Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][CH2:19][C:14]=3[C:13]([C:24]([OH:26])=O)=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:27]>CO>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][CH2:19][C:14]=3[C:13]([C:24]([NH2:27])=[O:26])=[N:12]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(=O)O)c3c2-c2ccccc2OC3)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1nn(-c2ccc(S(N)(=O)=O)cc2)c2c1COc1ccccc1-2
Temperature: 60 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
To a suspension of methyl ester of 1-[4-(aminosulfonyl)phenyl]-1,4-dihydro-[1]benzopyrano[4,3-c]pyrazole-3-carboxylic acid (0.77 g, 2.0 mmol) in MeOH (50 ml) in a pressure tube, liquid NH3 (5 ml) was added. The pressure tube was sealed at RT and then heated to 60° C. overnight. The suspension became clear solution. After 24 h, the solution was cooled to RT and pressure was relieved. The solvent was removed under reduced pressure. The resulting white solids were recrystallized in MeOH, to yield pure product 1-[4-(aminosulfonyl)phenyl]-1,4-dihydro-[1]benzopyrano[4,3-c]pyrazole-3-carboxamide (0.3584 g, 48%). Mass (MH+) 137. Anal. Calc'd for C17H14O4N4S+0.4H2O: C, 54.08; H, 3.95; N, 14.86. Found: C, 54.13; H, 3.90; N, 14.86.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])([O-:3])=[O:2].B1([O-])O[O:19]1.O.O.O.O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][C:9]=1[C:10]([OH:19])=[O:11])([O-:3])=[O:2]
Reactant: O=Cc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86.3 %

Procedure:
This aldehyde (454 mg, 2.0 mmol) was dissolved in acetic acid (10 ml) and treated with sodium perborate tetrahydrate (385 mg, 2.5 mmol), the mixture was heated to 50° C. for 48 h then cooled, concentrated to a paste and washed with water (2×50 ml). The residue was dried in a desiccator to afford 3-nitrobiphenyl-4-carboxylic acid as a white solid (420 mg, 87%);
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16][CH3:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: CSc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-(3-iodo-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (7.0 g, 18.7 mmol) in DMF (70 mL) was added NaH 60% in mineral oil (1.5 g, 37.4 mmol) followed by TsCl (5.3 g, 28.1 mmol). The reaction was stirred at RT for 8 h, and the mixture was then poured into ice/H2O. The resulting precipitate was filtered, washed with water and dried to give 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (7.7 g, 78%). MS (ESI, pos. ion) m/z: 528 (M+1); 1H-NMR (DMSO-d6, 300 MHz): 2.3 (s, 3H), 2.8 (s, 3H), 7.4 (d, 2H) 7.8 (d, 1H) 7.95 (m, 3H), 8.1 (d, 1H), 8.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[C:17]([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid (1.08 g, 5.02 mmol) in methanol (20 mL) is treated with H2SO4 (0.20 mL). The mixture is stirred at 80° C. for 16 hours and cooled to room temperature. The mixture is neutralized with aqueous Na2CO3 and concentrated, the residue is extracted with ethyl acetate (30 mL×2) and the combined organic layers are dried over sodium sulfate and concentrated to provide 4-bromo-2-methyl-benzoic acid methyl ester (1.25 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.40 (s, 1H), 7.35 (d, 1H), 3.82 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([NH2:13])=O)[CH2:7][CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:13][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C:2]([F:15])([F:1])[F:14])[CH2:6][CH2:7]1
Reactant: NC(=O)C1CCN(CCC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(CCC(F)(F)F)CC1
Yield: 96 %

Procedure:
Prepared from 1-(3,3,3-trifluoropropyl)-piperidine-4-carboxamide (1.0 g, 4.46 mmol) and LAH (0.34 g, 8.9 mmol) according to general the procedure used for Example 8 (Step B) to give 0.9 g of title compound as a white solid.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1[CH:10]=[CH:9][NH+:8]=[CH:7][CH:6]=1)#[N:3].Cl[CH2:12][CH2:13][N:14]([CH2:22][CH2:23]Cl)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[C:2]([C:4]1([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:23][CH2:22][N:14]([C:15]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:21])[CH2:13][CH2:12]1)#[N:3]
Reactant: N#CCc1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
4-Cyanomethylpyridinium hydrochloride (1.0 g, 6.5 mmol), 2.0 g tert-butyl bis(2-chloroethyl)carbamate (J. Med. Chem. 1992, 35, 11, 2033-2039) (8.1 mmol), 9.1 g caesium carbonate (28 mmol) and 20 ml DMSO were combined in a round bottom flask and stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate and the organic layer washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The product was purified by column chromatography on silica, using a gradient from 10% to 100% ethyl acetate in hexanes as eluent. 778 mg of the title compound were isolated as an oil (42% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:44][CH2:45][C:46]1[N:51]=[CH:50][C:49]([C:52](=[N:54]O)[NH2:53])=[CH:48][CH:47]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:54]=[C:52]([C:49]3[CH:48]=[CH:47][C:46]([CH2:45][OH:44])=[N:51][CH:50]=3)[N:53]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)cn1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)nc3)no2)cc1Cl

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 3-chloro-4-isobutylbenzoic acid (0.13 g, 0.61 mmol) that was obtained in Example 24 (24h), 1-hydroxybenzotriazole (86 mg, 0.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.64 mmol), 6-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxypyridine-3-carboximidamide (0.16 g, 0.58 mmol) that was obtained in Example 23 (23c), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:3 to 1:1) as the eluent to afford the title compound (0.19 g) in a yield of 94% as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:8]([CH3:24])[NH:7][C:6]=1[CH3:25])=[O:4]>C(O)(=O)C>[CH3:23][O:22][C:20]([C:9]1[C:8]([CH3:24])=[N:7][C:6]([CH3:25])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1ccccc1[N+](=O)[O-]
Yield: 83 %

Procedure:
Over a boiling solution of 3 kg (8.7 mol) of 2,6-dimethyl-4-(2nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3,5-dimethyl ester in 8,251 of acetic acid, 870 g (8.7 mol) of CrO3 were portionwise added, with stirring. When the addition was complete, the reaction mixture was refluxed with stirring for one additional hour. When the mixture reached the room temperature, it was slowly poured, with stirring, over 22.5 1 of a mixture of 25% aq. H4NOH and ice (2:1), and the product precipitated. The solid was isolated by filtration, washed with water until neutral pH, and crystallised (mp 99-101° C., MeOH) with a yield of 83%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl>C(OCC)C>[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[C@@H:24]([OH:25])[CH2:11][C@@H:10]([CH3:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[C@H](CBr)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C[C@@H](COCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
A Grignard solution prepared from 3.6 g of (S)-(+)-3-benzyloxy-2-methyl-propyl bromide (A. Fischli et al., Helv. Chim. Acta 60, 925 (1977)) and 360 mg of magnesium in diethyl ether is added dropwise within 15 minutes at 0° to 1.50 g of 2(S)-tert.-butoxycarbonylamino-3-cyclohexyl-propionaldehyde (J. Boger et al., J. Med. Chem. 28, 1779 (1985)) in 15 ml of diethyl ether After 30 minutes at 0°, the reaction solution is poured onto 50 ml of 1N HCl and the crude product (diastereoisomer ratio (4S):(4R)=4:1) is extracted with dichloromethane. The desired diastereoisomer having the 4(S)-configuration is isolated in pure form by flash chromatography on 250 g of silica gel 60 (eluant dichloromethane/ether 20:1). Rf (L)=0.10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: CCc1ccccc1NCc1nnn(C)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: CCc1ccccc1N(Cc1nnn(C)n1)[C@H]1c2cc([N+](=O)[O-])ccc2O[C@](C)(C(OC)OC)[C@@H]1O
Yield: 22 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (270 mg, 0.98 mmol) obtained in step 1 of example 2 and N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (100 mg, yield: 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BrH:12].BrBr.C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])=[O:11]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: Br
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To an ice-cooled solution of 2′,5′-dichloroacetophenone (1.0 g, 5.0 mmol) in acetic acid (10 mL) was added HBr (˜1%) followed by a solution of bromine (0.80 g, 5.0 mmol) in acetic acid (3 mL). The resultant mixture was warmed to room temperature and stirred overnight. The mixture was poured into ice water and then neutralized with saturated aqueous sodium carbonate solution. Saturated aqueous sodium thiosulfate solution was then added to the mixture. The resultant mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography afforded 2-bromo-1-(2,5-dichlorophenyl)ethanone as an oil (0.70 g, 50% yield). 1H NMR (400 MHz, CDCl3): 7.54 (d, J=2.4 Hz, 1H), 7.43 (m, 1H), 7.40 (m, 1H), 4.68 (s, 2H).
Reaction SMILES: O[CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH2:6]1.Cl>CO>[C:11]1([C:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]=[CH:2][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[CH2:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCc2cc(C(O)CCN3CC=C(c4ccccc4)CC3)ccc2N1
Agent: Cl
Solvent: CO
Product: O=C1CCc2cc(C=CCN3CC=C(c4ccccc4)CC3)ccc2N1

Procedure:
1.0 Gram of 6-[1-hydroxy-3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)propyl]-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol, then 2 ml of concentrated hydrochloric acid was added to the solution and the mixture was refluxed by heating for 2 hours. The reaction mixture was concentrated under a reduced pressure, then thus obtained residue was treated with 50 ml of 0.5% of sodium hydroxide and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried, next chloroform was removed by distillation at a room temperature then the residue thus obtained was recrystallized from ethanol to obtain 0.6 g of 6-[3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)-1-propenyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Melting point: 182°-183° C. (decomposed).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1C(Cl)Cl.[C:11](=[O:14])(O)[O-:12].[Na+]>C(O)C.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:11]([OH:12])=[O:14]
Reactant: Cc1nc(C(Cl)Cl)c(Br)s1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-(dichloromethyl)-2-methyl-1,3-thiazole (7.58 g, 29.0 mmol) in ethanol (180.0 mL) was added saturated aqueous sodium bicarbonate (60.0 mL) and the system was stirred at 80° C. overnight. The mixture was then cooled to room temperature, diluted with EtOAc, extracted with water, dried over sodium sulfate and concentrated. The crude reaction mixture was purified using normal phase conditions (0%→÷30% EtOAc: hexanes) to afford a mixture of the desired compound and an acetal byproduct. This mixture was then treated with 1N HCl (12.25 mL, 12.25 mmol) for 0.5 h at room temperature followed by neutralization with 2N NaOH to a pH of 7.0. Extraction with EtOAc and water afforded the product as a pale yellow crystalline solid. To this solid (5.0 g, 24.26 mmol) in THF/t-BuOH/Water (40 mL/80 mL/20 mL) was added sodium phosphate (17.22 g, 121.0 mmol), 2-methyl-2-butene (64.0 mL, 607 mmol) and sodium chlorite (5.49 g, 60.7 mmol) and was stirred at room temperature for 1 h. The system was then acidified with 1N HCl to a pH of 3.0, extracted with EtOAc, washed with water, dried over sodium sulfate and concentrated. Removal of solvent in vacuo afforded the title compound (2-5) as a powder. 1H NMR (500 MHz, CDCl3) δ 2.72 (s, 3H). ESI+ MS: 222.8 [M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.Cl[CH2:15][C:16]1[C:17]([CH3:25])=[C:18]([CH3:24])[CH:19]=[C:20]([CH3:23])[C:21]=1[CH3:22]>CCO.O>[CH3:22][C:21]1[C:20]([CH3:23])=[CH:19][C:18]([CH3:24])=[C:17]([CH3:25])[C:16]=1[CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:8][CH:9]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: Cc1cc(C)c(C)c(CCl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=O)c1ccc(OCc2c(C)c(C)cc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
NaOH (1.6 g, 40 mmol) is added to the solution of 1-(4-hydroxy-phenyl)-propan-1-one (3.0 g, 20 mmol) in EtOH (50 mL) and water (30 mL), followed by the addition of 3-Chloromethyl-1,2,4,5-tetramethyl-benzene (5.5 g, 30 mol). The resulting mixture is heated to turn into clear solution and stirred at room temperature overnight. The reaction is quenched by 1N HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, brine, dried (MgSO4), concentrated and chromatographed to afford the titled compound as a white solid (4.0 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccccc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:28])([CH2:25][CH:26]=[CH2:27])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C1CCN2C(=NCCC2)CC1>C1COCC1.N1C=CC=CC=1>[CH2:25]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:28][C:30](=[O:32])[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)[CH:26]=[CH2:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCNCC1CCN(c2ccccc2)CC1)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1(c2ccc(F)cc2)CCN(CC2CCN(c3ccccc3)CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (120 mg, 0.314 mmol) was dissolved in THF (30 mL) and pyridine (c.a. 500 μL, excess). A solution of triphosgene (60 mg, excess) in THF (5 mL) was added slowly in 4 batches. After stirring 4 h at rt, DBU (94 μL, 2 equiv.) was added and the mixture was heated to reflux for overnight. There was still a lot of starting material on LC-MS spectra. The mixture was concentrated, redissolved in EtOAc (40 mL), washed with 5% aq HCl (2×8 mL), brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-((1-phenylpiperidin-4-yl)methyl)-1,3-oxazinan-2-one (17 mg, 13%). LC-MS Method 1 tR=1.32 min, m/z=409 (M+1); 1H NMR (CD3OD) 7.62-7.53 (m, 4H), 7.39 (m, 2H), 7.13 (t, 2H), 5.67 (m, 1H), 5.04 (dd, 2H), 3.05 (m, 2H), 2.63 (d, 2H), 2.57 (d, 1H), 2.32 (m, 1H), 2.06 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N-:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:5]([OH:18])[C:6]([F:17])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C:8]=1[CH3:9])#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:17][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[C:4]2[C:5]=1[O:18][C:20]([CH:21]([CH3:23])[CH3:22])=[N:19]2
Reactant: Cc1c(C#N)c([N-]CC(C)C)c(O)c(F)c1-c1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc(O)c2)c(F)c2oc(C(C)C)nc2c1C#N
Yield: 54.4 %

Procedure:
A mixture of N-(5-cyano-2-fluoro-3,3′-dihydroxy-6-methylbiphenyl-4-yl)isobutylamide (I-56) (60 mg, 0.183 mmol), p-toluenesulfonic acid monohydrate (10.4 mg, 0.0548 mmol) and toluene (5 ml) was heated under reflux for 2.5 hours. After cooling, this was diluted with ethyl acetate, successively washed with 1 N hydrochloric acid and saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (30.9 mg, 54%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CN([C:30]([O:34][N:35]1N=NC2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[N:35]([O:34][CH3:30])[CH3:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (2.29 g, 10 mmol) in DMF (20 ml) was treated sequentially with N,N-diisopropylethylamine (4.0 ml), HATU (3.8 g, 10 mmol) and O,N-dimethylhydroxylamine.HCl (0.98 g, 10 mmol). The reaction mixture was stirred under argon at room temperature for 16 h. The volatiles were removed in vacuo and the residue was chromatographed (silica gel, diethyl ether) to afford the title compound as a white solid (2.60 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]O)[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:44]([C:51]([NH:53][O:54][C:55]([O:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:56])=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[NH2:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([CH2:23][N:53]([C:51]([O:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:52])[O:54][C:55]([O:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:56])=[N:11]2)=[CH:18][CH:17]=1)(=[O:21])=[O:20]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Cl)cc2)cc1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(-n2nc(CN(OC(=O)Oc3ccccc3)C(=O)Oc3ccccc3)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 4-[5-(4-chlorophenyl-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide from Step 4 (7.28 g, 0.02 mol), triphenylphosphine (6.29 g, 0.024 mol) and N,O-bis(phenoxycarbonyl)hydroxylamine prepared as described by A. O. Stewart and D. W. Brooks, [J. Org. Chem., 57, 5020-5023 (1992)] (6.01 g, 0.022 mol) in 250 mL of anhydrous tetrahydrofuran (THF) was cooled to 0° C. and treated with diisopropylazodicarboxylate (3.75 g, 0.024 mol) dissolved in 25 mL of THF. The solution was stirred at room temperature for 3 hours, concentrated in vacuo and the residue purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (2:3) to afford 9.30 g, 75% of the protected hydroxylamine as a thick clear oil that was used directly in the next step.