0 g of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 6.10 g of sodium hydride (oily, 60%) at 0° C. After 40 minutes of stirring at the same temperature, 16.0 g of 2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added at 0° C., followed by 3 hours of stirring at room temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding 2 mol/L hydrochloric acid at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was diluted with ethyl acetate. After the solution was treated with active carbon, purification by recrystallization (ethyl acetate/ether) afforded 24.8 g of the title compound as colorless powder.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH:11]1([O:14][C:15]2[CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12]1>>[CH:11]1([O:14][C:15]2[CH:20]=[C:19]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2cccc(OC3CC3)c2)OC1(C)C
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2cccc(OC3CC3)c2)cc1F
Yield: 11.3 %

Procedure:
The title compound (170 mg) was prepared from 4-bromo-2,6-difluoroaniline (1.2 g, 5.76 mmol) and 2-(3-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 5.76 mmol) as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([O:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)(C(OCC)=O)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.C[Mg]Br>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([C:3]([OH:2])([CH3:4])[CH3:8])([O:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.4 %

Procedure:
Under a nitrogen atmosphere, to a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (0.28 g) in THF (5 ml) was added methylmagnesium bromide (1M THF solution, 2.61 ml) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (0.16 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCCCc1ccccc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 83.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.521 mmol), TEA (0.079 g, 0.782 mmol) and 4-phenylbutylamine (0.117 g, 0.782 mmol) in MeCN (3 mL) was heated in a microwave reactor at 120° C. for 5 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a 75:25 mixture of heptane and EtOAc as eluant, to give the title compound (0.174 g, 84%); 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.45-7.41 (m, 3H), 7.30-7.26 (m, 2H), 7.22-7.17 (m, 1H), 7.10-7.06 (m, 2H), 5.28-5.23 (m, 1H), 4.45-4.38 (m, 1H), δ 2.89-2.84 (m, 2H), 2.49-2.44 (m, 2H), 1.59 (d, 6H), 1.43-1.38 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 158.8, 141.8, 135.6, 131.8, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 106.8, 47.7, 44.2, 35.4, 29.2, 28.3, 20.4; Mass Spectrum: M−H+ 399.