Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][CH2:48][CH2:49][OH:50].P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][CH2:48][CH2:49][OH:50])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)NCCC3)cc1
Reactant: OCCCBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCO)CCC3)cc1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
A solution of 2.08 g (3.37 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [example 1(c)], and 1.41 g (10.14 mmol, 3.0 equiv.) of 3-bromo-1-propanol in 10 ml of toluene and 0.1 ml of N-methyl-pyrrolidone was treated with 1.44 g (10.14 mmol, 3.0 equiv.) of anhydrous disodium hydrogen phosphate. The suspension was refluxed for 24 h under an inert atmosphere. Subsequently, the reaction mixture was poured into 200 ml of an ice/water mixture and extracted three times with 150 ml of ethyl acetate. The combined organic phases were washed five times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 1:1 mixture of hexane and ethyl acetate as the eluent and yielded 1.94 g (2.87 mmol, 85.2% of theory) of (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 675 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:5][CH:4]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]2[S:7][C:6]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=4[N:12]=3)=[CH:5][CH:4]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CBr)s3)nc2c1
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Product: CN1CCN(Cc2ccc(-c3nc4cc([N+](=O)[O-])ccc4o3)s2)CC1
Yield: 73.9 %

Procedure:
2-[5-(Bromomethyl)-2-thienyl]-5-nitrobenzoxazole (1.16 g, 0.0034 mole, prepared as described in Example 1) and N-methylpiperazine (1.4 g, 0.014 mole) are dissolved in 50 ml of benzene and heated at reflux for 24 hours. The precipitated N-methylpiperazine hydrobromide is removed by filtration and the benzene removed under vacuum yielding a solid. Crystallization from ethanol yields 0.9 g of the title compound, melting point 135°-137°C.
Reaction SMILES: BrBr.[OH-:3].[Na+].[C:5]([C:8]1[CH:9]=[C:10]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:11]=[CH:12][C:13]=1[OH:14])(=[O:7])C.[Br-].Cl>O.O1CCOCC1>[OH:14][C:13]1[CH:12]=[CH:11][C:10]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:9][C:8]=1[C:5]([OH:7])=[O:3]
Reactant: CC(=O)c1cc(C2CCC(=O)CC2)ccc1O
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Br-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(c2ccc(O)c(C(=O)O)c2)CC1
Temperature: 25 °C

Procedure:
43.15 g (270 mmols) of bromine was added dropwise to a solution of 39.60 g (990 mmols) NaOH in 194 ml of water over a period of 30 minutes at 0-5° C., and stirred for a further hour at this temperature. 20.91 g (90 mmols) of 4-(3-acetyl-4-hydroxyphenyl)-cyclohexanone was dissolved at 70° C. in 100 ml of dioxane, allowed to cool to room temperature, and the emulsion formed was then added to alkali bromide solution. The reaction mixture was stirred for 3 hours at 40° C., and then over night at room temperature. 52 ml 37% HCl was added dropwise with slight cooling and the mixture was stirred for a further hour at room temperature. The precipitate was filtered off and washed with water. Recrystallisation from acetic ester gave 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:32][C:29]=4[C:30]#[N:31])=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)cc4C#N)ncnc32)CC1
Temperature: 160 °C
Yield: 23.5 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), 5-chloro-2-hydroxybenzonitrile (Maybridge, Tintagel, Cornwall, UK; 28 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.392 mmol) in dimethylformamide (1 mL) was heated in the microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture and the resulting precipitate was filtered through a silica gel plug, eluting with methanol. The solvent was removed and the residue was purified by HPLC to give 4-[4-(4-chloro-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 24%) as a white solid. Mass spectrum MH+=455. 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.96-2.04 (m, 4H), 2.96-3.08 (m, 2H), 4.02-4.12 (m, 2H), 4.96-5.06 (m, 1H), 7.69 (d, 1H, J=8.7 Hz), 7.94 (dd, 1H, J=2.6, 8.9 Hz), 8.25 (d, 1H, J=2.4 Hz), 8.50 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.ClCCl>[CH2:20]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 108.5 %

Procedure:
(2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2.65 g, 10.80 mmol) was dissolved in dimethylformamide (75 ml) and cooled in an ice bath. Sodium hydride (60% in hexanes, 0.57 g, 23.75 mmol) was added and stirred for 10 min. To this solution, benzyl bromide (1.39 ml, 11.69 mmol) dissolved in dichloromethane (9 ml) was dropwise added and the reaction mixture was overnight stirred at room temperature. The solvent was evaporated under reduced pressure and the residue redissolved in ethyl acetate. This organic phase was washed with water, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 3.93 g (77% yield) of the final product were obtained, pure enough to perform the next synthetic step.
Reaction SMILES: [CH:1]([N:4]([CH3:43])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)OCC[O:18]3)[C:12]2=[O:32])[C@H:7]([CH2:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:6]1)([CH3:3])[CH3:2]>CC#N.Cl.C(OCC)(=O)C>[O:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=1)[CH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:43])[CH2:6][C@H:7]2[CH2:33][S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[C:12]1=[O:32]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@@H](CC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
A solution of Example 40 (74.4 mg, 0.120 mmol) in CH3CN (0.9 mL) and 1 M HCl (0.9 mL) was heated at 60° C. for 5 h. The mixture was diluted with ethyl acetate (500 mL), washed with satd NaHCO3 (3×150 mL) and brine (2×100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was lyophilized from CH3CN/H2O to the title compound as a white solid (70.2 mg, >99): ESI MS m/z 579 [C30H37F3N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5](O)=[O:6].[ClH:38].[Cl-].[NH2:40][CH2:41][CH2:42][N+:43]12[CH2:50][CH2:49][N:46]([CH2:47][CH2:48]1)[CH2:45][CH2:44]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[Cl-:38].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5]([NH:40][CH2:41][CH2:42][N+:43]12[CH2:50][CH2:49][N:46]([CH2:45][CH2:44]1)[CH2:47][CH2:48]2)=[O:6]
Reactant: NCC[N+]12CCN(CC1)CC2
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCC[N+]45CCN(CC4)CC5)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a suspension of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.11 g, 0.19 mmol), 1-(2-aminoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane chloride hydrochloride (0.066 g, 2.5 mmol), and HATU (0.088 g, 0.23 mmol) in DMF (0.7 mL) was added DIPEA (0.2 mL, 1.16 mmol). The reaction was stirred for 2 h and purified by HPLC (MeCN/H2O, 10-99%, 0.05% TFA modifier). The product fractions were concentrated and then dissolved in THF (2 mL) and 2N solution of HCl in ether (2 mL). The mixture was filtered to afford the title compound (59 mg) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 9.67 (s, 1H), 7.84 (s, 1H), 7.84-7.76 (m, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.01-6.97 (m, 2H), 6.50-6.43 (m, 4H), 4.22 (s, 2H), 3.86-3.71 (m, 10H), 3.67 (s, 3H), 3.53-3.49 (m, 6H), 1.49 (s, 6H); MS (ES): 700 [M]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C([N:29]1CCO[C@H:31]([CH2:35][C:36]2C=CC=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30]1)(OC(C)(C)C)=O.C(C1C=CC=CN=1)=C.C(O)(C(F)(F)F)=O>>[N:29]1[CH:30]=[CH:31][CH:35]=[CH:36][C:37]=1[CH2:38][CH2:42][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Agent: C=Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCc2cccc(C[C@@H]3CNCCO3)c2)nc1

Procedure:
Example 69 was prepared using the procedure as described for example 31, but starting with N-Boc-(R)-2-(3-bromobenzyl)morpholine, example 31, intermediate (b), and 2-vinylpyridine. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 68 as a yellow oil (16 mg).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24](N)=[CH:23][CH:22]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 25 %

Procedure:
Prepared from VII and N,N-dimethyl-p-phenylene-diamine. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 25%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2228, 1609, 1572, 1523, 1460, 1368, 1274, 1229, 1204, 1188, 1163, 1141, 1058, 1009, 948, 842, 811; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H, J=9.0 Hz), 8.16 (s, 1H), 7.86 (d, 1H, J=9.0 Hz), 7.37 (d, 2H, J=8.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 3.00 (s, 6H); HRMS calcd for C18H15N6S (M+H+): 347.1079, found 347.1066.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:10][S:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[C:14]1([S:11]([C:10]2[C:3]3[C:2](=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[CH:4]=3)[NH:1][N:24]=2)(=[O:13])=[O:12])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(C=O)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)-benzaldehyde (2.4 g, 6.85 mmoles) in THF (10 mL) and 4M HCl (20 mL) was stirred in a round bottom flask at 3° C. A solution of sodium nitrite (0.49 g, 7.19 mmoles in H2O (2 mL) was added. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.84 g, 5.5 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH2:15][C:16](CC3(C)COC(C4C=CC(F)=CC=4)OC3)=O)([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:39]1CCCC1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:14])([CH:15]([CH3:16])[OH:39])[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(CC(=O)CC2(C)COC(c3ccc(F)cc3)OC2)COC(c2ccc(F)cc2)OC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)C1(C)COC(c2ccc(F)cc2)OC1

Procedure:
2-(p-Fluorophenyl)-5-methyl-1,3-dioxan-5-yl-methyl ketone (11.85 g) in dry ether (100 ml) was added to a slurry of lithium aluminium hydride (2.5 g) in dry ether (50 ml) and the mixture was heated under reflux for 4 hours. Moist tetrahydrofuran (20 ml) was added and the mixture was filtered. The filtrate was concentrated and the crude product was recrystallised from ethyl acetate/light petroleum (b.p. 60°-80°) as white crystals, m.p.78°, of the pure cis isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:17]=[C:18]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:22]=3)[CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(C(=O)c2ccc(F)cc2)c1
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)c2cc(CCNS(=O)(=O)c3ccc(Cl)cc3)cc(CCC(=O)O)c2)cc1
Reaction time: 20 h
Yield: 41 %

Procedure:
A solution of 3-[2-[(4-chlorophenyl)sulphonylamino]ethyl]-5-(4-fluorobenzoyl)benzenepropanoic acid (0.25 g) and sodium methanesulphinate (0.61 g) in dimethylsulphoxide (1.0 ml) was heated at 130° C. under dry nitrogen for 30 hours. Additional sodium methanesulphinate (1.2 g) was added and heating was continued for a further 20 hours. The solution was diluted with water, acidified with 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (97:3) as eluent. The product fractions were combined and evaporated to give the title compound as a foam (0.115 g), Rf 0.25(SS 8). Found: C,54.96; H,4.53; N,2.18. C25H24CINO7S2 requires: C,54.59; H,4.40; N,2.55%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 0 °C

Procedure:
4-chloro-3-(methylsulfonyl)benzoic acid (Enamine, 500 mg; 2.13 mmol; 1 eq.) was dissolved in MeOH (10 mL) The solution was cooled down to 0° C. Thionyl chloride (0.62 mL; 8.52 mmol; 4 eq.) was added dropwise.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[SH:13])([O-])=O.Cl>[Zn]>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[SH:13]
Reactant: O=[N+]([O-])c1ccc(S)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Zn]
Product: Nc1ccc(S)c(N)c1

Procedure:
Employing standard chemical reactions, the 2,4-diaminothiophenol was prepared by first reacting sodium hydrosulfide with 2,4-dinitrochlorobenzene to produce 2,4-dinitrophenylmercaptan. The 2,4-dinitrophenylmercaptan was reduced with zinc and hydrochloric acid to produce 2,4-diamino-thiophenol.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:17][C@H:18]2[CH2:22][NH:21][C@@H:20]3[C@@H:23]([OH:26])[CH2:24][O:25][C@H:19]23)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O.O1CCOCC1>[OH:26][C@@H:23]1[C@H:20]2[N:21]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:22][C@H:18]([O:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=3)(=[O:16])=[O:15])[C@H:19]2[O:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 0.58 h
Yield: 95 %

Procedure:
A solution of sodium carbonate (281 mg, 2.65 mmol) in water (5 mL) was added whilst stirring to a solution of (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate in 1,4-dioxane (5 mL). A solution of benzyl chloroformate (0.225 mL, 1.96 mmol) in 1,4-dioxane (2.5 mL) was added over 20 minutes then the mixture stirred for 35 minutes, then water (50 mL) was added and the product extracted into dichloromethane (2×50 mL). The organic layer was washed with brine (50 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 25:75 to 50:50 gave bicyclic alcohol (34) (518 mg, 95%) as a white solid. TLC (Rf=0.25, EtOAc:heptane 3:2), analytical HPLC single main peak, Rt=17.86 min., HPLC-MS 434.2 [M+H]+, 456.1 [M+Na]+, 889.3 [2M+Na]+; [α]D16.5 −23.1° (c=1.190, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 3:2; 1.96 (0.4H, d, J=4.11 Hz, OH minor), 2.43 (1.8H, s, aryl-CH3 major), 2.44 (1.2H, s, aryl-CH3 minor), 2.59 (0.6H, d, J=3.42 Hz, OH major), 3.35 (0.4H, dd, J=13.43 and 3.71 Hz, CbzNCH2 minor), 3.41 (0.6H, dd, J=13.31 and 3.80 Hz, CbzNCH2 major), 3.74-3.88 (3H, m, 2×OCH2CHOH and 1×CbzNCH2), 4.29 (0.4H, s, CbzNCH minor), 4.31 (0.6H, s, CbzNHCH major), 4.37 (0.4H, brs, OCH2CHOH minor), 4.49 (0.6H, brs, OCH2CHOH major), 4.51 (0.6H, d, J=4.59 Hz, TsOCHCH major), 4.64 (0.4H, brd, J=4.44 Hz, TsOCHCH minor), 4.77 (0.4H, d, J=3.43 Hz, TsOCHCH minor), 4.79 (0.6H, d, J=3.53 Hz, TsOCHCH major), 5.06-5.13 (1.6H, m, CH2Ph), 5.21 (0.4H, d, J=12.22 Hz, CH2Ph minor), 7.30 (7H, m, aromatic-CH and CH3CCH), 7.75-7.79 (2H, m, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.658 (aryl-CH3), 51.015/51.082 (CbzNCH2), 67.511/67.622 (CH2Ph), 67.953/68.902 (CbzNCH), 74.375/74.420 (OCH2CHOH), 75.322/76.156 (OCH2CHOH), 79.944/80.600 (TsOCHCH), 83.537/84.651 (TsOCHCH), 127.791, 127.837, 127.942, 128.011, 128.382, 128.485, 128.558, 128.703 and 130.102 (aromatic CH), 133.021/133.087 (CHOSO2C quaternary), 135.895/136.018 (Cbz quaternary), 145.441 (CH3C quaternary), 153.976/154.591 (Cbz C═O).
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38]C(=O)C)[CH2:25][C@@H:26]2[O:34]C(=O)C)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[Li].C([Cu]CCC(C)C)CC(C)C.[CH2:54]([Li])[CH2:55][CH:56]([CH3:58])[CH3:57].[Cl-].[NH4+]>C(OCC)C>[CH3:57][CH:56]([CH2:55][CH2:54][CH2:3][C@H:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:38])[CH2:25][C@@H:26]2[OH:34])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:1])[CH3:58]
Reactant: [Li]CCC(C)C
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: CC(C)CC[Cu]CCC(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 82 mg of 20-methyl-1α,3β-diacetoxy-21-p-toluenesulfonyloxypregna-5,7-diene in 1.5 ml of diethyl ether was added dropwise, at -50° C. to -60° C., to a diethyl ether solution of diisoamylcopper lithium prepared from 100 mg of cuprous iodide and 0.9 ml of a 1.1N diethyl ether solution of isoamyllithium in 2 ml of diethyl ether. After stirring at -30° C. for 1 hour, the reaction mixture was poured into a cold aqueous solution of ammonium chloride, followed by extraction with diethyl ether. The extract was washed with 10% aqueous ammonia, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was dissolved in 1 ml of methanol, 10 mg of potassium carbonate was added, and the mixture was stirred at ambient temperature for 10 hours. Thereafter, the isolation and purification procedure of Reference Example 8 was repeated to give 35 mg of cholesta-5,7-diene-1α,3β-diol, whose 1H NMR spectrum was identical with that obtained in Reference Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:13][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: Clc1ccncc1Br
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnccc1OCC1CC1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of 3-bromo-4-chloropyridine (CAN 36953-42-1, 8 g, 41.6 mmol) in dry DMF (100 ml) under argon atmosphere at room temperature were added cyclopropylmethanol (CAN 2516-33-8, 3.15 g, 3.45 ml, 43.6 mmol) and by portions sodium hydride 60% (1.75 g, 43.6 mmol). The resulting reaction was stirred at room temperature until gas evolution stopped. The reaction mixture was then stirred at 100° C. for 3 hours, cooled down to room temperature and quenched by addition of water. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an aqueous solution 1.0M sodium bicarbonate. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (8.25 g, 87%) as a light yellow oil. MS (ESI, m/z): 228.2 (M+H+).