Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Ni].C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
A mixture of 3-(4-nitro-phenyl)-1-phenyl-prop-2-en-1-one (24.9 g, 98.3 mmol), Raney nickel (7.0 g), MeOH (100 mL), and THF (400 mL) was shaken in a hydrogen atmosphere of 51 psi at 20° C. for 18.5 hours. The catalyst was filtered, and the filtrate was concentrated. The residue was recrystallized from 95% EtOH, to give the title compound, m.p. 76-78° C. 1H NMR (CDCl3) δ 2.98 (t, 2 H), 3.25 (t, 2 H), 3.62 (bs, 2 H), 6.65 (d, 2 H), 7.05 (d, 2 H), 7.40-7.61 (m, 3 H), 7.96 (d, 2 H).
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][C@@H:32]([C:36](O)=[O:37])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[CH:1]1([N:4]([CH:5]([C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19]([O:20][CH3:21])=[O:22])[N:10]=[C:11]([O:13][CH3:14])[CH:12]=2)[CH3:6])[C:36]([C@@H:32]2[O:33][CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31]2)=[O:37])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: COC(=O)NC/C=C/c1cc(C(C)NC2CC2)cc(OC)n1
Product: COC(=O)NC/C=C/c1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc(OC)n1

Procedure:
Methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate and (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid were treated in the similar manner to Example 162 to give tert-butyl (2R)-2-({cyclopropyl[1-(2-methoxy-6-{(1E)-3-[(methoxycarbonyl)amino]prop-1-en-1-yl}pyridin-4-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(298-3)] as a colorless oil.
Reaction SMILES: C([CH:8]([NH2:32])[C:9]1[CH:31]=[CH:30][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(=O)OC(C)(C)C)=[O:14])=[CH:11][CH:10]=1)(OC(C)(C)C)=O.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:32][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[O:14])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 391 (840 mg, 1.9 mmol) in 2:1 mixture of DCM/TFA (6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound as a mixture of the mono and di-TFA salt. (1.33 g, 100% yield). LRMS: (calc) 241.2; (found) 242.2 (M+H1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].ClS([N:39]=[C:40]=O)(=O)=O.CN(C=O)C.[OH-].[NH4+]>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[C:40]#[N:39])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Yield: 6 %

Procedure:
To an ice-cooled solution of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole (173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen is added a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35 eq.) in 1 ml of acetonitrile, after stirring for 20 mim, a solution of DMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred for additional 1 h. The reaction mixture is poured into ice water and basified with diluted ammonium hydroxide solution; the mixture is extracted with dichloromethane, dried over sodium sulfate. The solvent is evaporated; the residue is purified through flash chromatography to give 11 mg of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.38 (1H, d, J=3Hz), 7.15˜7-36 (4H, m), 7.07 (4H, dd, J=1.2, 8.4 Hz), 6.89-6.93 (2H, m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d, f=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H, m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS (+VE) m/z 502 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC1C=C(C=C(C)C=1)N.Br[C:20]1[O:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:20]2[O:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Cc1cc(C)cc(S)c1
Agent: Cc1cc(C)cc(N)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2cc(C(=O)O)co2)c1

Procedure:
3,5-Dimethylthiophenol (4.33 g., 31.4 mmoles; prepared from 3,5-dimethylaniline by the procedures of Tarbell and Fukushima, Org. Synth. III, 809) and cuprous oxide (2.25 g., 15.7 mmoles) were reacted in 40 ml. of dimethylformamide at 140° C. for three hours. The mixture was cooled slightly and 5-bromofuran-3-carboxylic acid (3.0 g., 15.7 mmoles) in 40 ml. of dimethylformamide added. The mixture was refluxed for approximately 16 hours. Isolation of crude product as an oil was according to the procedure of Example 16 below. The oil was chromatographed on silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant. Product was recovered by evaporation of clean, middle fractions and trituration with water (706 mg.). Recrystallization from methanol/water gave purified 5-(3,5-dimethylphenylthio)furan-3-carboxylic acid (440 mg., m.p. 82°-86° C., m/e 248).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:13]1([CH2:1][C:3]2[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-formyl-1,3-thiazole-4-carboxylate (315 mg) in anhydrous DCM (25 ml) was added morpholine (0.164 ml) and the mixture stirred under nitrogen for 3 h at RT. Sodium triacetoxyborohydride (759 mg) was added and the mixture stirred at RT for 16 h. Sodium bicarbonate (50 ml) and DCM (50 ml) were added and the aqueous layer was extracted with DCM (2×25 ml) using a hydrophobic frit. The solvent was removed in vacuo, the residue was dissolved in DCM (5 ml) and purified by chromatography on silica gel eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. The solvent was removed in vacuo to give a white solid. The solid was dissolved in methanol (15 ml) and loaded onto an SCX SPE cartridge (50 g), which was preconditioned with methanol and allowed to stand for 15 min. The column was washed with methanol (50 ml) and elution with 2M ammonia in ethanol gave the title compound.
Reaction SMILES: CO.[CH2:3](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1SCCCC)[C:4]1C=CC=CC=1.[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([O:41][CH2:3][CH3:4])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cc1ccccc1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc(SCc2ccccc2)c(Cc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 124, methanol with ethanol and 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid with 4-benzyl-3-benzylthio-5-sulfamylbenzoic acid and following the procedure described, ethyl 4-benzyl-3-benzylthio-5-sulfamylbenzoate is obtained with a melting point of 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:22][C@@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([C:18]4[NH:30][N:29]=[N:28][N:19]=4)=[CH:20][CH:21]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:22][C@@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(C#N)cc2)cc1O[C@@H]1CCOC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccnn2-c2ccc(-c3nnn[nH]3)cc2)cc1O[C@@H]1CCOC1
Temperature: 110 °C
Yield: 39.6 %

Procedure:
4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile (40.0 mg, 0.111 mmol), sodium azide (35.82 mg, 0.5510 mmol), ammonium chloride (29.5 mg, 0.552 mmol), and 1 mL of N,N-dimethylformamide were mixed in a 500 mL flask and heated under an atmosphere of N2 at 110° C. for 6 hours. The mixture was cooled to room temperature and poured into 5 mL of ice cold 3.0 M aqueous HCl. The precipitate was collected by vacuum filtration and washed with several portions of water. The solid was dried in vacuo overnight to give 20 mg (0.044 mmol, 40%) of 5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-tetrazole as a yellow solid. LC/MS (EI) tR 3.52, m/z 405.1 (M++1) 1H NMR (CDCl3 300 MHz) δ 2.0 (m, 2H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.8 (m, 1H); 6.6 (s, 2H); 7.0 (d, 1H); 7.1 (d, 1H); 7.4 (d, 2H); 7.8 (d, 2H); 7.8 (s, 1H).
Reaction SMILES: [CH3:1][SH:2].[Na].O.[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][S:2][CH3:1])=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]
Reactant: COc1cc(C(=O)CBr)ccc1OC(C)=O
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C(=O)CSC)ccc1OC(C)=O
Reaction time: 20 h
Yield: 83 %

Procedure:
As shown in the above-described reaction formula, the mixture of 600 ml of sodium methyl mercaptan (8.56 ml) and three drops of aliquat/5 ml of water solution was added to the solution containing 2.46 g of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (8.56 mM) dissolved in 10 ml of benzene. The mixture solution was stirred for 20 hours. The resulting product was extracted with ethylacetate, dried with anhydrous magnesium sulfate and the remaining solvent was removed. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 2-methoxy-4-[2-(methylthio)acetyl]phenyl acetate (3; 2.18 g).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>CCO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])=[O:16]
Reactant: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCNC(=O)c1cccc(N)c1

Procedure:
To a solution of N-(2-dimethylaminoethyl)-3-nitrobenzamide (21.0 g, 88.0 mmol) in EtOH (50 mL) was added 10% Pd/C (2.52 g) and the hydrogenated with hydrogen at 35 psi for 3 h. The reaction mixture was filtered through a pad of Celite, the filterate was evaporated to dryness and the solid obtained was recrystallize from EtOH to give 3-amino-N-(2-dimethylaminoethyl)benzamide; 17.19 g (93%); mp 97-100° C.; 1H NMR (CDCl3) δ 2.20 (6H, s, 2×Me), 2.52 (2H, J=5.8 Hz, CH2), 3.51 (2H, q, J=5.4 and 5.8 Hz, CH2), 3.80 (2H, brs, exchangeable, NH2), 6.75-6.80 (1H, m, ArH), 6.82 (1H, brs, exchangeable, NH), 7.10 (H, d, J=7.6 Hz, ArH) 7.12-7.30 (2H, m, ArH) 8.33 (1H, m, ArH), 8.66 (1H, s, ArH). Anal Calcd. for (C11H17N3O): C, 63.74; H, 8.27; N 20.27. Found: C, 63.51, H, 8.45; N 20.12.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CO>[OH:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CN
Solvent: CO
Product: CC(=O)NCc1ccccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
2-Methoxybenzylamine (822 mg, 6.0 mmol) in methanol (10 mL) was treated with acetic anhydride (613 mg, 6.0 mmol) at room temperature for 2 h. The volatiles were removed in vacuo. The residue was dissolved in CH2Cl2, cooled to 0° C., 1M solution of BBr3 in CH2Cl2 (12 mL, 12.0 mml) was added slowly. After addition was completed the reaction mixture was stirred at room temperature overnight, cooled to 0° C., methanol (3 mL) was added and after 10 min volatiles were removed in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum spirit) to give the subtitled compound (400 mg).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[C:11]([CH2:12][Br:17])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1F)C(C)(C)CCC2(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(F)cc21
Temperature: 25 °C
Yield: 124.4 %

Procedure:
To a solution of 10.0 g (45.4 mmol) of 2-fluoro-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 91 mL of carbon tetrachloride was added 8.48 g (47.7 mmol) of N-bromosuccinimide and 0.330 g (1.36 mmol) of benzoyl peroxide. The solution was heated at reflux for 35 minutes and then cooled to room temperature. 200 mL petroleum ether was added and the solution filtered and concentrated in vacuo to afford 16.9 g of 2-fluoro-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>C1(C)C=CC=CC=1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][O:8][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCC1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: BrCCCCOC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
NaH (560 mg, 13.93 mmol, 60% disp. in mineral oil) was washed with hexanes (3×20 mL) in a pressure tube and toluene (6 mL,) was added. The solution was cooled to 0° C. and cyclopentanol (1 g, 11.61 mmol) in toluene (6 mL) was added over 20 min. After stirring at 0° C. for 30 min., 1,4-dibromobutane (1.39 mL, 11.61 mmol) and KI (250 mg) were added. The solution was heated to 100° C. for 14 hours. Upon cooling, the reaction was quenched with NaCl (sat. aq.) and the product extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. Purification of the residue via flash column chromatography afforded (4-bromobutoxy)cyclopentane.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:20][CH:21]1[CH2:26][C:25](=O)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>ClCCl>[CH3:20][CH:21]1[CH2:26][C:25]2([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]23)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1-n1cccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)Oc1ccccc1-n1cccc12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (443 μL, 5.75 mmol) was added to a solution of 2-pyrrol-1-ylphenol (457 mg, 2.87 mmol) and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (613 mg, 2.87 mmol) in dichloromethane (19 mL) and the solution was vigorously stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the organics were extracted with EtOAc (3×200 mL). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel: 0-10% EtOAc in dichloromethane) to give tert-butyl 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate as a brown oil. The crude residue was dissolved in a solution of HCl in dioxane (1.4 mL of 4.0 M, 5.6 mmol) and stirred for 30 min at room temperature. The volatiles were removed in vacuo and the residue was dissolved in diethylether. The solids were collected by filtration to provide 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride (386 mg, 46%) as a reddish brown solid. ESI-MS m/z calc. 254.1. found 255.5 (M+1)+; Retention time: 1.12 minutes (3 min run).
Reaction SMILES: S(=O)(=O)(O)N.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[CH:19]=[O:20])=[CH:14][CH:13]=1.Cl([O-])=[O:23].[Na+].S([O-])(O)=O.[Na+]>O.C(Cl)(Cl)Cl>[CH3:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:21])[C:19]([OH:23])=[O:20])=[CH:14][CH:13]=1
Reactant: Cc1ccsc1-c1ccc(C(C)C=O)cc1
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
In 20 ml of water was dissolved 3.2 g (0.033 mole) of sulfamic acid. To the solution was added a solution of 5.0 g (0.0217 mole) of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde [obtained in (1)] in 20 ml of chloroform. To the mixture, while maintaining the temperature at 0° to 10° C., was added dropwise with stirring 10 ml of an aqueous solution containing 2.6 g (0.0242 mole) of sodium chlorite (84% pure). After completion of the addition, the mixture was stirred for 10 minutes, admixed with 2.6 g (0.025 mole) of sodium hydrogensulfite, further stirred for 30 minutes, and allowed to stand, upon which the mixture separated into two layers. The organic layer was washed with 20 ml of water and extracted by the addition of 25 ml of 1 N aqueous sodium hydroxide solution. To the alkaline extract layer, which had been admixed with 20 ml of cyclohexane, was added gradually with stirring 5% hydrochloric acid to adjust the pH to 4. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure to obtain an oily substance which was crystallized by the addition of a small quantity of n-hexane to yield 4.8 g (90% yield) of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)(=[O:15])=[O:14])[CH2:9]1.[C:25]1([CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)(=[O:15])=[O:14])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(c1ccc2[nH]ncc2c1)C1CCNC1
Reactant: O=CCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2[nH]ncc2c1)C1CCN(CCCCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=384.2(M+H+) was prepared from (RS)-5-(pyrrolidine-3-sulfonyl)-1H-indazole trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 15.0 g. of 4-bromo-3-trifluoromethylaniline in 75 ml. of dry pyridine add 6.8 g. of isobutyrylchloride and heat the resulting mixture at 70° C for 2 hours. Allow the reaction mixture to cool to room temperature and then pour the mixture into 600 ml. of ice-water, filter and dry the precipitate which is recrystallized from 1:1 petroleum etherdichloromethane to yield 4'-bromo-3'-trifluoromethylisobutyranilide, m.p. 126.5°-128° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:27](O)=[O:28])[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].Cl.[C:31]([S:37][CH2:38][CH2:39][NH2:40])(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].Cl.C(SCCN)(=O)C.Cl.C(SCCN)(=O)C1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([NH:4][C@H:5]([C:27]([NH:40][CH2:39][CH2:38][S:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH2:6][S:7][C:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(C)(C)C(=O)SCCN
Agent: CC(=O)SCCN
Agent: Cl
Agent: NCCSC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)(C)C
Yield: 86 %

Procedure:
The coupling reaction of 7 (7.4 mmol) with S-pivaloylcysteamine hydrochloride [(compound obtained according to the same methods as those described by T. Wieland and E. Bokelman, Ann. Chem., 1952, 576, 20-34, during the syntheses of S-acetylcysteamine hydrochloride and S-benzoylcysteamine hydrochloride) M.p.=212-213° C.] is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 30%). 11 is collected in the form of a colorless foam with a yield of 86%. Rf (AcOEt/petroleum ether, 7/3): 0.5. [α]D20=+8.5° (c 1.29, CHCl3).