Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: C[C@H](SCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](SCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.3 %

Procedure:
To a solution of 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-hydroxy-3-methylbutylthio)pregna-5,7,16-triene (58.5 mg, 0.107 mmol) in tetrahydrofuran (3 ml) was added 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml), and the mixed solution was heated under reflux for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, and washed with ice-cooled 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a pale yellow oil (41.8 mg, 90%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-])=O)[C:8]1=[O:20])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH2:17])[C:8]1=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCn1ccc2c(N)cccc2c1=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2-(5-Nitro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (2.45 g, 0.00842 mol) was dissolved in methanol (100 mL), palladium on charcoal (10%) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was filtered through celite, and solvent was removed. The product was obtained as a light orange solid (1.98 g). MS m/z=246.5(M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH3:30]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:28])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]O.S(=O)(=O)(O)O>O>[I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: CO
Reactant: COc1cccc(C(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(OC)c1I
Temperature: 25 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-iodo-3-methoxybenzoic acid (20 g, 0.07 mol; prepared in a manner similar to that described above), methanol (300 ml) and concentrated sulphuric acid (3.5 ml) was heated under reflux for 8 hours, cooled to ambient temperature and added to water (1500 ml). The product was extracted into dichloromethane (3×500 ml), the combined extracts were washed with 5% aqueous sodium hydroxide solution (3×500 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give methyl 2-iodo-3-methoxybenzoate (18.5 g, 90%) as a solid, m.pt. 58–61° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@H:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[C@H:13]1([NH:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[CH:3]=3)[N:8]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Brc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound, brown oil, MS (ISP): m/e=359.3 (M+H+), was prepared in accordance with the general method of example 163, step B from (6-bromo-quinolin-2-yl)-(R)-indan-1-yl-amine (see example 163, step A) and commercially available 1-methyl-piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH3:25]>CO>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:12]([C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([CH3:15])[NH:25][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: N
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OCc1ccccc1
Solvent: CO
Product: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2Cl)C(C(=O)OCc2ccccc2)=C(C)N1
Temperature: 90 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
In a 7% ammonia solution in methanol were dissolved 2.6 g of 2,3-dichlorobenzaldehyde and 5.8 g of benzyl acetoacetate, and the solution was stirred in a closed tube at 90° C. for 10 hours, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4 ) to obtain 4.8 g (yield: 30%) of dibenzyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate as a yellow crystal .
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14].CN(C1C=CC=CC=1)[CH:17]=[O:18].S(=O)(=O)(O)O>O1CCCC1.CCOCC>[Cl:14][C:8]1[C:7]([Cl:6])=[CH:12][CH:11]=[C:10]([F:13])[C:9]=1[CH:17]=[O:18]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN(C=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(F)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution wa stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:42][CH:34]([CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41]1)[CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: NCCC(O)CCN1CCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCC(O)CCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-pyrrolidin-1-yl-pentan-3-ol by the procedure analogous to Example 1. MS (APCl, m/z): 516 [M+H]+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])OC1C=CC=CC=1)#[N:2].Cl.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32].C(N(CC)CC)C>C(O)(C)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])[N:32]=1
Reactant: COc1ccc(N=C(NC#N)Oc2ccccc2)c(OC)c1
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(N)n(-c3ccccc3F)n2)c(OC)c1
Temperature: 100 °C
Yield: 89.3 %

Procedure:
A mixture of N-cyano-N′-(2,4-dimethoxyphenyl)-O-phenylisourea (0.10 g, 0.34 mmol), 2-fluoro-phenylhydrazine hydrochloride (0.08 g, 0.50 mmol) and triethylamine (0.01 mL, 0.68 mmol) in isopropanol (3 mL) was heated at 100° C. for 18 h and evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided the title compound (0.10 g, 85% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=O)[N:23]=1>>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH2:32][N:18]2[CH2:19][C@@H:20]([CH3:21])[C@H:16]([C:12]3[NH:13][C:14](=[O:15])[C:9]4[CH:8]=[N:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)[CH2:17]2)[N:23]=1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Reactant: O=Cc1cc2ccccc2nn1
Product: C[C@@H]1CN(Cc2cc3ccccc3nn2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and cinnoline-3-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.49 (d, J=8.7 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.83-7.81 (m, 1H), 7.79-7.71 (m, 1H), 5.16-5.09 (m, 1H), 4.47-4.44 (m, 1H), 4.35-4.32 (m, 1H), 3.49-3.45 (m, 2H), 3.10-3.07 (m, 1H), 2.87-2.71 (m, 2H), 2.49-2.48 (m, 1H), 2.23 (m, 1H), 2.11-1.87 (m, 5H), 1.73-1.63 (m, 2H), 1.22 (d, J=7.1 Hz, 3H). MS: (M+H m/z=430.1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])(CC)C.C1CCCCC1.I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[CH2:6]([O:5][P:4]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:10][CH2:11][CH:12]=[CH2:13])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=CCCCP(=O)(OCC)OCC
Reactant: CCCCCCCCCCI
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C=CCCC(CCCCCCCCCC)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 4-pentenyl phosphonic acid diethyl ester (2.832 g, 13.7 mmol) in anhydrous tetrahydrofuran (20 mL) and cooled to about −78° C. A 1.3 M solution of sec-butyl lithium in cyclohexane (15 mL, 19.5 mmol) was added slowly to the mixture keeping the temperature below −60° C. 1-Iododecane (6.32 g, 23.6 mmol, 1.8 eq.) was then added slowly to the reaction mixture. The mixture was warmed to 0° C. and was stirred for three hours. The reaction was then quenched with NH4Cl (saturated, 20 mL). The mixture was warmed to room temperature and the THF was removed by rotary evaporation. The resulting solution was extracted with ethyl acetate (50 mL). The organic layer was separated and dried over Na2CO3. The solvent was removed and the resulting residue was purified by column chromatography (silica, ethyl acetate/hexane=2/8 then 4/6) to provide the pure product (3.46 g, 73% yield). 1H NMR (CDCl3) δ=5.8 (m, 1H), 5.0 (m, 2H), 4.1 (m, 4H), 2.2 (m, 2H), 1.8-1.2 (m, 27H), 0.9 (t, 3 H). 31P NMR (CDCl3) δ=35.8.
Reaction SMILES: [CH2:1]([C@:3]1([C:31]([O:33]C)=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:2].[OH-].[Na+].CO.Cl.C(N(CC)CC)C>C1COCC1>[CH2:1]([C@:3]1([C:31]([OH:33])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:2]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1

Procedure:
Methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (315 mg, 0.653 mmol) was combined with aqueous 5M sodium hydroxide solution (0.65 mL, 3.3 mmol) in THF, with MeOH added to homogenize the mixture. This solution was stirred at 50° C. for 5d, after which triethylamine hydrochloride (540 mg, 3.9 mmol) was added. The heterogeneous mixture was concentrated, and chased twice with methanol and twice with benzene to give (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid as a white solid that was carried on without further purification. The solid was combined with BOP (349 mg, 0.790 mmol), hydroxylamine hydrochloride (100 mg, 1.43 mmol) and triethylamine (0.45 mL) in DMF (3 mL) and heated at 50° C. overnight. Additional BOP (362 mg, 0.819 mmol), hydroxylamine hydrochloride (150 mg, 2.1 mmol) and Et3N (0.3 mL) were then added and the reaction was stirred at 50° C. overnight. The reaction was still incomplete and more BOP (750 mg, 1.70 mmol), hydroxylamine hydrochloride (333 mg, 4.76 mol) and Et3N (0.6 mL) were added. After 5 h the reaction mixture was diluted with brine and extracted three times with ethyl acetate. The combined organic extracts were dried over Na2SO4, concentrated, and purified via HPLC, eluting with a gradient of 15-100% MeCN/H2O (10 min) to give (1S,2R)-N-hydroxy -1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (162 mg, 0.331 mmol, 51%) as a colorless solid. LCMS (M−H): 1.81 min, 483.8; 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.67 (t, J=7.45 Hz, 3H) 1.08-1.20 (m, 2H) 1.31-1.42 (m, 2H) 1.49-1.60 (m, 3H) 1.82-1.87 (m, 2H) 2.56-2.58 (m, 3H) 3.19-3.28 (m, 1H) 5.49-5.52 (m, 2H) 6.23 (d, J=8.59 Hz, 1H) 7.08-7.13 (m, 2H) 7.42 (s, 1H) 7.48 (td, J=7.64, 1.39 Hz, 1H) 7.64 (ddd, J=8.40, 6.88, 1.39 Hz, 1H) 7.70-7.75 (m, 2H) 7.91 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:12])[CH2:9][CH2:8][N:7]1[CH3:13])=[O:5])C.[OH-].[Na+].Cl.CCOCC>CCO>[CH3:13][N:7]1[CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CN(C)CCN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CN1CCN(C)C(C(=O)O)C1
Yield: 48.2 %

Procedure:
Ethyl 1,4-dimethylpiperazin-2-yl carboxylic acid (1.86 g) was dissolved in EtOH (10 mL) and 5M aqueous NaOH (20 mL) added. The mixture was refluxed for 2 hours, allowed to cool, 10M HCl (9.1 mL) added to give pH4 and the mixture evaporated to dryness. The white solid was stirred with MeOH (25 mL), CH2 Cl2 (10 mL) added and the filtrate evaporated to give, after trituration with Et2O, the title compound as a grey solid (761 mg, 48%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:10]=3O[C:12](=O)[C:13]=2[C:14]#[N:15])[CH2:4][CH2:3]1.[H-].[Na+]>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH2:23][C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:10]=3[C:10]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:23][C:12]=3[C:13]=2[C:14]#[N:15])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2c3c(oc(=O)c2C#N)-c2ccccc2C3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CCN(c2c(C#N)c3c(c4c2Cc2ccccc2-4)-c2ccccc2C3)CC1

Procedure:
A mixture of 4-(4-methylpiperidin-1-yl)-2-oxo-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (306 mg), indanone-2 (132 mg) and NaH (45 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 166-168° C.; IR (KBr) 2215 cm−1 (CN); MS (ESI) 377 (M++1).
Reaction SMILES: [C:1]([C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[ClH:12]>C(O)C.[Pd]>[ClH:12].[NH2:2][CH2:1][C:3]1([C:9]([NH2:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: N#CC1(C(N)=O)CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCC1(C(N)=O)CCCCC1
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 1-cyano-cyclohexanecarboxylic acid amide (2.34 g, 20.0 mmol) in ethanol (50 mL) was treated with concentrated HCl (3 mL) and 10% degussa palladium on carbon (0.50 g). The mixture was subjected to hydrogenation conditions (50 psi) for 24 hours, then filtered through Celite. The filtrate was concentrated, then azeotroped with methanol to give a viscous oil. The oil was then resubjected to the above hydrogenation conditions for an additional 20 hours. It was filtered and concentrated as above to give the product (3.85 g, 100%) as a white solid. [M+H]+ 157.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:27][CH3:26])=[O:19])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)CCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 11-8 (3.0 g, 11 mmol) was dissolved in 50 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2 M in methylene chloride, 16.2 mL, 32.4 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 27 mL, 54 mmol). Upon addition of the methylamine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3% methanol in ethyl acetate to give 4-[3-(ethylsulfonyl)propyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 11-9 as a white powder. MS (ESI+)=302 (M+1).
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[Cl:41][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[C:16]4[N:7]3[CH2:14][CH2:13][CH2:12][C@H:8]3[C:9]([OH:11])=[O:10])[N:30]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC[C@H]5C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of sodium hydride (60%; 9.99 mg, 0.250 mmol), dimethyl sulfoxide (DMSO) (2 ml) and proline (36.0 mg, 0.312 mmol) were stirred at room temp under nitrogen for 1 hour. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was heated at 120° C. under nitrogen for 3 hr. The cooled reaction mixture was loaded onto an SCX column. The column was washed with methanol and then eluted using 2M methanolic ammonia. The appropriate fractions were combined and the solvent was removed in vacuo to give an orange oil which was dissolved in DCM and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (40 mg).
Reaction SMILES: CNC(=O)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(O)C=CC=CC=1.C(=O)([O-])N.CN=C=O.[C:27]([O-])(=O)[NH:28][C:29]([NH2:31])=[O:30].NC1C=CC=CC=1>>[CH3:27][NH:28][C:29]([NH:31][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:30]
Reactant: NC(=O)NC(=O)[O-]
Reactant: CNC(=O)Oc1ccccc1
Agent: CN=C=O
Agent: NC(=O)[O-]
Solvent: Oc1ccccc1
Solvent: Nc1ccccc1
Product: CNC(=O)Nc1ccccc1

Procedure:
Following pyrolysis the residual material in the flask had a composition of 25 mole percent phenyl N-methylcarbamate and 75 mole percent phenol. The flask was cooled, a vacuum applied and phenol was stripped at a pressure of 20 mm Hg. Recovered phenol was also chromatographically pure. The residual carbamate remaining after phenol was stripped was returned to the pyrolysis flask. After 3 cycles of pyrolysis and phenol stripping, analysis showed: 96% conversion to methyl isocyanate, 2% unconverted material and 2% conversion to the allophanate. The methyl isocyanate was identified by reaction with aniline to give 1-methyl-3-phenylurea melting at 149°-150.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH2:8])[CH2:4][CH2:3]1.N1(CCC[C:18]2[CH:19]=[C:20]([NH:28][C:29](=[O:31])[CH3:30])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)CCCCC1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:18]2[CH:19]=[C:20]([NH:28][C:29](=[O:31])[CH3:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Reactant: C=C1CCN(C)CC1
Product: CC(=O)Nc1cc(CC2CCN(C)CC2)cc(C(F)(F)F)c1

Procedure:
N-[3-(1-Methyl-piperidin-4-ylmethyl)-5-trifluoromethyl-phenyl]-acetamide was prepared from 1-Methyl-4-methylene-piperidine similar to that described in the preparation of N-[3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>>[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:7]=1)=[CH:19][N+:20]([O-:22])=[O:21])[CH3:14]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)c1
Yield: 61 %

Procedure:
3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.09 g) and 1,1-bis(methylthio)-2-nitroethene (413 mg) were heated as an intimate mixture on a steam bth for 90 minutes. The resulting oil was washed with ether and purified by column chromatography on silica using 2% 0.88 ammonia in methanol to give the title compound as a pale yellow oil (0.74 g). Rf 0.30, silica/2% 0.88 ammonia in methanol.