Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl.CCOCC>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:29])=[O:28])[N:24]=[CH:23]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred ice-cold solution of tert-butyl piperazine-1-carboxylate (C1, 10.0 g, 53.76 mmol) in CH2Cl2 (50 mL) at 0° C. was added Et3N (22.66 mL, 161.29 mmol) and a solution of 1-methyl-1H-imidazole-4-sulfonyl chloride (11.61 g, 64.51 mmol) in CH2Cl2 (50 mL) drop wise over 30 minutes while maintaining the temperature of the reaction mixture below 5° C. and under an atmosphere of N2. The reaction mixture was warmed to room temperature and stirred for an additional 5 h then quenched with a saturated solution of NaHCO3 (50 mL). The aqueous mixture was extracted with CH2Cl2 (3×100 mL), and the combined organic extracts were washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a crude solid. The solids were suspended in Et2O and stirred for 30 minutes at room temperature then filtered, washed with cold diethyl ether and dried under vacuum to afford tert-butyl 4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazine-1-carboxylate (36) as an off-white solid (16.8, 95%): 1H NMR (300 MHz, CDCl3) δ (dd, J=1.5 Hz, 14.56 Hz, 2H), 3.76 (s, 3H), 3.55-3.45 (m, 4H), 3.20-3.10 (m, 4H), 1.43 (s, 9H); MS (ESI+) m/z 331 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[C:8](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])[CH:7]=[CH:6]2.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:24][C:23](=[O:25])/[CH:22]=[CH:21]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(-c2c(/C=C/C(=O)O)ccc3cc(OC)ccc23)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc3cc(OC)ccc23)cc1

Procedure:
As in Example 113, (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid (1.4 g) was reacted with 4-nitrophenol (0.64 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (0.87 g) overnight at room temperature to give, after the normal work up and crystallization of the crude product from 2-propanol, 1.6 g of (E)-3-[6-methoxy-1-(4-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester, mp 160°-161° C. Anal. Calcd for C27H21NO6 : C, 71.20; H, 4.65; N, 3.08 Found: C, 70.87; H, 4.89; N, 3.06
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[CH2:18][CH2:19][CH2:20][S:21]2(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1Cc1ccc(Br)cc1
Yield: 93.7 %

Procedure:
A solution of 4-bromobenzylamine (1.85 g, 10 mmol) and triethylamine (2 g, 20 mmol) in dimethylformamide (30 ml) was treated with 3-chloropropanesulfonyl chloride (1.78 g, 10 mmol) by dropwise addition over 10 minutes with stirring under argon. This mix was stirred for 30 minutes before being treated with a 60% suspension of sodium hydride in mineral oil (1.2 g, 30 mmol of NaH) portionwise and the whole mix stirred at room temperature for 3 days. The reaction mixture was partitioned between water (50 ml) and dichloromethane (30 ml). The organic layer was dried over sodium sulphate and reduced to minimum volume by rotary evaporation. The residue was added to a 20 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.72 g, 94%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:6]1=2.C(C(O)=O)(F)(F)F.[ClH:35]>C(Cl)Cl.CCOC(C)=O.CCOCC>[ClH:35].[CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:6]1=2
Reactant: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCNCC2
Reaction time: 0.67 h
Yield: 95 %

Procedure:
tert-Butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.113 g, 0.305 mmol) was dissolved in CH2Cl2 (3 mL) at rt. CF3CO2H (1 mL) was added and the reaction mixture was stirred for 40 min. The reaction mixture was concentrated to give a crude product (0.145 g). The crude product was dissolved in EtOAc (3 mL), then 1 N HCl in Et2O (6 mL) was added and the precipitated salt was collected by filtration. N,N-Dimethyl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide hydrochloride (0.0896 g) was obtained in 95% yield. 1H NMR (300 MHz, CD3OD) δ 2.99, 3.14-3.17, 3.21-3.24, 3.26, 3.47-3.50, 5.16, 7.08, 7.15, 7.30, 7.50; MS (ESI+) for C16H21N3O m/z 272.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a solution of crude methyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D13) (54 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and the residue was purified by Mass Directed AutoPrep (basic conditions) to give 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E4) (10 mg) as a TFA salt (off-white solid). δH (DMSO-d6, 400 MHz): 1.09 (3H, t), 1.35 (6H, d), 2.89 (2H, m), 3.61 (2H, m), 4.28 (3H, br. s.), 4.53 (2H, m), 4.84 (1H, m), 7.38 (1H, d), 7.44 (1H, m), 7.58 (2H, m), 7.96 (1H, dd), 8.10 (1H, d), 13.06 (1H, br s). δF (DMSO-d6, 376 MHz): −73.4. MS (ES): C24H26ClN3O3S requires 471. found 472.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:35][C:36]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)=[O:37])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[C@H:21]([CH3:22])[C:20](=[O:23])[N:19](CC4C=CC(OC)=CC=4)[S:18]3(=[O:34])=[O:33])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:35][C:36]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)=[O:37])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[C@H:21]([CH3:22])[C:20](=[O:23])[NH:19][S:18]3(=[O:34])=[O:33])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)[C@@H](C)N(Cc3cccc(-n4nc(C(C)(C)C)cc4NC(=O)Nc4cccc5ccccc45)c3)S2(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NS(=O)(=O)N1Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)c1

Procedure:
A solution of 1-(5-t-Butyl-2-{3-[5-(4-methoxy-benzyl)-(R)-3-methyl-1,1,4-trioxo-1λ6-[1,2,5]-thiadiazolidin-2-ylmethyl]-phenyl}-2H-pyrazol-3-yl)-3-naphthalen-1-yl-urea (20 mg, 0.030 mmol) in trifluoroacetic acid (2 mL) was stirred at 50° C. for 4 h. After the solvent was removed, the residue was purified by preparative-HPLC to afford 1-{5-t-butyl-2-[3-((R)-3-methyl-1,1,4-trioxo-1λ6-[1,2,5]thiadiazolidin-2-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-3-naphthalen-1-yl-urea as a white power (6 mg). 1H NMR (DMSO-d6): 8.99 (s, 1H), 8.80 (s, 1 H), 8.00 (d, J=7.2 Hz, 1 H), 7.90 (d, J=7.2 Hz, 2 H), 7.60-7.64 (m, 2 H), 7.44-7.54 (m, 7 H), 6.41 (s, 1 H), 4.31-4.49 (dd, J=8.0 Hz, 2 H), 4.03 (q, J=7.6 Hz, 1 H), 1.27 (s, 9 H), 1.19 (d, J=8.0 Hz, 3 H). MS (ESI) m/z: 533 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.Cl>O1CCCC1.O>[CH2:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:7]=2)[CH:11]=[CH:10]1
Reactant: OC1CCc2cc(-c3nccs3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C1=Cc2ccc(-c3nccs3)cc2C1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of 5-(1,3-thiazol-2-yl)indan-1-ol (900.00 mg, 0.0041420 mol) in tetrahydrofuran (20.00 mL) was added a 1.0 M solution of hydrogen chloride in water (20.00 mL). The reaction mixture was heated to reflux overnight. After cooling down to room temperature, the reaction was quenched with 30 mL of 1 N NaOH aqueous solution. The organic layer was separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford the desired product (381 mg, 46%). LC-MS [M+1]=200.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.7 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in DMF (3 mL) was added 4-tert-butylphenyl isocyanate (54 μL, 0.3 mmol) and the solution stirred at 50° C. for 4 h. The reaction was allowed to cool to room temperature, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (54 mg, 0.11 mmol, 38%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.40-7.21 (m, 7H), 6.91 (d, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 473 (M+14)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([NH:21]C(=O)OC(C)(C)C)([CH3:20])[CH3:19])=[C:14]([C:31]2[N:32]([CH3:37])[N:33]=[CH:34][C:35]=2[Br:36])[CH:13]=1.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C:18]([CH3:20])([CH3:19])[CH2:17][O:16][C:15]1[CH:29]=[CH:30][C:12]([NH:11][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][C:14]=1[C:31]1[N:32]([CH3:37])[N:33]=[CH:34][C:35]=1[Br:36]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OCC(C)(C)N
Reaction time: 8 h

Procedure:
4-Fluorobenzoyl chloride (6.63 μL, 0.056 mmol) was added to a solution of tert-butyl 1-(4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)phenoxy)-2-methylpropan-2-ylcarbamate (0.25 mL of a 0.2M solution in dichloromethane, 0.050 mmol) and N,N-diisopropylethylamine (13.1 μL, 0.075 mmol) in dichloromethane (0.5 mL) and the reaction vessel was agitated on a mechanical shaker overnight. TFA (0.25 mL) was added, and the reaction vessel was shaken for another 30 min. The solvent was evaporated in vacuo, and the crude product was purified by RP-HPLC and lyophilized to give the title compound as a TFA-salt (26 mg, 92%). LCMS m/z (%)=463.2 (M+H 81Br 43%), 461.2 (M+H 37Br 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (s, 3 H), 1.11 (s, 3 H), 3.60 (s, 3 H), 3.76 (d, J=9.60 Hz, 1 H), 3.92 (d, J=9.85 Hz, 1 H), 7.21 (d, J=9.09 Hz, 1 H), 7.27-7.36 (m, 2 H), 7.60 (s, 1 H), 7.62 (d, J=2.53 Hz, 1 H), 7.86 (s, 3 H), 7.87 (dd, J=9.09, 2.53 Hz, 1 H), 7.93-8.00 (m, 2 H), 10.30 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)cc1

Procedure:
To a dispersion of 3.6 grams (0.017 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile and 4.7 g (0.02 mol) of 4-acetamidobenzenesulfonyl chloride in 50 ml of chloroform is added 2 ml of pyridine. There is an exothermic reaction and an upper yellow, oily layer is formed. After 48 hours at room temperature 50 ml of chloroform are added, followed by water. The water and chloroform layers are separated and discarded, and the oily layer is shaken with water, separated and then dissolved in 30 ml ethanol. After cooling, crystals are recovered having a melting point of 204°-205° C and consisting of 3-[4-(4-ACETAMIDOBENZENESULFONAMIDO)BENZENESULFONYL]acrylonitrile: ##SPC35##
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH2:20])[CH:17]=3)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1C[O:25]CC1.[OH-].[Na+].OO>C1COCC1.O>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][OH:25])[CH:17]=3)[NH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCO)cc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of 3-(phenylsulfonyl)-5-vinyl-1H-indole (1.9 g, 6.7 mmol) in THF (10 mL) at 0° C. was added dropwise BH3-THF (6.7 mL of 1 M THF solution, 6.7 mmol). The solution was stirred for 3 hours at 0° C., and H2O (7 mL) was added slowly. To this mixture was added 10% NaOH (10 mL), 30% H2O2 and the mixture was stirred vigorously at room temperature for 15 hours. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ethyl acetate/dichloromethane) gave the title compound as a white solid (1.5 g, 76%). Mp: 55-60° C. MS (ES−): 300 (M−H)
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1/[CH:9]=[CH:10]/[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[NH:8][CH:7]=[N:6][C:5]=1/[CH:9]=[CH:10]/[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(/C=C/c2nc[nH]c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(/C=C/c2nc[nH]c2N)cc1
Reaction time: 24 h
Yield: 71.3 %

Procedure:
5% Palladium on carbon (0.5 g) was added to a solution of (E)-4-(2-(5-nitro-1H-imidazol-4-yl)vinyl)benzonitrile (10 g, 0.04 mol) in methanol (500 mL) and the resulting mixture hydrogenated at atmospheric pressure for 24 hours. The catalyst was removed by filtering through a short bed of Celite™, and the Celite™ washed with 10% MeOH/DCM (200 mL). The filtrate was evaporated to dryness and purified by column chromatography (10% MeOH/DCM) to leave the product as a yellow/brown solid (6 g, 69%). δH (DMSO-d6) 11.76 (1H, bs, NH), 7.70 (2H, d, J=8.4), 7.50 (2H, d, J=8.4), 7.44 (1H, d, J=16.0), 7.36 (1H, s), 6.42 (1H, d, J=16.0), 5.17 (2H, bs, NH2); IR (cm−1) 2220 (CEN), 1629 (C═C); MS (m/z) 211.0969 (C12H11N4 (M+1)) requires 211.0984.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:1][C:2]2[C:11]3[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: Nc1cccc2c1CC(O)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1cccc(Br)c1)Nc1cccc2c1CC(O)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.8 %

Procedure:
To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (500 mg, 3.06 mmol) and 3-bromophenylacetic acid (725 mg, 3.37 mmol) in DMF was added triethylamine (465 mg, 4.60 mmol), l-hydroxybenzotriazole (497 mg, 3.68 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (705 mg, 3.68 mmol). The mixture was stirred for 16 hours at room temperature. To the product mixture was added water and extracted with ethylacetate. The organic layer was washed with aqueous HCl solution then aqueous NaOH solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (hexane:acetone, 2:1) to afford 2-(3-bromophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (130 mg, 12% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])C2C=CC=CC=2)=O)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:8]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(c1ccccc1)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a suspension of 4-fluoro-N-(2-hydroxyphenyl)-3-nitrobenzanilide (see Working Example 15-1) (2.00 g, 7.24 mmol) in toluene (50 mL) was added p-toluenesulfonic acid monohydrate (2.07 g, 10.9 mmol), and this was stirred and heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, and after the solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added and this was stirred for 10 minutes at room temperature. The precipitated crystals were filtered off, and after washing with toluene the crystals were dried to yield the title compound (1.30 g, 70% yield) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C[Al](C)C.C[O:16][C:17](=O)[C:18]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=1[NH2:25].Cl>C1(C)C=CC=CC=1>[NH2:25][C:19]1[CH:20]=[CH:21][C:22]([Br:24])=[CH:23][C:18]=1[C:17]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:16]
Reactant: COc1ccccc1CN
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccccc1CNC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 2-methoxy benzylamine (10 g, 73 mmol) was suspended in anhydrous toluene (30 ml). This suspension was cooled down in ice bath and (2 M) trimethyl aluminum solution in hexanes (36 ml, 72 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 hour after the completion of the addition. The resulting solution was then cooled in an ice bath and methyl-2-amino-5-bromobenzoate was added in small portions. The reaction was allowed to stir at room temperature overnight. This solution was poured into a pre-cooled solution 2N HCl (300 ml). The solid obtained was collected by filtration and triturated in methanol (50 ml). The solid was collected and dried under high vacuum oven at 65° C. overnight. Pure product was recovered (16 g). 1H NMR (DMSO) δ=3.8 (s, 3H), 4.35 (sd, 2H), 6.5 (2H), 6.6 (1H), 6.85 (1H), 6.9 (1H), 7.1–7.25 (3H), 7.7 (1H), 8.7 (br, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=O)(C)(C)C.ClCl.C(O)(C(F)(F)F)=O>>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:11]1[CH2:10][CH:9]2[CH2:15][CH2:14][CH:12]1[CH2:13][NH:8]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC1CC2Cc1ccc(Cl)c(Cl)c1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CC2CC3CCC2CN3)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 5-(3,4-dichloro-benzyl)-2-aza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (0.24 g, 0.65 mmol) in 2 mL of CH2 Cl2 was added 1 mL of TFA. After the mixture was stirred at rt for 1 h, it was quenched with NaHCO3 (sat.). It was then extracted with CH2Cl2 and the organic layer was washed with NaCl (sat.), dried over Na2SO4 and concentrated to give 170 mg of 5-(3,4-Dichloro-benzyl)-2-aza-bicyclo[2.2.2]octane (M++1: 270).
Reaction SMILES: C[Li].[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:13]1[CH:16]([CH2:17][C:18]([C:20]2C=CC=CC=2)=S)[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4].[NH4+].[Cl-].CC[O:54]CC>C1COCC1.C(Cl)Cl>[N+:3]([C:6]1[CH:49]=[CH:48][CH:47]=[CH:46][C:7]=1[CH2:8][O:9][C:10]([CH:12]([PH:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[N:13]1[CH:16]([CH2:17][C:18]([CH3:20])=[O:54])[CH2:15][C:14]1=[O:26])=[O:11])([O-:5])=[O:4]
Reactant: O=C(OCc1ccccc1[N+](=O)[O-])C(N1C(=O)CC1CC(=S)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CC1CC(=O)N1C(C(=O)OCc1ccccc1[N+](=O)[O-])[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
Cuprous iodide (0.380 g) is suspended in 10 ml anhydrous ether under N2, in a dry flask and cooled to 0°. Methyl lithium (3.0 ml, 1.3 Molar) is added dropwise and the mixture is stirred at 0° for 5 min to give a yellow suspension. The mixture is then cooled to -50°. 1-(o-nitrobenzyloxycarbonyl-triphenylphosphoranylmethyl)-4-(phenylthiocarbonylmethyl)-2-azetidinone (0.674 g) in 10 ml THF is added dropwise over 5 min. The mixture is stirred at -50° for 5 min and allowed to come to -20° over 20 min and stirred at -20° for 5 min. Saturated NH4Cl solution 5 ml is added and the mixture is diluted with CH2Cl2. Stirred at r.t. for 5 min. The organic phase is separated, dried and evaporated. The residue is chromatographed on silica gel using EtOAc as eluant to give 0.162 g of the product 0.112 g of recovered thio ester.