Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]([F:46])([F:45])[C:4]1[CH:5]=[C:6]([CH2:14][N:15]([C:39]2[N:40]=[N:41][N:42]([CH3:44])[N:43]=2)[C@@H:16]2[C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]3)[CH2:19][CH2:18][CH2:17]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[OH-].[Na+:48]>>[Na+:48].[F:13][C:10]([F:11])([F:12])[C:8]1[CH:7]=[C:6]([CH2:14][N:15]([C:39]2[N:40]=[N:41][N:42]([CH3:44])[N:43]=2)[C@@H:16]2[C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([C:36]([O-:38])=[O:37])[CH2:32][CH2:31]3)[CH2:19][CH2:18][CH2:17]2)[CH:5]=[C:4]([C:3]([F:2])([F:46])[F:45])[CH:9]=1
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Add to a 500 mL bottle Trans-4-[[(5S)-5-[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]-2,3,4,5-tetrahydro-7,9-dimethyl-1H-1-benzazepin-1-yl]methyl]-cyclohexanecarboxylic acid hydrate (20.16 g) ethanol SDA 3A (200.94 mL). Stir using a magnetic stir bar and slowly add 1 N sodium hydroxide (31.95 g). This is a clear solution.
Reaction SMILES: [N:1]1([C:5]2[O:6][C@H:7]3[CH2:13][C@H:12]([CH2:14][F:15])[C@@H:11]([O:16]CC4C=CC=CC=4)[C@H:10]([O:24]CC4C=CC=CC=4)[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[N:1]1([C:5]2[O:6][C@H:7]3[CH2:13][C@H:12]([CH2:14][F:15])[C@@H:11]([OH:16])[C@H:10]([OH:24])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC[C@H]1C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O[C@@H]1[C@@H](CF)C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@H]1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-2-(azetidin-1-yl)-4,5-bis(benzyloxy)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (80.0 mg, 0.189 mmol) in DCM (2 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 0.47 mL, 0.47 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 5 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (5 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 3%-8% 2 M NH3 MeOH solution in DCM to give the product (3aR,4R,5R,6S,7aS)-2-(azetidin-1-yl)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol (36.5 mg, 79%) as a white solid. MS m/z 267.2 (M+23, 100%); 1H NMR (400 MHz, MeOD) δ 4.61-4.69 (m, 1.5H), 4.53-4.57 (m, 1H), 4.43 (dd, J=9.0 Hz, 2.8 Hz, 1H), 4.00 (t, J=7.6 Hz, 1H), 3.58 (t, J=7.2 Hz, 1H), 3.15-3.28 (m, 2H), 2.22-2.36 (m, 3H), 1.75-1.87 (m, 2H); 13C NMR (100 MHz, MeOD) δ 164.81, 85.13 (d, J=160.7 Hz), 81.98, 80.60 (d, J=0.6 Hz), 71.88 (d, J=4.8 Hz), 69.03, 39.37 (d, J=18.6 Hz), 28.09 (d, J=3.9 Hz), 17.75.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:19])[F:18])[CH:7]=1.C(N(CC)CC)C.C[O:30][C:31](=O)[C:32]1[C:37]([NH:38][C:39]([CH:41]2[CH2:43][CH2:42]2)=[O:40])=[CH:36][CH:35]=[C:34]([Cl:44])[C:33]=1[CH2:45]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH:17]([F:18])[F:19])[CH:7]=1)[N:20]1[CH2:45][C:33]2[C:32](=[C:37]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[CH:36]=[CH:35][C:34]=2[Cl:44])[C:31]1=[O:30]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(Cl)c1CBr
Reactant: COC(=O)CC(N)c1ccc(OC(F)F)c(OC(F)F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2c(Cl)ccc(NC(=O)C3CC3)c2C1=O
Temperature: 90 °C
Yield: 17.2 %

Procedure:
To a solution of 3-amino-3-(3,4-bis-difluoromethoxy-phenyl)-propionic acid methyl ester (50 mg, 0.16 mmol) and triethyl amine (0.09 ml, 3.1 mmol) in DMF (2 ml) was added 2-bromomethyl-3-chloro-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (67 mg, 0.19 mmol). The mixture was heated at 90° C. under nitrogen atmosphere overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and 1N HCl (50 ml). The organic layer was washed with water (30 ml), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give 3-(3,4-bis-difluoromethoxy-phenyl)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid methyl ester as a off-white solid (15 mg, 17%). mp, 175-177° C.; 1H NMR (CDCl3): δ 0.88-0.94 (m, 2H, cyclopropyl ring CH2), 1.07-1.13 (m, 2H, cyclopropyl ring CH2), 1.65-1.68 (m, 1H, cyclopropyl ring CH), 3.14 (dd, J=6, 15 Hz, 1H, CHHCO), 3.28 (dd, J=10, 15 Hz, 1H, CHHCO), 3.70 (s, 3H, OCH3), 4.13 (d, J=17 Hz, 1H, CHHN), 4.36 (d, J=17 Hz, 1H, CHHN), 5.79-5.85 (m, 1H, CHN), 6.23 (t, JH-F=75 Hz, 1H, OCF2H), 6.26 (t, JH-F=75 Hz, 1H, OCF2H), 7.28-7.41 (m, 4H, Ar), 8.45 (d, J=9 Hz, 1H, Ar), 10.38 (s, 1H, NHCO); 13C NMR (CDCl3): 8.45, 15.25, 16.16, 36.46, 46.34, 51.62, 52.31, 65.38, 111.38, 111.42, 115.57, 115.61, 118.64, 119.76, 119.80, 121.76, 121.81, 122.77, 125.45, 133.14, 136.89, 137.03, 138.86, 142.29, 142.21, 168.79, 170.20, 172.73; Anal. Calcd. for C24H21ClF4N2O6: C, 52.90; H, 3.88; N, 5.14; Found: C, 52.78; H, 3.80; N, 5.01;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH3:15][O:16][C:17](OC)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(OC(C)=O)=O>>[CH3:15][O:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]1=[O:14]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C2
Reactant: COC(OC)(OC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)C2=C(OC)c1ccccc1

Procedure:
Alternatively, the 6-methoxycarbonyl-2-oxindole may be reacted directly with trimethylorthobenzoate in the presence of acetanhydride to obtain the “enolether” (methyl 3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate). This alternative embodiment is described in the General Synthesis Scheme as step II′ and may be carried out as described above for step IIb.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[OH-].[Na+].[CH2:14](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:15][CH3:16]>C(O)(=O)C>[CH3:1][N:2]([CH3:11])[C:3]1[N:4]=[C:5]([O:10][CH2:14][CH2:15][CH3:16])[CH:6]=[C:7]([OH:9])[N:8]=1
Reactant: CN(C)c1nc(O)cc(O)n1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCOc1cc(O)nc(N(C)C)n1
Reaction time: 16 h

Procedure:
124 g (0.8 mol) of 2-dimethylamino-4,6-dihydroxy-pyrimidine are stirred with 800 cc of sodium hydroxide solution 1N at 60° for 1 hour. 171 g (0.8 mol) of p-toluene-sulphonic acid-n-propyl ester are added dropwise at 90° over the course of 1 hour and the pH is kept at 8-8.5 by the dropwise addition of sodium hydroxide solution 1N. The mixture is stirred at 90° for 16 hours, cooled to 5°, neutralized with glacial acetic acid and allowed to stand at room temperature for 6 hours. The precipitated crystals are subsequently filtered by suction, washed with water, dissolved in approximately 700 cc of chloroform, dried over sodium sulphate and evaporated to dryness in a vacuum. The residue is decomposed with 500 cc of petroleum ether, filtered by suction and recrystallized from benzene, washed with petroleum ether and dried at 60° in a high vacuum. M.P.: 194°-195°
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([C:11]1[N:15]2[C:16]([CH2:20]Cl)=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)([O:8]CC)=O.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:20][C:16]3[N:15]4[C:11](=[CH:12][N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:8])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCCN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 60 %

Procedure:
A solution prepared by dissolving 3.59 g (10.66 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate, 3.10 g (12.79 mM) of 3-(1-tert-butoxycarbonylpiperidin-4-yl)-1-propylamine, and 5.94 ml (42.64 mM) of triethylamine in 30 ml of ethanol was refluxed for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=50:1) to provide 2.55 g (yield 62.1%) of the title compound as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[C:16]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:13][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1(c2ccc(OC)cc2)CC1
Yield: 1980.2 %

Procedure:
To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13.1 mmol) at room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH was removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53.5 g, 99%). 1H NMR (CDCl3, 400 MHz) δ 7.25-7.27 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (q, J=3.6 Hz, 2H), 1.15 (q, J=3.6 Hz, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12]([O:14]C)=[O:13])[CH3:7])[CH3:2]>CO.O1CCCC1>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12]([OH:14])=[O:13])[CH3:7])[CH3:21]
Reactant: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)OC)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)O)c1
Reaction time: 8 h

Procedure:
A mixture of methyl 3-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-5-methylbenzoate (296 mg, 1.01 mmol) and 3:1:1 methanol/tetrahydrofuran/2 N sodium hydroxide (10 mL) is stirred overnight and then partitioned between ethyl acetate and water. The aqueous layer is acidified to pH 3 with 1 N hydrochloric acid and extracted with chloroform. The aqueous layer is concentrated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 4.56 (m, 2H), 4.31 (m, 2H), 3.98 (m, 2H), 3.17 (m, 4H), 2.51 (s, 3H), 2.50 (s, 3H), 1.27 (m, 6H).
Reaction SMILES: [N:1]([C:4]([CH3:7])([CH3:6])[CH3:5])=[C:2]=[S:3].[NH2:8][C@H:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[C:4]([NH:1][C:2]([NH:8][C@H:9]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1)=[S:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CC(C)(C)N=C=S
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=S)NC(C)(C)C)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 2-isothiocyanato-2-methylpropane and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 495.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=C(CBr)c1ccccc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-phenylethanone and isolated as light-green solid (9.5 mg, 55%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:6]([CH3:9])=[CH:7][CH:8]=1)[NH2:5].[C:10](Cl)(=[O:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Br)cc1N
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 3-bromo-6-methylaniline (1.00 g , 5.37 mmol) in pyridine (8 mL) was added acetyl chloride (0.76 mL, 10.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was extracted with EtOAc, washed with 5% citric acid, dried over MgSO4, concentrated, and triturated with ether to give 0.750 g (61%) of the desired product as off-white crystal. MS (DCI/NH3) m/z: 227.9 (M+H)+, 229.9 (M+2+H)+; 1H NMR (300 MHz, CDCl3) δ 2.21 (s, 6H), 6.90 (m, 1H), 7.04 (d, J=8.14 Hz, 1H), 7.20 (d, J=7.80 Hz, 1H), 8.06 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[CH2:2]([N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 87.9 %

Procedure:
To a stirring solution of 5-bromo-pentene (6.0 g, 0.040 mol) in DMF (30 mL) was added K2CO3 (4.7 g, 0.034 mol) and potassium phthalimide (6.21 g, 0.033 mmol) and the reaction mixture was heated at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and water (50 mL) was added. The aqueous layer was then extracted with ethyl acetate (2×50 mL), and the combined organic layers were washed with 5% aq. NaHCO3 (2×20 mL), brine (30 mL) and dried over Na2SO4. Filtration and solvent evaporation gave an oil, which was purified by flash chromatography (silica gel/hexanes:ethyl acetate 0-35%) to yield the desired 2-(pent-4-enyl)-isoindoline-1,3-dione as a solid (6.36 g, 0.029 mmol, 72.5% yield): MS m/e [M+H]+ calcd 216.1, found 216.1; NMR (250 MHz, DMSO-d6) δ 7.79-7.95 (m, 4 H), 5.70-5.91 (m, 1 H), 4.90-5.11 (m, 2 H), 3.58 (t, 2 H), 1.98-2.10 (m, 2 H), 1.59-1.78 (m, 2 H).
Reaction SMILES: [Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[OH:34][CH2:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]2[C@H:42]3[C@H:51]([CH2:52][CH2:53][C@:37]12[CH3:38])[C:50]1[CH2:49][CH2:48][C:47](=[O:54])[CH2:46][C:45]=1[CH2:44][CH2:43]3>N1C=CC=CC=1>[OH:34][CH2:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]2[C@H:42]3[C:51]([CH2:52][CH2:53][C@:37]12[CH3:38])=[C:50]1[C:45](=[CH:46][C:47](=[O:54])[CH2:48][CH2:49]1)[CH2:44][CH2:43]3
Reactant: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@H]1CC[C@H]2CO)CC(=O)CC4
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: c1ccncc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]1CC[C@H]2CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
Phenyltrimethylammonium tribromide (2.28 g) was added in small portions and in 10 min. to a solution of (14β,17α)-17-(hydroxymethyl)estr-5(10)en-3-one (Example 2; 1.75 g) in dry pyridine (47 ml). After 1.5 h stirring at room temperature the mixture was poured into ice-water and the product was extracted into ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium thiosulfate, water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography provided (14β,17α)-17-(hydroxymethyl)estra-4,9-dien-3-one (0.36 g), [α]D20=−241 (c=1, dioxane).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC(C#Cc1cccs1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(C#Cc1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-thiophenyl)ethynyl]-benzenemethanol (321 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13]C(C)(C)C)=[O:12])[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:19]=[CH:18][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3cccc(O)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CCc2ccc(C(=O)O)c(Nc3cccc(O)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((3-hydroxyphenyl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 50-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((3-hydroxyphenyl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoic acid 17 mg of a white solid.
Reaction SMILES: [CH2:1]([N:17]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)=O.CN([CH:36]=[O:37])C>>[CH:36]([C:25]1[S:24][C:23]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=1)=[O:37]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CCC)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(=O)CCC)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
78 g of N-hexadecyl-N-(2-thienyl)-butyric acid amide are dissolved in 59 cc. of anhydrous DMF and 36.7 g of phosphorus oxychloride are added thereto with ice cooling such that the temperature of the reaction mixture does not rise above 20° C. Stirring is continued for 1 hour at 20° C. and the mixture is finally heated for 3 hours to 80° C. Ice is added to the reaction mixture and 5 N soda lye is added until reaching a pH of 6. The mixture is extracted with ether, the ethereal layer is separated, washed with water and dried over Na2SO4. The desired final product crystallizes from the ethereal solution upon cooling to low temperature.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C-]#N.[Na+]>O.O1CCOCC1>[CH:1]1([O:6][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccs1
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1csc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
To a mixture of cyclopentanol (51.1 ml, 0.56 mol) and dioxane (50 mL) was added sodium hydride (60% in mineral oil, 4.91 g, 0.12 mol) at 0-5° C. under argon. The mixture was heated at 80° C. until an homogenous solution was observed. 2-Bromothiophene (10 g, 5.9 mL, 0.061 mol) was added at 80° C., followed by cuprous iodide (11.7 g, 0.061 mol). The mixture was heated at 120° C. for 6 hours. After cooling to 20-25° C., sodium cyanide (30 g, 0.61 mol) in water (200 mL) was added. The mixture was vigorously stirred for 20 minutes, filtered, and extracted with hexane. The hexane extract was washed with water, dried (Na2SO4), and concentrated to dryness. Filtration through a column (silica, 100% hexane) gave 2-cyclopentyloxythiophene (2.6 g, 25.2%) as a colorless oil; 1H NMR (300 MHz, CDCl3) δ 6.7 (dd, J=5.7, 3.7 Hz, 1H), 6.54 (dd, J=5.7, 1.5 Hz, 1H), /86.18 (dd, J=3.7, 1.5 Hz, 1H), 4.66 (Sept, J=2.7 Hz, 1H), 1.5-2.0 (m, 8H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:50])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:50])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C(Cl)OCc1ccc(OC(F)(F)F)cc1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccc(OC(F)(F)F)cc3)C2)cc1

Procedure:
4-(Trifluoromethoxy)benzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 4-(trifluoromethoxy)benzyl carbonochloridate (65.8 mg, 0.18 mmol) according to General Procedure H to give 30 mg (34.7%) of light brown solid. Anal. Calcd. for C27H31F3N4O3 m/z 516.2, found: 517.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.04 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 5.05 (t, J=8.1 Hz, 2H), 3.89 (m, 1H), 3.8 (m, 1H), 3.10 (m, 1H), 2.77 (m, 1H), 2.39 (m, 2H), 1.92 (m, 1H), 1.81 (m, 2H), 1.66 (m, 3H), 1.47 (m, 1H), 1.18 (m, 7H), 1.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[Cl:16].[OH:17][S:18](O)(=[O:20])=[O:19].O=S(=O)=O>O>[Cl:15][C:4]1[C:3]([Cl:16])=[C:2]([Cl:1])[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[C:5]=1[S:18]([OH:20])(=[O:19])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)c(Cl)c2[nH]1
Agent: O=S(=O)=O
Solvent: O
Product: O=S(=O)(O)c1c(Cl)c(Cl)c(Cl)c2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Yield: 92 %

Procedure:
4,5,6-trichloro-2-trifluoromethylbenzimidazole (145 parts) was added gradually to stirred oleum (1260 parts) and the mixture then refluxed for 2 hours. After cooling, the mixture was poured into water (3000 parts), the temperature being allowed to rise to near boiling. The mixture was cooled to room temperature overnight and the crystalline product was filtered off, washed with water and dried to give 165.9 parts (92% yield) of 5,6,7-trichloro-2-trifluoromethylbenzimidazole-4-sulphonic acid.