Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[N:16]=1>CN(C)C=O.[Cu]I>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Cl)nc(OCc2ccsc2)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccsc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To a solution containing meta-trifluoromethylphenol (1.40 g, 0.0021×4.0 mol), sodium hydride (0.25 g, (ca.60% in mineral oil), 0.0021×3.0 mol) and CuI (0.20 g, 0.0021×0.5 mol) in dimethylformamide, 2-chloro-4-methoxy-6-(3-thienylmethyloxy)pyridine (0.54 g, 0.0021 mol) was added and the resultant solution was refluxed for about 6 hours.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][O:7][NH2:8])[CH3:4].[N+:9]([C:12]1[CH:25]=[CH:24][C:15]([CH:16]=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[CH3:2][N:3]([CH2:5][CH2:6][O:7][N:8]=[C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]1=[CH:16][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:25][CH:24]=1)[CH3:4]
Reactant: CN(C)CCON
Reactant: O=C1CCCCC1=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN(C)CCON=C1CCCCC1=Cc1ccc([N+](=O)[O-])cc1

Procedure:
On starting from 17.7 g (0.1 moles) of dimethylaminoethoxyamine hydrochloride and 23.1 g (0.1 moles) of 2-(p-nitrobenzal)-cyclohexanone, one proceeds in the way as specified in Example 32.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30]>>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Reactant: CN1CCNCC1
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A mixture of 1-methylpiperazine (7 ml) and 7-(2-bromoethoxy)-6-methoxy4-phenoxyquinazoline (1.0 g, 2.67 mmol), (prepared as described for the starting material in Example 22), was stirred at ambient temperature for 5 hours. The excess 1-methylpiperazine was removed by evaporation and the residue was partitioned between aqueous sodium hydrogen carbonate and methylene chloride. The organic phase was separated, passed through phase separating paper and the volatiles removed by evaporation to give 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-4-phenoxyquinazoline (970 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)=[N:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:10][C@@H:11]([CH3:14])[CH2:12][OH:13])=[O:9])=[CH:6][C:5]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][CH2:30][CH2:29][N:28]([C:22]4[C:21]5[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=5)[N:25]=[CH:24][N:23]=4)[CH2:34][C:33]=3[CH:35]=2)=[CH:4][N:3]=1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Reactant: C[C@@H](CO)CS(=O)c1cc(Br)cnc1N
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)C[C@@H](C)CO)c5)cc4C3)ncnc2c1

Procedure:
Prepared according to the method of example 5 by using (2S)-3-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylpropan-1-ol (reagent preparation 41) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.42 (s, 1H), 8.36 (br, 1H), 8.02 (br, 1H), 7.93 (d, 1H), 7.52 (br, 1H), 7.40 (d, 1H), 7.08 (m, 2H), 7.01 (d, 1H), 5.03 (s, 2H), 4.43 (m, 2H), 4.22 (m, 2H), 3.90 (s, 3H), 3.64 (dd, 0.5H), 3.57 to 3.46 (m, 1.5H), 3.40 (dd, 0.5H), 3.14 (dd, 0.5H), 3.01 (dd, 0.5H), 2.82 (dd, 0.5H), 2.15 (m, 1H), 1.12 (dd, 3H); MS (EI) for C27H29N5O4S: 520 (MH+).
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].N#N.Cl.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][N:16]=[CH:17]2)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[C:12]([S:2]([OH:5])(=[O:3])=[O:1])[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: O=S(=O)(O)O
Agent: Cl
Agent: N#N
Product: O=S(=O)(O)c1cc(Br)cc2cnccc12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
Add fuming H2SO4 (2,000 mL, 21.33 mol; 26-29.5% free SO3) to a 5-L round bottom flask, equipped with a mechanical stirrer, reflux condenser, N2 line, and thermometer. Cool the fuming H2SO4 to ˜10° C. with an ice/acetone bath, then add 7-bromoisoquinoline HCl (500.00 g, 2.04 mol) portion-wise, keeping the temperature of the reaction mixture below ˜15-20° C. Upon complete addition of 7-bromoisoquinoline HCl, heat the resulting reaction mixture at ˜100° C. overnight. Cool the reaction mixture to room temperature, then slowly pour into a stirring solution of ice H2O. Recover the resulting precipitate by vacuum filtration, washing with H2O, then Et2O, and dry under vacuum filtration, followed by drying in a drying oven under reduced pressure at ˜35° C. to afford the title compound (501.42 g, 85% yield) as an off-white solid: TOF-MS [ES+; m/z] 287.9331/287.9330.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][S:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: BrCCOC1CCCCO1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(SCCOC2CCCCO2)ccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (890 mg of a 50% suspension in mineral oil, 19 mmol) was added to a solution of 4-mercaptopyridine (2.34 g, 21 mmol) in DMF (75 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 4-(2-(tetrahydropyran-2-yloxy)ethylthio)pyridine (2.8 g, 56%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[N:6]/[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: NC(=O)c1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 91 %

Procedure:
A suspension of 2,4-difluorobenzamide (5 g, 32 mmol) in DMF-DMA (10 mL) was heated at 120° C. for 2.5 h, allowed to cool down to RT and filtered to afford the title compound as a white solid (6.16 g, 91%). 1H NMR (CDCl3): 8.60 (1H, s), 8.19-8.12 (1 H, m), 6.91-6.79 (2 H, m), 3.19 (6 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][S:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:41][CH2:40][C:39]3[CH:38]=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:43][CH:42]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: CS(=O)(=O)c1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methanesulfonylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=614.91 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH:6]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[CH:11]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:17]1[C:13]2[CH:14]=[CH:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH:11]([CH:21]3[CH2:22][CH2:23][N:24]([S:1]([CH3:4])(=[O:3])=[O:2])[CH2:25][CH2:26]3)[C:12]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
0.59 gram (5.17 millimoles) of mesyl chloride was added neat and in a dropwise manner over a 5 minute period to a stirred solution of 1.00 gram (3.62 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine and 1.45 grams (14.35 millimoles) of triethylamine in 10 milliliters of methylene chloride. The resulting solution was stirred an additional one-half hour and then diluted with 100 milliliters of methylene chloride. Thereafter the solution was washed with saturated sodium bicarbonate solution, then with brine and dried over magnesium sulfate. The drying agent was filtered off and the solvent vaporized in vacuo to obtain the desired 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(methylsulfonyl)piperidine product as a yellow solid residue. The product after recrystallization from ethyl acetate had a melting point of 260°-268° C. and elemental analyses as follows:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl>>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 0 °C

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 87 ml morpholine. The temperature of the thick mixture rose to 75° C. After being stirred at reflux temperature for five hours, the mixture was poured into ice water, made acidic with concentrated HCl, filtered, dried and recrystallized from ethanol to give 20.3 grams 2-morpholino-5-nitrobenzoic acid. m.p. = 168°-170° C. The nitro compound was reduced catalytically in ethanol-water (3:1) with 5% palladium on carbon catalyst to give 5-amino-2-morpholinobenzoic acid. m.p. = 307°-308° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N(C)c4ccccc4)cc3oc2=O)cc1
Yield: 43.3 %

Procedure:
The title compound (90 mg, 43% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (175 mg, 0.51 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[CH3:13]OS(OC)(=O)=O.[Br-].C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[CH3:13][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: O=c1ccoc2ccc(O)cc12
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2occc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A mixture of 6-hydroxychromone (4.5 g; 27.7 mmol), CH2Cl2 (150 ml), water (150 ml), dimethylsulphate (4 ml; 41.5 mmol), benzyltributylammmonium bromide (2 g; 5.5 mmol) and NaHCO3 (1.67 g; 41.5 mmol) was stirred for 24 hours at ambient temperature. The organic phase was decanted, washed with water, a dilute solution of ammonium hydroxide and with 1N HCl, it was dried over MgSO4 and evaporated. It was purified by chromatography, eluting with ethyl acetate/petroleum ether (50/50) to give 6-methoxychromone (4 g; 83%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:28]([CH3:31])([O-:30])=[O:29].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:31][N+:28]([O-:30])=[O:29])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C=O)ccc1OCc1cccc2ccccc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])ccc1OCc1cccc2ccccc12

Procedure:
36 g of 3-methoxy-4-(naphthalen-1-ylmethoxy)-benzaldehyde, 8.7 9 of ammonium acetate and 10 ml of nitromethane are together heated at reflux for 5 hours in 140 ml of glacial acetic acid. After cooling, the reaction mixture is introduced into 1.5 liters of water. Extraction is carried out twice using 1 liter of ethyl acetate each time. The organic phases are washed 4 once with 500 ml of water and three times using 400 ml of 2N potassium hydrogen carbonate solution each time, dried over magnesium sulfate and concentrated, yielding 1-[2-methoxy-4-(2-nitro-vinyl)-phenoxymethyl]-naphthalene, which can be purified by chromatography on silica gel with ethyl acetate/n-hexane 1:4 and recrystallisation in ethyl acetate/n-hexane, m.p. 120-123° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5](C)[CH2:6][CH:7]([C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)C.C(N(CC)CC)C.[OH-:37].[NH4+].[Cl-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5](=[O:37])/[CH:6]=[CH:7]/[C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: [OH-]
Reactant: COC(=O)C=C(C)CC(C)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 2 liter round-bottomed flask equipped with a magnetic stirrer and nitrogen delivery line, 30.5 g of crude 5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylhex-2-enoic acid methyl ester are dissolved in 250 ml of THF, 13.49 g (133.3 mmol) of triethylamine are added and the yellow solution is heated under reflux for 2 hours. The reaction mixture is then cooled to room temperature, 53 ml (212 mmol) of 4N ammonium hydroxide solution are added and the mixture is stirred vigorously for 3 hours. The reaction mixture is then poured into 1 liter of saturated sodium chloride solution and extracted three times with 250 ml of ethyl acetate. The combined organic phases are washed once with 100 ml of 1N hydrochloric acid and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product (22.78 g of an orange resin) is purified by means of flash chromatography (hexane/ethyl acetate=9:1). A resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])C.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>CC#N>[OH:27][CH:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:8]2[C:9](=[O:10])[N:5]([CH:1]([CH3:3])[CH3:4])[S:6](=[O:18])(=[O:19])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: NC1CCC(O)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCC(O)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.53 mmol), 4-aminocyclohexanol (0.092 g, 0.80 mmol) and TEA (0.081 g, 0.80 mmol) was dissolved in dry MeCN (3 ml). The reaction was heated in a microwave reactor at 120° C. for 10 mins. A few extra drops of 4-aminocyclohexanol was added and the reaction was heated in a microwave reactor at 140° C. for 20 mins. The residue was purified by silica gel column chromatography using a 25:75 mixture of hexane and EtOAc, to give a 50:50 mixture of cis and trans isomers (0.130 g, 67%). The mixture was separated by HPLC (C8, 0.05M NH4OAc (pH=4.1):MeCN 1:1) to give cis (Example 38) and trans (Example 48) isomers.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[N:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:27])[CH2:17]2)=[CH:22][CH:23]=1
Reactant: O=C1CN(c2ccncc2)CCN1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CN(c2ccncc2)CCN1c1ccc(O)cc1

Procedure:
To a solution of the product of step (i) (1.1 g) in a mixture of methanol (500 ml) and tetrahydrofuran (100 ml) was added 30% palladium-on-charcoal catalyst (300 mg) and the mixture stirred in an atmosphere of hydrogen at ambient temperature and pressure until all the starting material had been consumed. After removal of the catalyst by filtration, the solvent was evaporated in vacuo to give 4-[4-(4-pyridyl)piperazin-2-one-1-yl]phenol as a colourless solid, essentially one spot by tlc, which was used without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[CH2:23][N:24]([CH3:26])[CH3:25])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[CH2:23][N:24]([CH3:26])[CH3:25])=[C:6]([CH:7]([OH:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:16]=1
Reactant: CN(C)Cc1cnn(C)c1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)Cc1cnn(C)c1-c1ccc(Cl)cc1C(O)c1ccccc1F

Procedure:
The solution of 1.86 g of 5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-2'-fluorobenzophenone in 100 ml of ethanol is stirred for 21/2 hours at room temperature with 500 mg sodium borohydride. It is evaporated under reduced pressure and the residue shaken with methylene chloride and 5% aqueous sodium hydroxide. After drying the organic layer and removal of the solvent, the residue is crystallized from diethyl ether-hexane, to yield the α-[5-chloro-2-(1-methyl-4-dimethylaminomethyl-5-pyrazolyl)-phenyl]-2-fluorobenzyl alcohol melting at 125° to 127°; the hydrochloride thereof melts at 225°-230°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[C:11]([C:21]([F:24])([F:23])[F:22])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:21]([F:23])([F:22])[F:24])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c(C(F)(F)F)nc(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Yield: 38.9 %

Procedure:
A solution of protected sulfonamide from step 2 (500 mg, 1 mmol) in a solution of 3 N HCl (5 ml) in EtOH (4 ml) was heated to reflux for 1 hour, cooled and diluted with water (20 ml). The resulting mixture was extracted with methylene chloride, dried (Na2SO4) and the solvent was evaporated. The residue was recrystallized from toluene containing a small amount of ethyl acetate to give the title product (150 mg, 40%): m.p. 259-260° C. Anal. Calc'd. for C16H11N3O2F4S: C, 49.87; H, 2.88; N, 10.90; S, 8.32. Found: C, 50.30; H, 3.10; N, 10.55; S, 8.73.
Reaction SMILES: C([O:8][C:9](=[O:50])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=2[CH2:36][N:37]2[C@@H:41]([CH3:42])[C@@H:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:39][C:38]2=[O:49])[CH:12]=1)C1C=CC=CC=1.[OH-].[Li+].Cl>CO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([OH:50])=[O:8])=[CH:12][C:13]=1[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][C:27]=1[CH2:36][N:37]1[C@@H:41]([CH3:42])[C@@H:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:39][C:38]1=[O:49])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1OCc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To {4-benzyloxy-3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid benzyl ester (0.05 g, 0.07 mmol) in MeOH (3 mL) was added 1N aqueous lithium hydroxide (1 mL), and the reaction was stirred at 65° C. overnight. The mixture was then acidified with 1N aqueous HCl, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]2[CH:44]=[CH:45][CH:46]=[CH:47][C:2]1=2
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2cc3ccccc3s2)[C@H](O)C[C@@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H](O)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: -25 °C

Procedure:
(Z)-Methyl 7-((1R,2R,3R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3,5-dihydroxycyclopentyl)hept-5-enoate, 10a, is dissolved in acetone (0.1 M) and cooled to −25° C. Jones reagent (1 molar equivalent) is added dropwise with stirring. Upon completion, as judged by TLC, the reaction is quenched with isopropyl alcohol and the crude reaction mixture is diluted with ethyl acetate, washed three times with brine, and dried over magnesium sulfate. After filtration and solvent evaporation, the product is purified by flash chromatography using hexanes-ethyl acetate as eluent to afford both (Z)-methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-oxocyclopentyl)hept-5-enoate (11a, first to elute) and (Z)-methyl 7-((1R,2R,3R)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoate (12a).