Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Cc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
Following the same procedure as outlined in Example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (2.19 g, 7.5 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-methylphenyl)pyrimidine (1.03 g, 5 mmol) in toluene (50 mL, anhydrous) and DBU (0.9 mL) were reacted to yield the product as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:31][CH:32]([CH3:36])[CH2:33][CH:34]=[O:35]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:34]([OH:35])[CH2:33][CH:32]([CH3:36])[CH3:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 36.2 mmol) in dry tetrahydrofuran (400 mL) at −78° C. was added a n-butyllithium solution in n-hexane (2.5 M, 21.7 mL, 54.3 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and then treated with 3-methyl-butyraldehyde (7 mL, 65.2 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-ol as a colorless oil (9.4 g, 71%): LC/MS m/e calcd for C20H22N2O4S [M+H]+ 363.43, observed 362.8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7](=[O:19])[C:8]2[C:13]3[C:14]=1[CH:15]=[N:16][CH:17]=[CH:18][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[CH2:15][N:16]=[CH:17][CH:18]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7](=[O:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C2C=NC=Cc3cccc(c32)C(=O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)c2cccc3c2=C1CN=CC=3

Procedure:
A solution of 1-oxo-1,2-dihydronaphtho[1,8-cd]azepine-3-carboxylic acid methyl ester (129 mg, 0.5 mmol) in EtOAc (5 mL) is hydrogenated at 1 atm over 10% Pd/C (35 mg) for 18 h. The catalyst is filtered, the solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:33][C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[N:32]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccc(F)cc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccc(F)cc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 6-(4-fluorophenyl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 421.35 g/mol.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1.O>C(O)(=O)C>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 40 °C
Yield: 98 %

Procedure:
Fuming nitric acid (262 mL) was added at about 20° C. to a suspension of 4-hydroxy-2(l H)-quinolinone (1.0 Kg) in acetic acid (7.57 L). The mixture was heated at 40° C. for 2.5 h. The resulting solution was cooled to about 20° C. and poured into 8 L of water. The resulting mixture was stirred for 20 rain, filtered, washed with water until the filtrate was neutral, and dried. The product 4-hydroxy-3-nitro-2(I H)-quinolinone was isolated in 98% yield and showed only one spot upon analysis by thin layer chromatography (silica gel, 20:80 (V/V) chloroform in methanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(COCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-methylbenzyloxy)ethyl]piperidine (470 mg, 1.41 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2 mL, 4.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[2-(4-methylbenzyloxy)ethyl]piperidine (269 mg, 82%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.20 (d, 2H, J=7.6 Hz), 7.13 (d, 2H, J=8.0 Hz), 4.44 (s, 2H), 3.47 (t, 2H, 6.0 Hz), 3.02 (d, 2H, J=12.0 Hz), 2.53 (m, 3H), 2.33 (s, 3H), 1.64 (d, 2H, J=12.4 Hz), 1.51 (m, 3H), 1.06 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5]1)[CH2:2][CH3:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:21])[CH2:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[OH:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:6][C:4]([OH:5])([CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH3:3])[CH:12]=1)[CH2:18][C:19]#[N:20]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: CCCC1(CCC)CO1
Product: CCCC(O)(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
Reaction between 2,2-dipropyloxirane and aniline 12 gave 3-hydroxy-3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propanenitrile as a pale yellow semi-solid. Yield (1.0 g, 40%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=8.0 Hz, 1H), 6.69-6.67 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 4.96-4.94 (m, 1H), 4.05 (bs, 1H), 3.08 (s, 2H), 2.76 (d, J=6.4 Hz, 2H), 2.36 (bs, 1H), 1.52 (t, J=8.4 Hz, 4H), 1.41-1.32 (m, 4H), 0.94 (t, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][OH:4].CO[C:21]([CH3:23])=[CH2:22].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:22][C:21]1([CH3:23])[O:1][CH:2]([C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:3][O:4]1
Reactant: C=C(C)OC
Reactant: O=C(NCc1ccccc1C(O)CO)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccccc2CNC(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.93 g of N-[2-(1,2-dihydroxyethyl)benzyl]-2,2,2-trifluoroacetamide and 20 ml of acetone were added 1.1 ml of 2-methoxyprop-1-ene and 140 mg of 4-methylbenzenesulfonic acid monohydrate under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.2 g of N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2,2,2-trifluoroacetamide.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=2)=[O:16])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.O[Li].O>C1COCC1>[C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=2)=[O:16])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(OC(=O)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-[N-Boc-cis-1-amino-4-cyclohexanoyloxy]-2-methoxybenzoate (220 mg, 0.52 mmol) in THF:H2O (5 mL: 1 mL) was added LiOH.H2O (67.6 mg, 1.59 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid passed through a plug of silca gel packed in 50:50 MeOH:CH2Cl2 and eluted with same. The solvent was removed under reduced pressure to afford 4-[N-Boc-cis-1-amino-4-cyclohexanoyloxy]-2-methoxybenzoic acid as a white solid.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([Br:24])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:13]=[CH:12]2)[CH3:6].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([CH2:48][OH:49])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1.C1CCCCC1>ClCCl>[Br:24][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([CH:5]([O:49][CH2:48][C:35]3([C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=4)[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40]3)[CH3:6])[CH:8]=1)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:13]=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Reaction time: 0.25 h

Procedure:
To a solution of (±)-1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (780 mg, 1.512 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (468 mg, 1.512 mmol) in dichloromethane (3 mL) at 0° C. was added cyclohexane (3 mL) and tetrafluoroboric acid diethyl etherate (0.041 mL, 0.302 mmol). After 15 min, the reaction was quenched by addition of triethylamine (ca. 0.05 mL). The reaction was diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→18% EtOAc/Hex) gave 543 mg (54%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.71 (d, J=1.8, 1H), 7.21 (m, 2H), 7.18 (s, 1H), 6.97 (m, 2H), 5.58 (qAB, JAB, 11.6, 2H), 5.06 (q, J=6.1, 1H), 3.68 (m, 2H), 3.41 (m, 2H), 3.24 (qAB, JAB=8.9, 2H), 3.02 (m, 2H), 2.12 (m, 1H), 2.04 (m, 1H), 1.83 (m, 2H), 1.42 (s, 12H), 0.80 (m, 1H), 0.71 (m, 1H), −0.11 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 162.4, 160.4, 155.0, 138.6, 136.1, 133.4, 129.3, 128.7 (d, J=7.7), 128.1, 127.4, 122.5, 115.3, 115.1, 114.8, 79.8, 79.4, 76.7, 72.8, 66.1, 41.1, 40.0 (br), 32.3, 32.1, 28.6, 22.8, 17.9, −1.4. Mass spec.: 662.02 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](O)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:20][CH:19]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: COC(=O)Cc1cc(Cl)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Cl)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 42 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanol (1.0 g), methyl 2-(5-chloro-2-hydroxyphenyl)acetate (0.74 g), triphenylphosphine (1.08 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.79 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[5-chloro-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.68 g, 42%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15](O)[CH:16]2[C:20](=[O:21])[C:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[C:18]([O:31]C)[CH2:17]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.Cl>CC(C)=O.O>[CH3:1][O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:20](=[O:21])[CH:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:18](=[O:31])[CH2:17]/2)[CH2:11][CH2:10]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCC(OCc3ccccc3)CC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC1CCC(/C=C2\CC(=O)C(c3c(C)cc(C)cc3C)C2=O)CC1
Temperature: 120 °C
Yield: 23.5 %

Procedure:
To a solution of 5-[(4-benzyloxy-cyclohexyl)-hydroxy-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (1.5 g, 4.0 mmol) in acetone (3 ml) is added 2N aqueous hydrochloric acid (3 ml) and the mixture heated for 1 hour at 120° C. by microwave irradiation. The reaction mixtures is then diluted with water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a brown gum. The gum is purified by flash chromatography eluting with hexane/ethyl acetate to give 4-[1-(4-Methoxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione as a colourless solid (0.32 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=4[CH3:31])[O:30][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)c(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Temperature: 50 °C

Procedure:
0.5 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.3 g potassium carbonate are suspended in 20 ml of DMF. 0.2 ml of ethyl bromoacetate is added and the reaction mixture is heated to 50° C. under a blanket of nitrogen for about 16 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in EA. The organic phase is washed twice with water and brine, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from diethyl ether yields the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]=[CH:9][CH:10]([CH3:13])[CH2:11][CH3:12])[CH:3](O)[CH:4]=[CH2:5].C[O:15][C:16](=O)[CH:17](C=O)[CH3:18]>>[CH3:18][CH:17]([CH2:5][CH:4]=[CH:3][CH:2]([CH3:1])[CH2:7][CH:8]=[CH:9][CH:10]([CH3:13])[CH2:11][CH3:12])[CH:16]=[O:15]
Reactant: C=CC(O)C(C)CC=CC(C)CC
Reactant: COC(=O)C(C)C=O
Product: CCC(C)C=CCC(C)C=CCC(C)C=O
Yield: 76.5 %

Procedure:
55 g (0.3 mole) of 4,8-dimethyl-deca-1,6-dien-3-ol and 46 g (0.4 mole) of α-formyl-propionic acid methyl ester are heated at from 140° to 200° C, whilst stirring, the methanol thereby eliminated is distilled off through a column, and the carbon dioxide eliminated is recorded by a gas flow meter. When the reaction has ceased, the contents of the flask are fractionated. 51 g of 2,6,10-trimethyl-dodeca-4,8-dien-1-al (yield, 77% of theory) are obtained. B.p. = 72° - 75° C at 0.01 mm Hg; nD25 = 1.4566. Odor: sweet, fruity, orange scent.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[CH2:36]Br>C1COCC1>[Cl:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[CH2:36][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: COc1cccc(Cl)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(0.05 g, 0.224 mmol) in dry THF (1.5 ml) under nitrogen was added a 1 M solution of lithium bis(trimethylsilyl)amide in THF (0.224 ml, 0.224 mmol, Aldrich) dropwise, fairly quickly. The solution was stirred for 30 min then a solution of 2-(bromomethyl)-3-chlorophenyl methyl ether (for a preparation see Intermediate 25)(0.053 g, 0.224 mmol) in dry THF (1.5 ml) was added and stirring continued for 90 min then the solution was left to stand overnight. The solvent was removed in vacuo and the residue was partitioned between chloroform and half saturated sodium bicarbonate and the aqueous phase further extracted with chloroform, the chloroform fractions being filtered through a phase separator. The chloroform was removed in vacuo and the residue purified on MDAP (Method B) to give the title compound as a white solid (0.07 g); LCMS: (System 4) MH+=378, tRET=2.77 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:16]([CH2:17]O)=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH2:5]([N:12]1[C:16]([CH2:17][Cl:3])=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CCl)n2Cc2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
Thionyl chloride (0.90 ml, 1.48 g, 12.4 mmol) was added dropwise to a stirred suspension of 1-benzyl-4-chloro-5-(hydroxymethyl)-2(4-nitrophenyl)imidazole (18.5 g, 5.4 mmole) in chloroform (15 ml) at room temperature. The brown solution was stirred for 2.5 hours then evaporated to dryness. Toluene (12 ml) was added to the residue and evaporated to dryness. The residue was dissolved in chloroform (20 ml) and used in the next step for introduction of the cyano functional group.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][C:7]([Cl:14])=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][N:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][C:7]([Cl:14])=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: CN(c1ccc(O)cc1)c1cnc2cc(Cl)c(Cl)cc2n1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)c(Cl)cc3n2)cc1

Procedure:
4-[N-Methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 1 Part (b), to give ethyl 2-{4-[N-methyl-N-(6,7-dichloro-2-quinoxalinyl)amino]phenoxy}propionate, mp 79° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.25 (1H, s, quinoxaline hetero-ring proton); 7.9 (1H, s, quinoxaline benzo-ring proton); 7.8 (1H, s, quinoxaline benzo-ring proton); 7.2 (4H, m, phenoxy protons); 4.85 (1H, q, CH-CH3); 4.3 (2H, q, CH2 -CH3); 3.55 (3H, s, N-CH3); 1.7 (3H, d, CH-CH3); 1.3 (3H, t, CH2 -CH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[N:11]1([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccncc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc2onc(N3CCNCC3)c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Isoxazolo[4,5-c]pyridin-3-yl-piperazine-1-carboxylic acid tert-butyl ester (960 mg, 3.1 mmol) was dissolved in CH2Cl2 (2 ml) and 4 N HCl in dioxane (15.7 ml, 63 mmol) was added. The resulting mixture was stirred 16 h at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 850 mg (97%) as a pink solid. m/z=205.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C#N)[CH:5]=[CH:4][N:3]=1.C[Mg]Br.Cl.CC[O:16][CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:17](=[O:16])[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1ccnc(Cl)c1
Reaction time: 20 h

Procedure:
To a solution of 20.4 g of 2-chloro -4-cyanopyridine in 290 ml of anhydrous ether at room temperature, 100 ml of 3.0 M methyl magnesium bromide in ether was slowly added under nitrogen. The mixture was stirred for 20 hours and then slowly poured onto cold aqueous hydrochloric acid. The layers were separated and the aqueous layer further extracted with ether. The combined organic layers were washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solution was concentrated and the residue chromatographed on silica gel (60:40 methylene chloride:hexane) to give 11.42 g of product.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:10](Cl)=[O:11].[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15]1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][CH:14]([NH:13][C:10]([C@H:3]3[C:2]4([CH3:1])[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[O:11])[CH2:15]2)=[CH:22][CH:23]=1
Reactant: CC12CCN(CC1)CC2C(=O)Cl
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: CC12CCN(CC1)C[C@H]2C(=O)NC1CCN(CCc2ccc(F)cc2)C1

Procedure:
4-Methylquinuclidine-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-4-methylquinuclidine-3-carboxamide.