Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)=[CH:7][CH:6]=2)[N:9]=[C:10]([C:21]([F:26])([F:27])[C:22]([F:23])([F:25])[F:24])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccc(Br)cc2)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
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: CCO
Product: CSc1cccc(-c2ccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
1-(4-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Preparation 15, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (13.0 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (550.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 20.0 mg of the titled compound as a white liquid.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:26]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH:26]1([S:31]([N:18]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:25])[C:24]=3[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)=[CH:17]2)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=S(=O)(Cl)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2S(=O)(=O)C1CCCC1
Reaction time: 72 h

Procedure:
Sodium hydride (0.132 g of a 60% dispersion in mineral oil) was added to a solution of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.0 g) in dry dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes and then cyclopentanesulphonyl chloride (0.558 g, prepared as described in J.O.C.1952, 17, 1529-1533) in dry dimethylformamide (5 ml) was added dropwise. The mixture was allowed to stand for 72 hours and then evaporated under vacuum. The residue was triturated with water and filtered to give a solid which was washed well with water, then stirred with ethyl acetate then filtered. The filtrate was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected and evaporated to give 7-cyclopentanesulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 188-188.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].[H-].[Na+].O1CCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(=O)C(C(=O)C(F)(F)F)CC2

Procedure:
A mixture of 7-methoxy-1-tetralone (7.8 g), ethyl trifluoroacetate (6 ml), sodium hydride (80% dispersion in mineral oil, 1.8 g) and tetrahydrofuran (75 ml) was stirred under reflux for 2 h under an atmosphere of argon. The cooled reaction mixture was treated with 20% acetic acid solution (250 ml) and the mixture was extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was recrystallised from ethanol to give 7-methoxy-2-(2,2,2-trifluoracetyl)-1-tetralone, m.p. 89°-90°.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=[CH2:27])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:8])[CH3:7].C(Cl)(=O)C1C=CC=CC=1.[CH3:39][Si:40]([CH3:43])([CH3:42])Cl.[OH2:44]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][CH2:17]/[C:18](=[CH:19]\[CH:20]=[C:21]3\[CH2:22][C@@H:23]([OH:28])[CH2:24][CH2:25][C:26]\3=[CH2:27])/[C@@H:13]2[CH2:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:9])([CH3:7])[CH3:8].[CH3:39][Si:40]([O:44][Si:40]([CH3:43])([CH3:42])[CH3:39])([CH3:43])[CH3:42]
Reactant: C[Si](C)(C)Cl
Reactant: O
Agent: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Product: C[Si](C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25-hydroxycholecalciferol (5.0 g.) in pyridine (25 ml.) at -15°, under an atmosphere of argon, is added 4-(N,N-dimethylamino)-pyridine (50 mg) followed by benzoyl chloride (2.10 ml.). The solution is warmed to 0° and kept at this temperature for 1.5 hours. After cooling to -15°, trimethylchlorosilane (1.75 ml.) is added and then the mixture is heated to room temperature for 10 minutes, before pouring into water. The mixture is extracted with hexane (500 ml.) and the extracts washed with brine, dilute hydrochloric acid, brine, sodium bicarbonate solution, brine and then dried over sodium sulfate. Evaporation of the solution yields 25-hydroxycholecalciferol, 3-benzoate, trimethylsilylether as an oil.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13]C(C#N)=[CH:11][C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6].[CH2:19]([OH:21])[CH3:20]>>[CH2:3]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:20]([C:19]([OH:1])=[O:21])=[CH:11][C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: CCO
Reactant: CCCCNC(=O)c1ccc(C#N)cc1C
Agent: [Na+]
Product: CCCCNC(=O)c1ccc(C(=O)O)cc1C
Temperature: 25 °C

Procedure:
Sodium hydroxide (4.080 g, 102 mmol) was added at ambient temperature to a solution of N-butyl-4-cyano-2-methyl-benzamide (0.919 g, 4.25 mmol) (Example I2) in ethanol (10 ml). The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated. The residue was diluted with water and acidified by addition of aqueous hydrochloric acid (concentrated). The precipitate was isolated by filtration and dried at 80° C. for 16 hours to give N-butyl-3-methyl-terephthalamic acid, which was used without further purification. 1H-NMR (DMSO-d6, 400 MHz): 0.97 (3H, t), 1.42 (2H, m), 1.62 (2H, m), 2.48 (3H, s), 3.47 (2H, q), 5.73 (1H, s), 7.45 (1H, d), 7.92 (2H, d), 7.5 (1H, s) ppm.
Reaction SMILES: [NH4+:1].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:7]([C:10]1[C:11]([O:26][C:27]([CH3:33])([CH3:32])[C:28](OC)=[O:29])=[C:12]([CH2:23][CH2:24][CH3:25])[C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[C:14]=2[CH:22]=1)[CH2:8][CH3:9]>C1(C)C=CC=CC=1>[CH2:7]([C:10]1[C:11]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([NH2:1])=[O:29])=[C:12]([CH2:23][CH2:24][CH3:25])[C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[C:14]=2[CH:22]=1)[CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCCc1cc2c(C(F)(F)F)noc2c(CCC)c1OC(C)(C)C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCc1cc2c(C(F)(F)F)noc2c(CCC)c1OC(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NH4Cl (86 mg) in toluene (10 mL) at room temperature was added AlCl3 (2.0 M, 0.8 mL) dropwise. The reaction was stirred for 3 h. The resultant clear solution was transferred to a solution of methyl 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionate (200 mg) in toluene (5 mL). The reaction was stirred at 80° C. overnight, cooled to room temperature, and then partitioned between EtOAc and 1.0 N aqueous HCl solution. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by chromatography gave the desired product. 1H NMR (CDCl3) δ 1.00 (m, 6H), 1.51 (s, 6H), 1.65 (m, 2H), 1.75 (m, 2H), 2.70 (t, 2H), 2.94 (m, 2H), 5.72 (s, broad, 1H), 6.87 (s, broad, 1H), 7.43 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20].CCCCCC>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[O:21][CH3:22])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(I)c([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a cooled (0° C.), yellow suspension of 4-iodo-3-nitroaniline (8.46 g, 32.0 mmol) in DCM (320 mL) and pyridine (2.85 mL, 35.2 mmol) was added methyl chloroformate (2.61 mL, 33.6 mmol) dropwise. The reaction mixture turned to light yellow solution and stirring was continued for 1.5 h. After 1.5 h, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution followed by brine. The organic layers were dried over MgSO4, filtered and concentrated to obtain a residue. The residue was then dissolved in DCM (˜100 mL), then hexane (600 mL) was added to give a yellow suspension. The above suspension was filtered and the filtered solid was rinsed with hexane and air-dried to obtain the desired product as yellow solid (10.3 g, 100%). MS (ESI) m/z: 321.3 (M−H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.0 g (6.51 mmol) of 3-[3-(imidazo-[1,2-a]pyridin-5-ylthio)propyl]thiazolidine-2,4-dione and 0.59 ml (6.51 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.65 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/4) to yield 1.57 g (66.7%, light orange oily substance) of the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C(O)=O>CN(C)C=O>[Si:21]([O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 13 h
Yield: 86.3 %

Procedure:
1 (S)-4-hydroxy-3-methyl-2-(2-propynyl)-cyclopent-2-ene-1-one (50.0 g) was dissolved in dry dimethylformamide (600 ml), and imidazole (27.3 g) was added to the dimethylformamide solution. Tert-butyldimethylchlorosilane (55.3 g) was added to the solution under ice-water cooling and the resulting mixture was allowed to react for 2 hours, then for 13 hours at 20° C. The reaction solution was poured into an aqueous oxalic acid solution under ice-water cooling, and extracted three times with diethyl ether (200 ml). The ether layers were combined, and the combined layer was washed with saturated aqueous sodium bicarbonate solution and brine in sequence. After dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resultant residue was subjected to distillation under reduced pressure to afford (S)-4-tert-butyldimethylsilyloxy-3-methyl-2-(2-propynyl)cyclopent-2-ene-1-one (76.0 g, yield 86.0%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:22])(F)S([O-])(=O)=O.[Na+].[OH-].[Na+].Cl>ClCCl.O>[CH2:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[C:10]=2[F:15])[CH2:5]1)[CH2:2][CH3:3].[CH2:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:16]([F:22])=[C:9]([OH:14])[CH:10]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCc2cc(O)ccc2C1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCC1CCc2c(ccc(O)c2F)C1
Product: CCCC1CCc2cc(O)c(F)cc2C1

Procedure:
200 g of the 2-propyl-1,2,3,4-tetrahydro-6-naphthol obtained in (7-1) was dissolved in 1000 ml of dichloromethane, 5 g of sodium trifluoromethanesulfonate was added, and the mixture was stirred vigorously. 243 g of N,N′-difluoro-2,2′-bipyridinium bistetrafluoroborate was gradually added to the reaction mixture, and the resulting mixture was stirred for a further 5 hours at room temperature. Water, and then a 10% aqueous solution of sodium hydroxide were added, any excess fluorinating reagent was decomposed, and following restoration to an acidic state by addition of dilute hydrochloric acid, the organic layer was separated. The aqueous layer was extracted with dichloromethane, the extract was combined with the separated organic layer, and this combined organic extract was washed with water and a saturated aqueous solution of sodium chloride, before being dried over anhydrous sodium sulfate. The crude product obtained by removal of the solvent by evaporation was separated and purified by silica gel column chromatography (toluene), to obtain 57.0 g of 2-propyl-5-fluoro-1,2,3,4-tetrahydro-6-naphthol, and 85.5 g of 2-propyl-7-fluoro-1,2,3,4-tetrahydro-6-naphthol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8].C1CCCCC1>C1C(Cl)=CC=C(Cl)C=1>[CH3:1][O:2][C:3]([C:4]1[C:5]([OH:11])=[CH:6][C:7](=[O:8])[N:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[N:12]=1)=[O:24]
Reactant: COC(=O)CC(=O)C(=NNc1ccc(OC)c(OC)c1)C(=O)OC
Solvent: Clc1ccc(Cl)cc1
Solvent: C1CCCCC1
Product: COC(=O)c1nn(-c2ccc(OC)c(OC)c2)c(=O)cc1O
Yield: 65.2 %

Procedure:
The hydrazone (28) (500 mg) was dissolved in dichlorobenzene and heated to reflux in a sealed tube for 4 hours. The reaction was allowed to cool and cyclohexane was added dropwise to crystallize the desired product. Filtration and drying in vacuo yielded the desired dihydropyridazine ester (29) (295 mg) as a solid. MS+: m/e=307.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[N:17]=2)=[CH:4][CH:3]=1.CCN=C=N[CH2:27][CH2:28][CH2:29][N:30](C)C.C1C=CC2N(O)N=NC=2C=1.[O:43]1[CH2:48]CC(CCN)[CH2:45][CH2:44]1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([NH:30][CH2:29][CH:28]3[CH2:27][CH2:48][O:43][CH2:44][CH2:45]3)=[O:21])[N:17]=2)=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: NCCC1CCOCC1
Reactant: O=C(O)Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1)NCC1CCOCC1
Yield: 72.7 %

Procedure:
A solution of the compound (122 mg, 0.402 mmol) obtained in step 8, WSC (116 mg, 0.603 mmol), HOBt (92.0 mg, 0.603 mmol), TEA (0.112 mL, 0.804 mmol) and 2-(tetrahydro-2H-pyran-4-yl)ethanamine (56.0 mg, 0.483 mmol) in DMF (1.6 mL) was stirred at 100° C. for 1 hr. The reaction mixture was cooled, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% methanol/ethyl acetate) to give 2-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}-N-(tetrahydro-2H-pyran-4-ylmethyl)acetamide (117 mg, 73%) as a yellow powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].ClS(N=C=O)(=O)=O>O>[NH2:13][S:12]([O:11][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: O
Product: CC(=O)Nc1cccc(OS(N)(=O)=O)c1

Procedure:
By the same method described for Example 62, the title compound was prepared from m-acetamidophenol (12.10 g, 0.08 m), reacting with the sulfamoyl chloride generated from water and chlorosulfonyl isocyanate. The crude product contained desired product and starting material. The product was isolated by chromatography on 100 g silica gel, eluted first with 7:3 methylene chloride/acetonitrile and then increasing the proportion of acetonitrile in the eluting solvent. The main fraction was evaporated and triturated with isopropyl alcohol/isopropyl ether to give 4 g of white solid, recrystallized from acetonitrile/isopropyl ether, and dried in vacuum at 60° C. overnight to give 3.73 g of solid, mp 148°-149° C.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Br)=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22].O>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccccc1Oc1cccc(CBr)c1OC
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1cccc(CC#N)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Powdered Potassium cyanide (2.50 g) was added to a solution of 2-methoxyphenyl 2-methoxy-3-bromomethylphenyl ether (12.0 g) in dimethylsulfoxide (100 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated. The resultant oily residue (9.80 g) was subjected to column chromatography on silica gel and eluted with a mixture of benzene and hexane (1:1). The eluate was evaporated to give oily 2-[2-methoxy-3-(2-methoxyphenoxy)phenyl]acetonitrile (6.20 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:11]=[CH:10]2
Reactant: COCCN
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COCCNc1ccc2nc(NCc3ccc(C)o3)ccc2c1

Procedure:
The title compound, MS: m/e=312.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxyethylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[C:11]3[C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:5][N:4]=1.CC(O)=[O:36].OO.[OH2:40]>>[CH3:1][S:2]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH:12]=[C:11]3[C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:5][N:4]=1)(=[O:36])=[O:40]
Reactant: CSc1nnc(-c2ccc3c(c2)c(-c2cnc4ccccc4c2)cn3C(=O)OC(C)(C)C)s1
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: CC(C)(C)OC(=O)n1cc(-c2cnc3ccccc3c2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a stirred solution of tert-butyl 5-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-3-(quinolin-3-yl)-1H-indole-1-carboxylate (38 mg, 80 μmol) in glacial HOAc (0.5 mL, 8659 μmol) with catalytic amount of NaWO4 (0.0003 mL, 4 μmol) was added dropwise H2O2, 35 wt. % solution in H2O (0.01 mL, 323 μmol) and the overall yellow mixture was stirred at RT for 1.5 h. The cloudy mixture was diluted with H2O and the resulting precipitate was filtered, washed with H2O and dried in vacuo to give tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(quinolin-3-yl)-1H-indole-1-carboxylate (38 mg, 94%) as a yellow solid. MS (ESI, pos. ion) m/z: 507 (M+1).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]C(=O)C)[CH2:20][C:21](OC)=[O:22])[CH2:14][C:15](OC)=[O:16])(=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[C:13](=[C:19](\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][SH:33])/[CH2:20][CH2:21][OH:22])/[CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CC(CCCCCCCCSC(C)=O)=C(CCCCCCCCSC(C)=O)CC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC/C(CCCCCCCCS)=C(\CCO)CCCCCCCCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a flamed-dried 20 mL vial fitted with a screw-cap septa was added Dimethyl 3,4-bis(8-(acetylthio)octyl)hex-3-enedioate (1 equiv, 0.36 mmol, 196 mg) and THF (4.5 mL). DIBAl-H (12 equiv, 4.3 mmol, 2.9 mL of a nominally 1.5 M solution in toluene) was added dropwise at rt. The reaction was stirred at rt for 2 h and quenched by the careful addition of 2N HCl (3 mL). The solution was transferred to a sepratory funnel and diluted with sat. aq. NH4Cl (15 mL) and Et2O (15 mL). The layers were separated and the aqueous layer extracted with Et2O (2×15 mL). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (40% EtOAc/Hex) to afford (Z)-3,4-bis(8-mercaptooctyl)hex-3-ene-1,6-diol (82.8 mg, 0.205 mmol, 57%). TLC Rf=0.41 (50% EtOAc/Hex); Mp=67.4-68.2° C.; 1HNMR (600 MHz): δ 3.64 (t, 4H, J=6.9 Hz), 2.54 (q, 4H, J=7.4 Hz), 2.35 (t, 4H, J=7.0 Hz), 2.08-2.02 (4H), 1.68 (bs, 2H), 1.62 (quint., 4H, J=7.4 Hz), 1.42-1.27 (22H); 13CNMR (150 MHz): δ 132.4, 61.3, 34.6, 34.0, 31.7, 29.7, 29.5, 29.2, 29.0, 28.3, 24.6; FTIR: 3402, 3349, 2923, 2850, 1465, 1348, 1028, 721 cm−1; HRMS-ESI: calc. for C22H44NaO2S2 (M+Na)+: 427.2680. found: 427.2679.