Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.Cl[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]>O1CCOCC1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:12](=[O:13])[O:14][CH2:15][CH:16]=[CH2:17])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: C1COCCO1
Product: C=CCOC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 43.7 %

Procedure:
5.5 g of Compound [II] was dissolved in 30 ml of dioxane, and 4.2 g of allyl chloroformate was added to the solution. The mixture was allowed to react for 8 hours under refluxing. After completion of the reaction, the solvent was distilled off, and hexane and a potassium carbonate aqueous solution were added to the residue to form crystals. Thus, 3.4 g of allyl N-(5-t-butyl-3-pyrazolyl)carbamate was obtained. This compound was recrystallized from hydrous methanol and found to have a melting point of 131° C. to 132° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].[C:12]([NH2:16])(=[O:15])[CH2:13]O>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[NH:16][C:12](=[O:15])[CH2:13][O:7]1)[CH3:2]
Reactant: NC(=O)CO
Reactant: CCOc1ccccc1C=O
Product: CCOc1ccccc1C1NC(=O)CO1

Procedure:
prepared by reaction of 2-ethoxybenzaldehyde with glycolamide; LC-MS: tR=0.75 min; [M+H]+=207.97.
Reaction SMILES: [CH:1]1([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][N:6]=[C:5]2[C:1]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:2][CH2:3][CH2:4]2)=[CH:10][CH:11]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1(c3ccccn3)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
After 15 minutes, the solution was cooled to -23° C. and a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (3 g) in tetrahydrofuran (34 ml) was added. After 30 minutes the mixture was cooled to -78° C., treated with 2-chloropyridine (1.56 ml), stirred for 1 hour then warmed to ambient temperature. The mixture was heated under reflux for 5 minutes, stirred for 16 hours at ambient temperature, then heated under reflux for 30 minutes. The reaction mixture was poured onto water and extracted with ethyl acetate. The extracts were dried and concentrated and the residual orange oil heated at 90° C. at 13.3 mbar to remove excess 2-chloropyridine. The residue was purified by flash chromatography over silica gel using a 5:1 mixture of light petroleum and triethylamine as eluant to give 7-methoxy-1-[1-(2-pyridyl)cyclobutyl]-3,4-dihydroisoquinoline as a solid (0.58 g).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[CH3:32]>>[CH3:32][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:28]=[O:29]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Product: Cc1cc(C=O)ccc1OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Yield: 28 %

Procedure:
Using a similar protocol as described in Example 71A employing 53B and 4-hydroxy-3-methylbenzaldehyde as starting materials afforded 0.8 g (28%) of 74A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.33 (s, 3H), 4.40 (m, 1H), 4.71 (m, 1H), 4.82 (m, 1H), 5.19 (m, 2H), 6.61 (s, 1H), 7.54 (t, 2H), 7.60 (t, 1H), 7.73 (d, 1H), 7.75 (s, 1H), 8.18 (d, 2H), 9.89 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:9]=1
Reactant: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2cc(C(=O)O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
A mixture of methyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylate (700 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (5 mL) and ethanol (3 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylic acid (610 mg, yield 90%). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 192-193° C.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([C:14](=[O:15])[N:13]([CH3:16])[CH2:12][CH:11]2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:13]1[CH2:12][CH:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[C:14]1=[O:15]
Reactant: CN1CC(c2cccnc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2cccnc2)C2(CCCNC2)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-Methyl-1-oxo-4-pyridin-3-yl-2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester [from diastereomer 1] (200 mg, 0.58 mmol) in DCM (5 ml) was cooled with an ice bath and TFA (0.70 ml, 8.68 mmol) was added. The resulting solution was stirred for 3 h at 0° C. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH solution (8 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(C=CC2CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCC2CCCCC2)cc1

Procedure:
The intermediate from Example 16, N-(p-cyclohexylvinylphenethyl)phthalimide (9.0 g) and 10% palladium on charcoal (0.9 g) in ethyl acetate (700 ml) is shaken with hydrogen at 3 atmospheres pressure over 7 hours. The mixture is filtered and the filtrate concentrated to dryness at reduced pressure to give N-[p-(2-cyclohexylethyl]-phenethyl]-phthalimide, m.p. 135°-138° after recrystallization from ethanol. The phthalimide (5.75 g) is added to a mixture of hydrazine hydrate (1.6 g) in methanol (100 ml) and heated under reflux for 18 hours. The mixture is concentrated to dryness at reduced pressure, made basic with cold concentrated aqueous potassium hydroxide and extracted with ethyl acetate. The organic extract is washed with water, then brine, dried over sodium sulphate and concentrated to dryness at reduced pressure to give the desired amine as an oil which gradually solidifies on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].Cl[C:16]1[C:17]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[C:17]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10]
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1F

Procedure:
The compound was prepared analogously to Example 1 by using (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (purchased from Combi Blocks) and tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate. m/z=287 (M+1-100).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, methanesulfonyl chloride (7.6 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and 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=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[NH:23]1[CH2:26][CH:25]([CH2:27][N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)[CH2:24]1>>[N:28]1([CH2:27][CH:25]2[CH2:26][N:23]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:24]2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: c1cnn(CC2CNC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Product: c1cnn(CC2CN(c3c4c(nc5ccnn35)CCNCC4)C2)c1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) 1-azetidin-3-ylmethyl-1H-pyrazole was used as the amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21][C:22](=O)[C@H:23]([OH:30])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21][CH2:22][C@@H:23]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:30])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)[C@H](O)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC[C@H](O)c1cccnc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of (2R)-N-((1R)-2-(7-(benzyloxy)-1H-indol-3-yl)-1-methylethyl)-2-hydroxy-2-pyridin-3-ylacetamide (283 mg, 0.681 mmol) in tetrahydrofuran (15 mL) is added a 2M solution of boranedimethyl sulfide complex in tetrahydrofuran (2.04 mL, 4.09 mmol), and the mixture is refluxed for 3 hours. To the reaction solution is added a 10% hydrogen chloride solution in methanol (30 mL), and the mixture is stirred for 30 minutes. The solvent is evaporated, and the residue is separated into a saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer is washed with a saturated brine, and dried over sodium sulfate. The solvent is distilled off, and the obtained crude product is purified by silica gel column chromatography (a saturated ammonia solution in chloroform-methanol=100:1) to give the title compound (184.8 mg, yield: 68%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1>CCO>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][N:41]([CH2:27][CH:25]([OH:26])[CH2:24][N:11]3[C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=4[C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=4)=[N:12]3)[CH2:40][CH2:39]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2ccn(C3CCNCC3)c2c1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(n3ccc4ccc(Cl)cc43)CC2)C1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
To a stirred solution of 86 mg (0.21 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine in 4 mL of EtOH was added 50 mg (0.39 mmol) of 6-chloro-1-piperidin-4-yl-1H-indole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, gradient elution from 0-5% 2 N NH3/MeOH in CH2Cl2) to afford 64 mg (48%) of a white solid. MS (electrospray), exact mass calculated for C30H33ClF3N5O3S: 635.19. m/z found, 636.2 [M+H]+. HPLC (reverse phase conditions 10-90%), tR=4.88 min. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.67 (A and B of AB quartet, J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34 (s, 1H), 7.18 (d, J=3.33 Hz, 1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50 (d, J=3.33 Hz, 1H), 4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz, 2H), 4.24 (dd, J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd, J=13.69, 6.46 Hz, 1H), 3.69 (m, 2H), 3.15 (br d, J=11.54 Hz, 1H), 3.11-2.91 (m, 3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H), 2.13-1.93 (m, 4H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2.Cl>CCCCCC.CCOCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Temperature: -45 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of dry ether (600 ml) and 15% BuLi in hexane (500 ml) was cooled to -45° C. A solution of 4-bromo-1-fluorobenzene (145 g) in dry ether (350 ml) was added dropwise at -45° C. followed by stirring for 1 h. A solution of 8-methyl-8-azabicyclo[3,2,1]octan-3-one (85 g) in dry ether (400 ml) was added dropwise at -50° C. followed by stirring for 30 min, the temperature raising to -20° C. The reaction mixture was poured into 2M hydrochloric acid and the phases separated. The ether phase was extracted with 2M hydrochloric acid and the combined aqueous phases made alkaline with aqueous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo, gave 3-(4-fluorophenyl)-3-hydroxy-8-methyl-8-azabicyclo[3,2,1]octane (96 g) as a solid, mp: 169° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:4][CH:3]1[C:5]([O:7][CH3:8])=[O:6].[CH2:10]([OH:12])[CH3:11]>Cl(O)(=O)(=O)=O>[CH2:10]([O:12][C:2]([CH3:9])([CH3:1])[CH:3]([OH:4])[C:5]([O:7][CH3:8])=[O:6])[CH3:11]
Reactant: COC(=O)C1OC1(C)C
Reactant: CCO
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(C)(C)C(O)C(=O)OC
Temperature: 50 °C
Yield: 91.6 %

Procedure:
Methyl 3,3-dimethylglycidate (20.0 g, 0.154 mmol) and ethanol (30 mL) were introduced into an eggplant type flask (100 cc) and stirred at room temperature while 70% perchloric acid (5 drops) was added gradually. The resulting reaction solution was heated at 50° C. for 2 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a small amount of anhydrous sodium carbonate was added. The reaction solution was left to stand at room temperature for a while, and then the solid was removed by filtration to obtain methyl 3-ethoxy-2-hydroxy-3-methylbutanoate (24.9 g, yield 91.6%) as a transparent liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:36].[Ca+2].[OH-:38]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)(=[O:38])=[O:36])[CH:12]=[CH:11]3)=[CH:6][CH:7]=1
Reactant: Cn1ccnc1Sc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: Cn1ccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
2-{[6-(4-Fluorophenyl)-2-naphthyl]thio}-1-methyl-1H-imidazole (125 mg, 0.4 mmol) was dissolved in CH2Cl2 (1 mL) and was cooled to 0° C. 3-Chloroperbenzoic acid (224 mg, 1.0 mmol) was added and the solution stirred at ambient temperature for 1.5 h. The solution was diluted with CH2Cl2 (1 mL) and calcium hydroxide (277 mg, 0.6 mmol) was added. The suspension was stirred for 30 minutes before filtering through a pad of Hyflo; the liquors were evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 55% ethyl acetate/isohexane, to give the title compound as a white solid (67 mg). 1H NMR (500 MHz, d6-DMSO): δ 8.74 (1H, s), 8.36 (2H, m), 8.22 (1H, d, J=8.7 Hz), 8.04 (1H, d, J=8.6 Hz), 7.93-7.91 (3H, m), 7.50 (1H, s), 7.38 (2H, t, J=8.8 Hz), 7.12 (1H, s), 3.97 (3H, s); m/z (ES+) 367 [MH+].
Reaction SMILES: [S:1]1(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18].[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]1(=[O:18])(=[O:12])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1CCCCc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 213.2 %

Procedure:
To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide ((4R,5R)-XXIV) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol, Sigma) at 0° C. After stirring at 0° C. for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na2SO3 was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHCO3 solution. The methylene chloride layer was separated, dried over MgSO4, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide ((4R,5R)-XXV) as a light yellow solid: 1H NMR (CDCl3) d 0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J=15.6 Hz, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 5.48 (s, 1H), 6.54 (dd, J=10.2 Hz, 2.4 Hz, 1H), 6.96-7.07 (m, 3H), 7.40 (d, J=8.1 Hz, 2H), 8.11 (dd, J=8.6 Hz, 5.9 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]([CH2:13][C:14](OC)=[O:15])[C:10](=[O:18])[N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pd]>[O:18]=[C:10]1[N:11]2[CH2:13][C:14](=[O:15])[NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:12]=32)[N:9]1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reaction time: 2 h

Procedure:
A mixture of dimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate from Step B (270 mg, 0.84 mmol) and 10% Pd/C (50 mg) in MeOH (100 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 2 h, the reaction was filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in toluene (3 mL) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) was added. The mixture was heated at reflux for 30 min and then concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][NH:25][C:26](C3C=CC=CC=3)([C:33]3C=CC=CC=3)[C:27]3C=CC=CC=3)=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:46]>CO.CC(C)=O>[ClH:46].[ClH:46].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:45])[CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([NH:24][N:25]=[C:26]([CH3:27])[CH3:33])=[CH:22][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCC(O)COc2ccc(NNC(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1OC
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(CCNCC(O)COc2ccc(NN=C(C)C)nn2)cc1OC

Procedure:
A solution of 3-[3-[[2-(3.4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]-6-(2-triphenylmethylhydrazino)pyridazine (330 g) and 37% hydrochloric acid (0.12 liter) in methanol (0.5 liter) and acetone (0.5 liter) was heated at reflux for 3 hours, then the solvent was evaporated under vacuum. The residue was diluted with n-butanol (100 ml). evaporated to dryness and triturated with acetone (1 liter) to afford 235 g of crude product which was dissolved in hot methanol (0.65 liter). The solution was filtered and dilured, while hot, with acetone (1.6 liter).
Reaction SMILES: [CH3:1][CH:2]([N:11]1[C:15](=[O:16])[CH:14]=[C:13](Cl)[NH:12]1)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([Cl:10])[CH:4]=1.[NH3:18]>C(O)C>[NH2:18][C:13]1[NH:12][N:11]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([Cl:10])[CH:4]=2)[C:15](=[O:16])[CH:14]=1
Reactant: Cc1ccc(C(C)n2[nH]c(Cl)cc2=O)cc1Cl
Reactant: N
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(N)cc2=O)cc1Cl
Temperature: 150 °C

Procedure:
0.2 mol of 1-(α-methyl-3-chloro-4-methylbenzyl)-3-chloropyrazol-5-one was dissolved in 100 ml of ethanol, 17 g of ammonia were added and the mixture was heated to 150° C for 2 hours in a stirred autoclave. After concentrating the reaction solution, the crude product was obtained. It was recrystallized twice from ethanol.