Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][CH2:9][C:10]([CH3:13])([CH3:12])[N:11]=1.C([Li])CCC.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=1>CCOCC.CCCCCC>[CH3:13][C:10]1([CH3:12])[CH2:9][O:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:14][C:23]2[N:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[N:22]=2)=[N:11]1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccccc1C1=NC(C)(C)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)COC(c2ccccc2Cc2nc(Cl)cc(Cl)n2)=N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.25 g of 2-o-tolyl-4,4-dimethyl-oxazoline in 20 ml of ether under N2 atmosphere at -30° C. is added by syringe 4.2 ml of 1.6M n-butyllithium in hexane with stirring which is continued for 1 hr at -10° C. 0.98 g of 4,6-dichloropyrimidine in 20 ml of ether are added slowly to the reaction mixture which is then stirred at -45° to -30° C. for 30 min and at 0° C. for a further 30 min. The reaction mixture is quenched with acetic acid (0.4 ml) and water (0.1 ml) in THF (1.3 ml) and then treated with 1.5 g of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in 6 ml of THF. The temperature is brought to RT and the mixture stirred for 5 min after cooling to 0° C. 7.6 ml of 1N NaOH (cooled) are added and the mixture stirred for 5 min. The organic phase is separated and dried over Na2SO4 filtered and the solvent removed. Following chromatography (10/90 ether/hexane) the title product is obtained.
Reaction SMILES: [N+:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@H:19]([OH:22])[CH2:20][O:21][C@H:15]23)=[O:12])[CH2:7][CH2:6]1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31]([O:22][C@H:19]2[C@H:16]3[O:17][CH2:18][C@@H:14]([O:13][C:11]([N:8]4[CH2:7][CH2:6][CH:5]([O:4][N+:1]([O-:3])=[O:2])[CH2:10][CH2:9]4)=[O:12])[C@H:15]3[O:21][CH2:20]2)=[O:32])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)piperidine-1-carboxylate (0.47 g, 1.48 mmol) and Et3N (0.45 g, 4.44 mmol) in THF (25 mL) was added 4-Nitrophenyl chloroformate (0.30 g, 1.48 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; 60% EtOAc in n-hexane), affording the title product as a white solid. 1H-NMR (300 MHz, CDCl3); δ 8.33-8.29 (2H, m), 7.45-7.40 (2H, m), 5.22-5.07 (3H, m), 4.88-4.80 (1H, m), 4.79-4.71 (1H, m), 4.20-3.71 (6H, m), 3.60-3.30 (2H, m), 2.12-1.98 (2H, m), 1.88-1.73 (2H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[Se:17][C:16]=1[C:24]([NH2:26])=[O:25].CN(C=O)C.[OH-].[Na+]>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:14][C:15]3[CH:19]=[C:18]([C:20]([CH3:23])([CH3:21])[CH3:22])[Se:17][C:16]=3[C:24]([NH2:26])=[O:25])=[N:7][CH:6]=[N:5][C:4]=2[S:8][C:9]=1[CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: CCc1c(C)sc2ncnc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1c(C)sc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c12

Procedure:
The reaction of 4-chloro-5-ethyl-6-methylthieno[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as an off-white color solid, mp 234-236° C. IR (KBr) vmax 3332, 3154, 2962, 1665, 1585, 1362, 1221, 1048, 927, 838, 778 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.04 (1H, s, exchangeable with D2O), 8.64 (1H, s), 8.56 (1H, s), 5.34 (2H, br s, exchangeable with D2O), 3.15 (2H, q, J=7.5 Hz), 2.49 (3H, s), 1.45 (9H, s), 1.25 (3H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 168.0, 167.3, 167.0, 152.7, 151.7, 146.9, 131.0, 130.9, 122.8, 117.7, 110.6, 37.1, 32.5, 20.8, 15.6, 13.4; LC-MS (negative ion mode): m/z 419, 421 (M−H)−.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[C:12]([CH2:19][CH3:20])[CH:11]=1)(C(C)(C)C)(C)C.[Cl:21][C:22]1[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=O)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:21][C:22]1[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=1[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[O:18][N:17]=[C:15]([C:13]3[S:14][C:10]([CH2:9][OH:8])=[CH:11][C:12]=3[CH2:19][CH3:20])[N:16]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2Cl)cc1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3Cl)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 10 (10f) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.50 mmol) that was obtained in Example 10 (10d), 4-(2-chlorophenoxy)benzoic acid (0.14 g, 0.55 mmol) that was obtained in Example 19 (19a), dicyclohexylcarbodiimide (0.11 g, 0.55 mmol), and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.75 mL, 0.75 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 (3:7 to 5:5) as the eluent to afford the title compound (0.19 g) in a yield of 92% as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[OH:18][N:17]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:15][CH:14]=1)[NH2:13]
Reactant: NO
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(C2(O)CCOCC2)cc1
Temperature: 25 °C
Yield: 119.6 %

Procedure:
A solution of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1, 200 mg, 0.984 mmol), hydroxylamine hydrochloride (150 mg, 2.17 mmol) and triethylamine (219 mg, 2.17 mmol) in ethanol (5 mL) was stirred and heated at reflux for 4 h. After being cooled to rt, the reaction mixture as such was subjected to preparative HPLC, affording the pure title compound (278 mg, 99%): 1H NMR (500 MHz, DMSO-d6) δ 9.71 (broad, 1H), 9.58 (s, 1H), 7.62 (d, 2H), 7.48 (d, 2H), 7.22 (broad, 1H), 5.78 (s, 2H), 5.07 (s, 1H), 3.80-3.75 (m, 2H), 3.72-3.68 (m, 2H), 2.00-1.93 (m, 2H), 1.53-1.49 (m, 2H); ES-MS m/z 237 (MH)+; HPLC RT (Method F) 0.72 min.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30]>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:30])=[CH:19][CH:20]=1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)OC1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopentyl chloroformate (0.144 mL, 1.114 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 3 days. Additional N,N-diisopropylethylamine (0.486 mL, 2.79 mmol) and cyclopentyl chloroformate (0.28 mL, 2.22 mmol) were added, and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an off-white solid. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.390 g, 97%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 80 °C

Procedure:
Methyl 4-hydroxyindole-2-carboxylate (0.5 g) and 4-dimethylaminopyridine (50 mg) were dissolved in acetic anhydride (5 ml) and heated at 80° C. for 3 hours. The reaction was allowed to cool overnight to precipitate white crystals, which were filtered and dried in vacuo (0.44 g, 72%); NMR δ (CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H), 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH2:31][CH3:32])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].ClC1C=C(C(OO)=[O:42])C=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([S:30]([CH2:31][CH3:32])=[O:42])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(S(=O)CC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (50.6 mg, 0.10 mmol) in dichloromethane was added 3-chloro-benzenecarboperoxoic acid (m-CPBA) (19.1 mg, 0.11 mmol) at 0° C. After stirring at room temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 5% methanol in dichloromethane) to afford {(R)-4-[(3-ethanesulfinyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (39.6 mg, 76.2%) as a semisolid. MS cald. for C21H26F3N3O5S2521, obsd. (ESI+) [(M+H)+] 522.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=1[N:37]=[C:38]=[O:39].Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[CH:19]([C:38]([NH:37][C:28]1[C:29]([O:35][CH3:36])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[O:26][CH3:25])=[O:39])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:24]
Reactant: CCOC(=O)Cc1ccccc1
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a stirred, room temperature solution of diisopropylamine (43.4 mL, 0.310 mol) in dry THF (1.2 L) was added a 2.5M solution (124 mL, 0.31 mol) of n-butyl lithium in hexanes in one portion, and the mixture was cooled to -78° C. To the solution was added under nitrogen a solution of phenylacetic acid, ethyl ester (50.8 g, 0.309 mol) in THF (500 mL) over 15 minutes. Stirred 2 minutes. To the mixture was added a solution of 2,4,6-trimethoxyphenyl isocyanate (64.9 g, 0.310 mol) in THF (500 mL) over 10 minutes. Stirred 1.5 hours. The reaction was quenched with 1M HCl (310 mL, 0.310 mol) and allowed to warm to room temperature. The mixture was rotoevaporated to remove THF and partitioned between water and chloroform. The organic layer was washed (1M HCl ; saturated NaCl), dried (Na2 SO4), and rotoevaporated. The residue was chromatographed on silica gel (1.4 kg, 230-400 mesh) using petroleum ether-ethyl acetate (1:1). Fractions containing product were rotoevaporated, and the residue crystallized from ethanol-ether to give a white solid; yield 46.9 g (41%); mp 109°-111° C.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:18]([C:12]1[CH:13]=[CH:14][C:15]([C:7]([C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[C:10]([OH:9])=[O:11])=[O:8])=[CH:16][CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: CCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 0 °C

Procedure:
Trans-1,2-cyclohexanedicarboxylic anhydride (6.76 g , 0.044 mole) was heated with 1-phenylheptane (100 ml) and anhydrous aluminum chloride (12.86 g, 0.096 moles) at 100° C. for 1 hour. The reaction mixture was then poured into a mixture of ice water (500 ml) and concentrated hydrochloric acid (50 ml). The product was extracted with ether (2×200 ml) and the extracts dried over magnesium sulfate and filtered. The ether was removed under reduced pressure and the remaining solution chromatographed on silica (hexane and then hexane:ether:acetic acid at 70:30:1) to yield trans-2-(4-heptylbenzoyl) cyclohexane-1-carboxylic acid (7.36 g), m.p. 91°-94° C.
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 3H), 7.36 (app t, 2H, J=8 Hz), 7.13 (m, 2H), 4.54 (dd, 1H, J=8 Hz, 4 Hz), 3.31 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.44 (m, 1H), 1.94 (m, 2H), 1.78 (m, 1H), 1.48 (m, 1H), 1.08 (t, 3H, J=7 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(F)cc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.23 mmol) was added to a stirred solution of {4-[4-(2,4-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.028 g, 0.057 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,4-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.02 g, 74%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. S, 1 H) 8.23 (q, J=7.60 Hz, 1 H) 8.12 (d, J=7.82 Hz, 2 H) 8.01 (dd, J=9.40, 6.20 Hz, 1H) 7.91 (s, 1 H) 7.63 (t, J=9.40 Hz, 1 H) 7.56 (d, J=8.31 Hz, 2 H) 7.45 (t, J=8.60 Hz, 1 H) 7.39 (td, J=9.00, 2.60 Hz, 1 H) 6.64 (dd, J=11.00, 2.40 Hz, 1 H) 3.84 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16F3O4S [(M−H)−] 469, obsd. 469.3.
Reaction SMILES: [CH2:1]([S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCCCC)n1

Procedure:
A mixture of 6.3 g. 3-n-butylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 4 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-n-butylthio-1,2,4-triazole, b.p. 157° C./0.6 mm. (95.0% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:41]([O:45][C:46]([C:48]1[C:56]2[CH2:55][CH2:54][N:53]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[CH:52]([CH2:66][NH2:67])[C:51]=2[S:50][C:49]=1[NH2:68])=[O:47])([CH3:44])([CH3:43])[CH3:42]>O1CCCC1>[C:41]([O:45][C:46]([C:48]1[C:56]2[CH2:55][CH2:54][N:53]([CH2:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)[CH:52]([CH2:66][NH:67][C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:30]=3)=[O:39])[C:51]=2[S:50][C:49]=1[NH2:68])=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(=O)c2cn(Cc3ccccc3)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Diisopropylethylamine (1.8 ml, 10.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (760 mg, 4.0 mmol) were added to a mixture of 1-benzyl-1H-indole-3-carboxylic acid (902 mg, 3.6 mmol) in tetrahydrofuran (50 ml). After stirring for 1 hour, the solution was cooled to 0° C. and a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (700 mg, 1.7 mmol) in tetrahydrofuran (7 ml) was added dropwise. The reaction was allowed to slowly warm to room temperature. After 8 hours of stirring the solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml), washed with saturated aqueous sodium bicarbonate (2×30 ml), brine (1×30 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane/ethyl acetate/triethylamine, (50:50:1) as eluent, which afforded 560 mg (51%) of 2-amino-7-(((1-benzyl-1H-indole-3-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>[OH-].[Na+].CCOCC>[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:10][C:8](=[NH:9])[S:7][CH3:6])=[O:17])=[CH:14][CH:13]=1
Reactant: CSC(=N)N
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CSC(=N)NC(=O)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
A solution of 2-methyl-2-thiopseudourea sulfate (6.9 g, 0.025 mol) in 30 ml of sodium hydroxide (4%) was added a solution of 4-methylbenzoyl chloride (3.4 g, 0.022 mol) in ether (10 ml) at room temperature. The reaction mixture was stirred overnight and the precipitated solid was filtered, washed with water, later hexanes and dried under high vacuum. N-(4-methylbenzoyl)-S-methylisothiourea: yield 4.60 g (quantitative); purity 98% (HPLC); 1H-NMR (CD3OD) δ 2.4 (s, 3H, CH3), 2.6 (s, 3H, SMe), 7.2 (d, 2H, ArH), 8.1 (d, 2H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:20]1([S:26]([N:10]2[CH2:11][CH2:12][C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1cccc([C@@H]2CNCC[C@H]2c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N1CC[C@@H](c2ccccc2)[C@H](c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To the hydrochloride salt of rac-trans-3-(m-chlorophenyl)-4-phenylpiperidine (CAS Reg. No.: [134823-41-9]) (500 mg) in methylene chloride (10 mL) triethylamine (677 μL) and benzenesulfonyl chloride (229 μL) were added. The reaction mixture was stirred at room temperature for 4 h, water was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×3). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 3:1) yielded trans-1-benzenesulfonyl-3-(3-chloro-phenyl)-4-phenyl-piperidine (0.66 g, 98%) as a white foam, MS: 411 (M, 1 Cl).
Reaction SMILES: Br.Br.[N:3]1([CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br.Br.N1(CC2C3C(=CC(O)=CC=3)CCN2)CCCC1.[Cl:39][C:40]1[CH:41]=[C:42]([CH2:47][C:48](O)=[O:49])[CH:43]=[CH:44][C:45]=1[Cl:46].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:3]1([CH2:8][C:9]2([C:48](=[O:49])[CH2:47][C:42]3[CH:43]=[CH:44][C:45]([Cl:46])=[C:40]([Cl:39])[CH:41]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Oc1cccc2c1C(CN1CCCC1)NCC2
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1ccc2c(c1)CCNC2CN1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CCCC2)NCCc2cccc(O)c21

Procedure:
Prepared as Ex. No. 5, from 13.2 g (33.50 mmoles) of a mixture containing 1-(pyrrolidin-1-yl)methyl-8-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide and 1-(pyrrolidin-1-yl)methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 9.6 g (46.8 mmoles) of 3,4-dichlorophenylacetic acid, 14 ml (99.6 mmoles) of triethylamine and 17 g (82.52 mmoles) of dicyclohexylcarbodiimide, in 280 ml of dry chloroform.