Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]=O.[BH4-]>CO>[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][NH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:8]=2)[CH2:3]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)C[C@H](N)C3)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccccn1
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)C[C@H](NCc2ccccn2)C3)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
The amine is dissolved in methanol (160 mL), triethylamine (1.45 g, 14.4 mmol) and 2-pyridinecarboxaldehyde (1.59 g, 14.8 mmol) are added, and the mixture is stirred overnight. Polymer supported borohydride (Aldrich, borohydride on Amberlite IRA-400, 2.5 mmol/g, 6.0 g, 14.8 mmol) is added and the mixture is stirred for an additional 24 hours. The resin is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in a small amount of ethyl acetate and triturated with hexane to yield (R)-6-methyl4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethylamino)-indan-5-yl] amide as a solid. The solid is dissolved in ethanol (100 mL) and a saturated solution of HCl (g) in ethyl ether is added. The resulting solid is collected to yield (R)-6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-pyridylmethylamino)-indan-5-yl] amide hydrochloride, m.p. 281-283° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[C@H:13]([CH3:17])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1C(=O)c1ccccn1
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a solution of (3R)-1-[(4-chlorophenyl)sulfonyl]-3-methylpiperazine (0.15 g, 0.55 mmol) in dry acetonitrile (5 mL) was added potassium carbonate (90 mg, 0.66 mmol) and 2-pyridinecarbonyl chloride (106 mg, 0.60 mmol) and the reaction mixture heated at 85° C. for 24 h. To the mixture was added ethyl acetate (30 mL) and the organic phase washed with 10% aqueous sodium bicarbonate (50 mL) before it was dried (MgSO4), filtered and the solvent evaporated. The crude product was purified by Biotage SP4 (12+M silica column) eluting 0-4% MeOH in DCM to give the title compound as an off-white solid (95 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CN1CCC(=O)CC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C2CCN(C)CC2)C3)cc1

Procedure:
Compound eg was synthesized according to the procedure described in Example 8 reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-methylpiperidin-4-one. LC-MS: m/z=+494 (M+H)+.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>CS(C)=O.O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:2])[CH2:16][O:17]2)=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (3.5 g, 17.15 mmol, 1.2 equiv.) in DMSO (30 mL) was added sodium hydride 50%-55% dispersion in oil (0.97 g, 22.2mmol, 1.5 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 1-(4-fluorophenyl) ethanone (2 g, 14.47 mmol, 1 equiv.) in DMSO (10 mL) was added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The progress of the reaction was checked by TLC and the reaction mixture was poured in 100 mL water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (2×150 mL), followed by brine. The organic layer was dried over sodium sulfate and evaporated to dryness to yield a brown oil (2.2 g). 1H NMR (d6-acetone) was consistent with the structure. Product Rf 0.8 (ethyl acetate: hexane 10:90)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Cl[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
A solution of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (13.2 g) in tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of sodium hydride (8.0 g, 60% dispersion in oil) in tetrahydrofuran (150 ml) and the mixture was then treated dropwise with a solution of ethyl 4-chloroacetoacetate (16.5 g) in tetrahydrofuran (50 ml). The mixture was stirred at room temperature overnight and evaporated. The residue was quenched with 10% aqueous acetic acid and extracted twice into dichloromethane. The combined dichloromethane extracts were washed with saturated brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on SiO2 (100 g) using toluene plus 0-20% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (5.6 g) as an oil. This compound was used in Preparations 3 and 4 without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:13]([F:33])=[C:14]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH3:10].CCCCCC>C(#N)C>[Br:1][C:27]1[C:14]([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])=[C:13]([F:33])[C:12]([O:11][CH2:9][CH3:10])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Solvent: CC#N
Solvent: CCCCCC
Product: CCOc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)c(F)c1OCC
Reaction time: 6 h
Yield: 0 %

Procedure:
N-bromosuccinimide (1.43 g, 8.07 mol) was added to a solution of 2-(3,4-diethoxy-2-fluorobenzyl)isoindol-1,3-dione (2.52 g, 7.34 mol) in acetonitrile (30 mL) on ice. The mixture was stirred on ice for ten hours, and then at room temperature for six hours. The reaction mixture was extracted after the addition of a 5% aqueous solution of sodium thiosulfate and ethyl acetate; then the resultant organic layer was washed sequentially with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified by silica gel column chromatography (diethyl ether, no-hexane) to give 1.12 g of the title compound (yield: 36%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:30])([C:26]([F:29])([F:28])[F:27])[C:3]([F:25])([F:24])[C:4]([F:23])([F:22])[O:5][C:6]([F:21])([F:20])[C:7]([F:19])([F:18])[O:8][C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:31]([C:38]1[CH:39]=[N:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)=[N:42][CH:43]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:31]([C:38]1[CH:43]=[N:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([O:50][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([O:8][C:7]([F:19])([F:18])[C:6]([F:21])([F:20])[O:5][C:4]([F:23])([F:22])[C:3]([F:25])([F:24])[C:2]([F:30])([F:1])[C:26]([F:29])([F:28])[F:27])([F:17])[F:16])=[CH:48][CH:49]=2)=[N:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride (5.17 g of 95% purity, 8.4 mmol, Example 14) with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (4.0 g, 8.4 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation to provide a yield of 2.9 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[OH:29])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[NH:22][C:20]([C:11]1[C:12](=[O:19])[N:13]2[C:18]([CH:17]=[CH:16][CH:15]=[CH:14]2)=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)=[CH:7][N:6]=2)[CH:10]=1)=[O:21]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Br)cn2)c2ccccn2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3cc(C(=O)N[C@H]4CCCC[C@@H]4O)c(=O)n4ccccc34)nc2)cn1
Temperature: 100 °C

Procedure:
To a solution of 1-[(5-bromopyridin-2-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide (Example 2, 0.045 g, 0.099 mmol) in 2 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 N, 0.20 mL, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.062 g, 0.30 mmol), and bis(tri-tert-butylphosphine)palladium(0) (5.0 mg, 0.010 mmol). The reaction was heated at 100° C. for 15 h, cooled to rt, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a high resolution mass spectrum (ES+) m/z of 472.2330 calculated for M+H+ [C27H30N5O3: 472.2343]: 1H NMR (400 MHz, CD3OD) δ 9.50 (d, J=7.0 Hz, 1H), 8.83 (s, 1H), 8.53-8.50 (m, 1H), 8.35-8.30 (m, 1H), 8.16 (s, 1H), 8.06-7.97 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.52-7.48 (m, 1H), 4.62 (s, 2H), 3.95 (s, 3H), 3.86-3.81 (m, 1H), 3.55-3.48 (m, 1H), 3.21-3.12 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.87 (m, 1H), 1.79-1.73 (m, 2H), 1.40-1.24 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 45%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][NH2:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triethylamine (3.12 mL, 22.4 mmol) was added to a slurry of N-(2-chloro-3-nitroquinolin-4-yl)ethane-1,2-diamine (3.00 g, 11.2 mmol) in dichloromethane (80 mL). A solution of di-tert-butyl carbonate (2.95 g, 13.5 mmol) in dichloromethane (20 mL) was added over 5 minutes to the slurry. The solution was stirred at room temperature for three hours and then was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered, and concentrated to an orange solid. The crude product was purified by flash chromatography (silica gel, 3:1 hexanes/ethyl acetate as the eluent) to afford tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate (3.70 g) as a bright yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[C:17]([F:28])=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([O:26][CH3:27])[CH:22]=[CH:21]2>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:15][C:16]1[C:17]([F:28])=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([O:26][CH3:27])[CH:22]=[CH:21]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(F)ccc2ccc(OC)nc12)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To a suspension of NaH (60% dispersion in oil, 0.88 g, 22 mmol) in THF (100 mL), was added diethyl malonate (3.79 g, 23.66 mmol). The reaction mixture was cooled to 0° C. and 8-bromomethyl-7-fluoro-2-methoxy-quinoline (5.4 g, 20 mmol) was added in one portion. The reaction proceeded 30 min at 0° C. and 15 min at rt. The reaction mixture was quenched by adding water (20 mL) and 10% NaHSO4 (100 mL). The two layers were decanted and the aq. layer was extracted once with EA (100 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 4:1) to afford the title compound as a yellowish oil (6.4 g). The product was contaminated with 20% of diethyl malonate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Product: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O

Procedure:
The title compound, brown solid, MS: m/e=376.3 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and ethyl bromoacetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH3:23])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)Sc1ccc(O)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)Sc1ccc(OCC)cc1

Procedure:
To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester (11.3 g, 50 mmol), and K2CO3 (50 g, excess) in acetone (300 ml) ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At the end, reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform and washed well with water. It was dried and concentrated. The product, 2-(4-ethoxy-phenylsulfanyl)-propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[CH2:13]1[O:24][C:23]2[CH:22]=[C:21]3[C:17]([C:18]([C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=4)=[CH:19][NH:20]3)=[CH:16][C:15]=2[O:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:28]1[CH2:29][CH:30]=[C:25]([C:18]2[C:17]3[C:21](=[CH:22][C:23]4[O:24][CH2:13][O:14][C:15]=4[CH:16]=3)[NH:20][CH:19]=2)[CH2:26][CH2:27]1)=[O:12]
Reactant: C1=C(c2c[nH]c3cc4c(cc23)OCO4)CCNC1
Reactant: O=C(O)C1Cc2ccccc2C1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3cc4c(cc23)OCO4)CC1

Procedure:
Prepared from 9a and 5,6-methylenedioxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:15])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C=O)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole (0.7 g) was dissolved in tetrahydrofuran (5 mL), and a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mL/L, 4.3 mL) was added to the stirred solution. The mixture was stirred at room temperature for 1 hour. A small amount of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran) to give the title compound (0.6 g).
Reaction SMILES: [CH:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)=[O:2].[O-:24][Mn](=O)(=O)=O.[K+]>>[C:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)([OH:24])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Product: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 6α-formylandrostane-3,17-dione (1.77 g) in t-ButOH (35 mL) and 5% aqueous Na2HPO4 solution (21.5 mL), 1N aqueous KMnO4 (35 mL) was added. After 5 minutes at room temperature, the mixture was quenched by addition of 40% aqueous NaHSO3 solution. The suspension was filtered, washed with H2O and the filtrate was freeze-dried. The residue was taken up with H2O (50 mL) and extracted with EtOAc (4×70 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give the title compound II-aq (1.80 g, 96%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 11.99 (bb, 1H), 2.46-0.73 (m, 21H), 1.01 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[CH:3]=1.[Cl:11]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH2:10][Cl:11])=[CH2:9])[CH:3]=1
Reactant: C=C(C)c1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 17.1 %

Procedure:
A mixture of 4.3 g of 4-chloro-2-isopropenylpyridine, 3.8 g of N-chlorosuccinimide and 10 ml of carbon tetrachloride was stirred in an oil bath at 150° to 160° C. for hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 0.90 g of the objective compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([NH:11][C:12]1[O:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>CCOCC>[CH2:7]([N:11]([C:12]1[O:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCCCNc1nc(C)co1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)OCC)c1nc(C)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (10.5 ml, 0.11 mol) was added dropwise over 20 minutes to a stirred solution of 2-butylamino-4-methyl oxazole (15.4 g, 0.10 mol) and triethylamine (15.3 ml, 0.11 mol) in dry ether (100 ml) cooling to 5°-10° C. The mixture was stirred for a further 2 hours at ambient temperature, the white solid was filtered off and the filtrate evaporated under vacuum to a pale oil (22.4 g) NMR (CCl4) 6.3 δ (oxazole 5-H). This 3-acylated compound was dissolved in xylene and the solution was heated under reflux for 2 hours, cooled, washed with dilute HCl, saturated NaCl solution, dilute Na2CO3 and NaCl solution again, dried and evaporated. The residue was distilled under vacuum, b.p. 85°-90° C./0.6 mm NMR (CCl4) 7.12 δ (oxazole 5-H).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]2)C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[C:15]([CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10]1)#[N:16]
Reactant: CCOC(=O)Cl
Reactant: N#CCC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of 25 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 178 parts of tetrahydrofuran were added dropwise 37.97 parts of ethyl chloroformate at room temperature. The reaction mixture was stirred for 15 hours at room temperature and was then evaporated. The residue was taken up in 90 parts of ethyl acetate and the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.). The solvent was evaporated and the residue was distilled (100°-110° C./6.7 Pa), yielding 18.7 parts (81.4%) of ethyl 4-(cyanomethyl)-1-piperidinecarboxylate (interm. 24).