Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:26])[CH3:25]
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1
Reaction time: 20 h
Yield: 68 %

Procedure:
The 4-hydroxymethyl-4-(4-methoxyphenyl)cyclohexanone is dissolved in 12 ml. of pyridine and 6 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from a mixture of ether and Skellysolve B to give 2.95 g. (68% yield) of 4-acetoxymethyl-4-(4-methoxyphenyl)cyclohexanone, having a melting point of 86.5° to 88°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]Cl)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4].[I-:27].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][I:27])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1

Procedure:
A solution of 51.6 g (0.132 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 29.8 g (0.198 mole) of sodium iodide in 1000 ml of acetone is refluxed for 45 minutes. The reaction mixture is thereupon concentrated in vacuo. Water is added to the residue and extraction is performed twice with methylene chloride. The organic phase is washed once with diluted aqueous sodium bisulphate solution and twice with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product crystallises out. After filtration under suction and drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 139°-142°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([OH:22])=O)=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:22])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCC(F)(F)F
Yield: 84.8 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol), 2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56 mmol) and HATU (1.2 g, 3.2 mmol) in CH2Cl2 (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (50 mL) and is washed with water (10 mL×3) and brine. Then the organic layer is dried over anhydrous Na2SO4 and is concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide as a white solid (1.1 g, 84.6%). MS (m/z): 606.0 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@H:3]1[CH3:7].CS(C)=O.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:3]1[CH3:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1NCC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a suspension of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one (10.45 g) in dry THF (418 mL) was added dropwise Red-Al (104.9 g: 363 mmol: 70% toluene solution) under ice-cooling and a nitrogen stream. The mixture was stirred at room temperature for 20 min, and further refluxed for 3 hr. The reaction mixture was ice-cooled again, and sodium carbonate decahydrate (41.6 g) was added under a nitrogen stream. The mixture was stirred at room temperature overnight, insoluble materials were filtered through celite and washed with THF. The filtrate and washing were combined and concentrated under reduced pressure to give (2S,3S)-3-hydroxy-2-methylpyrrolidine. Without further purification, this compound was diluted with DMSO to give 0.9 mol/L-DMSO solution. A solution (170 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine in 0.9 mol/L-DMSO was diluted with water (200 mL), sodium hydrogen carbonate (24.6 g) and benzyl chloroformate (15 mL) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield: 20.64 g, 84%).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[C:34]([O-:37])(=[S:36])[CH3:35].[K+]>CN(C)C=O>[CH2:25]([C:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][S:36][C:34](=[O:37])[CH3:35])([CH3:33])[CH3:32])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: CC([O-])=S
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CSC(C)=O
Temperature: 70 °C
Yield: 74 %

Procedure:
A mixture of Compound 3 (300 mg) and potassium thioacetate (400 mg) in N,N-dimethylformamide (2 mL) was heated at 70° C. under argon for 16 hours. The N,N-dimethylformamide was removed under vacuum and the resulting residue was directly eluted on a silica gel using 1% ethanol in dichloromethane to obtain the required product in 74% yield (240 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[NH:24][C:33]2=[O:35])=[CH:15][CH:16]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cccnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a mixture of N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.080 g) and triethylamine (0.0638 g) in THF (1.5 mL) at 0° C., was added dropwise a solution of triphosgene (0.030 g) in THF (0.6 ml). The reaction mixture was stirred at 0° C. for 0.5 h. The cold bath was removed and the stirring continued at ambient temperature for another 0.5 h. After this time, a saturated aqueous solution of sodium bicarbonate was added. The organic layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylene chloride) to afford 3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.038 g) as a white solid.
Reaction SMILES: CN(C=O)C.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:35])[C:18]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:19][N:20]3[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:15][C:14]=2[F:36])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:37]([N:28]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:18]1[C:17](=[O:35])[C:16]2[C:21](=[CH:22][C:13]([NH:12][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)=[C:14]([F:36])[CH:15]=2)[N:20]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:19]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CNc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccccc1)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 3.2 ml DMF solution of 160 mg of ethyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate were added 0.05 ml of benzyl bromide and 75 mg of potassium carbonate, followed by overnight stirring at room temperature. By adding water to the reaction mixture and collecting the insoluble materials by filtration, 200 mg of ethyl {benzyl[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}acetate was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH2:20]([O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:15]=[CH:14][C:13]=1[NH2:16])[CH3:21]
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 101.8 %

Procedure:
1-methyl-4-{2-[3-(ethyloxy)-4-nitrophenyl]ethyl}piperazine (0.373 g, 1.14 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.223 g, 0.057 mmol) was added followed quickly by a screw cap septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.308 g, 1.16 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 6.57-6.65 (m, 3H), 3.99-4.08 (m, 2H), 3.62-3.74 (m, 2H), 2.65-2.75 (m, 2H), 2.47-2.59 (m, 8H), 2.31 (s, 3H), 1.36-1.45 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH3:15])[C:11](=[S:14])[NH:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(O)(=O)C>C(O)C>[Cl:20][CH2:19][CH2:18][CH2:17][S:14][C:11]1[N:10]([CH3:15])[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13][N:12]=1
Reactant: Cn1c(-c2ccc(F)c(F)c2)n[nH]c1=S
Reactant: ClCCCBr
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1-c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 5-(3,4-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.72 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.26 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.36 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])=[CH:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C=O)C>[CH3:15][Si:13]([CH3:16])([CH3:14])[CH2:12][CH2:11][O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=1
Reactant: COC(=O)CBr
Reactant: C[Si](C)(C)CCOC(=O)COc1ccc(N)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-trimethylsilanylethyl (4-amino-3-benzyloxyphenoxy)acetate (4.56 g, 12.2 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in DMF (25 mL) is added methyl bromoacetate (1.87 g, 12.2 mmol). The mixture is stirred at 60° C. for 1 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (1×), brine (5×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([NH2:8])[O:5][N:4]=1.Cl[C:12]([O:14][C:15]([CH3:17])=[CH2:16])=[O:13].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:7]=[C:6]([NH:8][C:12](=[O:13])[O:14][C:15]([CH3:17])=[CH2:16])[O:5][N:4]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=C(C)OC(=O)Nc1cc(C(F)(F)F)no1
Yield: 38.2 %

Procedure:
Using general method G, 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 9.1 mmol) and isopropenyl chloroformate (1.1 g, 9.1 mmol) in presence of LiHMDS (1.0M, 18 mL, 18.2 mmol) were combined to afford prop-1-en-2-yl 3-(trifluoromethyl)isoxazol-5-ylcarbamate (0.82 g, 38% yield).). 1H NMR (400 MHz, DMSO-d6): δ 12.3 (s, 1H), 6.48 (s, 1H), 4.83 (m, 1H), 4.80 (m, 1H), 1.93 (s, 3H); MS (ESI) m/z: 237.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)cc1N
Yield: 94 %

Procedure:
To a chilled solution of 2-amino-4-fluorobenzoic acid (1.57 g, 10.1 mmol) in absolute ethanol (20 mL) was added neat thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was refluxed for 4 days total, with addition of more SOCl2 (8 mL, 110 mmol), then concentrated, diluted with EtOAc, washed with 2N NaOH, dried and concentrated in vacuo to give ethyl 2-amino-4-fluorobenzoate (1.73 g, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:17]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
To a stirred solution 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.5463 mmol) in DMF (2 ml) cooled at 0° C. was added sodium hydride (124 mg, 3.0927 mmol) and stirred at 0° C. for further 20 min. Phenethyl bromide (344 mg, 1.8556 mmol) was then added drop wise and stirred the reaction at RT for 3 hrs. The reaction mixture was diluted with ice water (150 ml) and extracted with dichloromethane (2×50 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 300 mg (43.47% yield) of the titled compound. MS: m/z=299.4 (M+1). 1H NMR (CDCl3, 300 MHz): δ 7.81 (s, 1H), 7.54 (s, 1H), 7.29-7.21 (m, 2H), 7.10-7.08 (d, 1H), 4.35-4.30 (t, 2H), 3.19-3.14 (t, 2H), 1.28 (s, 12H).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13]>>[F:10][C:11]([F:15])([F:14])[CH2:12][NH:13][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCC(F)(F)F
Product: CC(C)(C)OC(=O)CNCC(F)(F)F
Yield: 74 %

Procedure:
The subtitled compound was synthesized by the method of example 15 step (i) from tert-butyl bromoacetate (13.6 g) and 2,2,2-trifluoroethylamine (8.9 g). The sub-title compound (11 g) was obtained as a colourless oil; 1H NMR (300 MHz, CDCl3); 3.39 (2H, s), 3.20 (2H, q, J=9.4 Hz), 1.44 (9H, s).
Reaction SMILES: [OH-].[Na+].BrBr.[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16](=[O:18])C)[CH3:6].S(=O)(O)[O-:20].[Na+]>O1CCOCC1.O>[CH2:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([OH:18])=[O:20])[CH3:6]
Reactant: CCc1sc2ccccc2c1C(C)=O
Reactant: O=S([O-])O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc2ccccc2c1C(=O)O
Temperature: 0 °C
Yield: 92 %

Procedure:
Into a one-litre flask equipped with a mechanical stirrer and a dropping-funnel were introduced 39 g (0.97 mol) of sodium hydroxide with 270 ml of water. The solution was cooled to 0° C by means of an ice-bath and 20 ml (0.333 mol) of bromine were then added through the dropping-funnel followed by 190 ml of dioxan, care being taken to maintain the temperature at 0° C. Finally, still at the same temperature, a solution of 22.6 g (0.111 mol) of 2-ethyl-3-acetyl-benzo[b]thiophene in 25 ml of dioxan were introduced drop-by-drop. The mixture was then allowed to return to room temperature and stirring was maintained for 2 hours. A solution of sodium bisulphite was then added and the reaction medium was acidified and extracted with ether. The organic phase was washed with water, dried and evaporated to dryness to give 20.2 g of 2-ethyl-3-carboxy-benzo[b]thiophene. Yield 92%; M.P. 136° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(O)[CH3:8].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:8]
Reactant: Cc1ncsc1C(C)(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: C=C(c1ccccc1)c1scnc1C

Procedure:
1-(4-Methyl-5-thiazolyl)-1-phenylethanol (2.5g) in chloroform (25ml) was treated with thionyl chloride (4.5ml). The mixture was heated under reflux overnight and then evaporated to dryness. Aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as an oil. Treatment with anhydrous hydrogen chloride in diethylether gave 1-(4-methyl-5-thiazolyl) -1-phenylethene hydrochloride, m.p. 131-133.5° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]([C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[CH:19]=[CH:20][N:21]([CH3:22])[C:15]=3[CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].C1C(=O)N([Cl:32])C(=O)C1>CN(C=O)C>[Cl:32][C:19]1[C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([C@:3]([OH:5])([CH3:4])[CH2:2][OH:1])=[CH:7][CH:8]=3)=[CH:14][C:15]=2[N:21]([CH3:22])[CH:20]=1
Reactant: Cn1ccc2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cn1cc(Cl)c2cnc(NC(=O)c3ccc([C@@](C)(O)CO)cc3)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
(R)-4-(1,2-dihydroxypropan-2-yl)-N-(1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)benzamide (750 mg, 2.3 mmol) was dissolved in DMF (20 ml) and NCS (310 mg, 2.3 mmol) was added to it. Stirring continued at 50° C. for 3 hours. The mixture was poured into 50 ml ice water and was extracted into ethyl acetate (3×100 ml). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparatory HPLC (TFA mode, 15-50% ACN in water). Fractions containing the desired mono chlorinated product were combined, concentrated, washed with saturated NaHCO3 and brine, and then extracted into ethyl acetate (2×100 ml). Combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (R)—N-(3-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (18 mg, 0.49 mmol, 21%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 3H) 3.45 (dd, J=5.81, 2.53 Hz, 2H) 3.78 (s, 2H) 4.74 (t, J=5.81 Hz, 1H) 5.03 (s, 1H) 7.46-7.69 (m, 2H) 8.01 (d, J=8.59 Hz, 2H) 8.34 (d, J=0.76 Hz, 1H) 8.59 (d, J=0.76 Hz, 1H) 10.64 (s, 1H); ESI-MS: m/z 360 (M+H)+; m.p. 210-212° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a stirred solution of 21 mL (42 mmol, 2.0M in THF) of benzylmagnesium chloride at room temperature under nitrogen was added a solution of 6.80 g (50.0 mmol) of thrice-fused zinc chloride, in 50 mL of THF. The resulting tan slurry was stirred for 1 hour. To this slurry was added 10.0 g (35.3 mmol) 1-bromo-4-iodobenzene and 450 mg (0.4 mmol) of tetrakis(tri-phenylphosphine)palladium in 30 mL of THF. The reaction was stirred at room temperature for 16 hours and then quenched with 50 mL of 2M hydro-chloric acid. The mixture was extracted thrice with hexanes, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (5×25 cm column, hexanes as elutent) to give 7.05 g (80%) of title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH-:13].[K+:14]>C(O)(C)(C)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][NH:8][C:9](=[S:13])[S-:10])=[CH:11][CH:12]=1.[K+:14]
Reactant: [SH-]
Reactant: S=C=NCOc1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: S=C([S-])NCOc1ccc(Cl)cc1

Procedure:
Potassium p-chlorophenoxymethyldithiocarbamate was prepared by the reaction of p-chlorophenoxymethyl isothiocyanate with potassium hydrosulfide in a mixture of t-butyl alcohol and acetone.