Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[C:24](=[N:32]O)([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:32]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:31]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=NO)c1ccccc1
Reactant: CCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccccc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 1.5 h
Yield: 34.9 %

Procedure:
CDl (0.98 g, 6.1 mmol) was added to a solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the mixture stirred at 110° C. overnight. The reaction mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude product was crystallised from methanol and then further purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a white solid (850 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.Cl>C1COCC1>[CH2:1]([N:8]1[C:12](=[O:13])[C@@H:11]([CH3:17])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (1000 mg, 4.56 mmol) in 55 ml of THF 10.03 ml of a 1M lithium bis(trimethylsilyl)amide solution in THF (10.03 mmol) were added slowly at −10° C., and stirring was continued at this temperature for 1 h. Subsequently iodomethane (0.284 ml, 647 mg, 4.56 mmol) in 9 ml of THF were added (slight exothermic reaction), and the reaction was completed by stirring overnight at room temperature. The brown reaction mixture was acidified using 2M HCl, extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The title compound was obtained as a brown oil, which was reacted in the next step without further purification (890 mg of raw material, yield: 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: COc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)c1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 15 using N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide and NBS (reaction time 30 min at room temperature). The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent giving the final product, after recrystallization using hexane/ethyl acetate, in 75% yield, m.p. 140-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]I)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:21])[CH:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:15]([CH3:16])([S:17]([CH3:20])(=[O:18])=[O:19])[C:14]([O:13][CH2:11][CH3:12])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: Brc1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A suspension of 1-bromo-4-(2-iodo-ethyl)-benzene (25.0 g, 80 mmol) and (+/−)-2-methanesulfonyl-propionic acid ethyl ester (15.9 g, 88.4 mmol) in DMF (100 mL) with solid Cs2CO3 (52.4 g, 161 mmol) was stirred overnight at room temperature. After 16 hours the reaction was poured into water (500 mL). The resulting suspension was stirred for 2 h. The mixture was extracted with diethylether (2×). The organic layers were combined and washed with water then brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate 9:1-8:2) afforded the title compound as a white solid (21.0 g, 72%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.22 Hz, 3H) 1.70 (s, 3H) 2.14-2.24 (m, 1H) 2.42-2.55 (m, 2H) 2.68-2.78 (m, 1H) 3.04 (s, 3H) 4.25-4.31 (m, 2H) 7.07 (d, J=8.20 Hz, 2H) 7.43 (d, J=8.20 Hz, 2H)
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](Cl)[N:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:21]2[N:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:25](=[O:27])[CH3:26])=[C:14]3[NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:8][CH2:9]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(COS(C)(=O)=O)CC1
Reactant: C1CCNC1
Product: CC(=O)c1cnc2ccc(N3CCCC3)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure V, {4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]-cyclohexyl}methyl methanesulfonate (180 mg, 0.437 mmol) was reacted with pyrrolidine (34 mg, 0.48 mmol) to afford the desired product (34 mg, 18%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 8.63 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 5.57 (br s, 1H), 3.61-3.53 (m, 4H), 2.63 (s, 6H), 2.45 (d, J=7.0 Hz, 2H), 2.30-2.18 (m, 2H), 2.14-2.04 (m, 4H), 1.98-1.91 (m, 2H), 1.89-1.80 (m, 4H), 1.68-1.55 (m, 1H), 1.40-1.28 (m, 2H), 1.18-1.08 (m, 2H); ESI MS m/z 422 [M+H]+; HPLC 97.5% (AUC), tR=9.68 min.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].CCN(C(C)C)C(C)C>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: COC(=O)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
To a solution of 40 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 1 mL of acetonitrile was added 0.011 mL of methyl 4-chlorobutyrate and 0.046 mL of DIPEA. The reaction was heated at 50° C. for 24 hours, then an additional 0.022 mL of methyl 4-chlorobutyrate, 0.030 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 80° C. for 60 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (5% methanol in methylene chloride) to give 27 mg of title compound. Mass spec (ESI): 550 (M+1).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)([OH:15])[CH3:14])[N:10]=[N:9]1)C>CO.O>[Br:22][C:18]1[N:17]=[C:16]([C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][CH2:6][OH:5])[CH:12]=2)([OH:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cn1cc(C(C)(O)c2cccc(Br)n2)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)(c1cn(CCO)nn1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (92 mg, 2.42 mmol) in MeOH (3.0 mL) at room temperature was added ethyl{4-[1-(6-bromopyridin-2-yl)-1-hydroxyethyl]-1H-1,2,3-triazol-1-yl}acetate (430 mg, 1.21 mmol) in MeOH (7.0 mL). The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×) and 5:1 CH2Cl2:MeOH (5×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (0-5% MeOH/EtOAc) afforded the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:6](COCCOC)[C:5]2[CH:13]=[C:14]([Cl:24])[C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][C:4]=2[N:3]=1.[NH:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:33]([O:32][C:30]([C:28]1[CH:29]=[N:25][N:26]([C:2]2[NH:6][C:5]3[CH:13]=[C:14]([Cl:24])[C:15]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:16][C:4]=3[N:3]=2)[CH:27]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COCCOCn1c(Cl)nc2cc(Oc3ccccc3)c(Cl)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0.251 g, 0.684 mmol) and ethyl pyrazole-4-carboxylate (0.115 g, 0.820 mmol) in dry DMF (4 mL) was added anhydrous cesium carbonate (0.535 g, 1.64 mmol). The stirred suspension was heated in 80° C. bath in a sealed tube for 2 h. After coming to ambient temperature, the reaction mixture was added to ice water (100 mL), acidified with 1N HCl (3 mL) and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried, filtered, and concentrated under reduced pressure to afford the titled product as a crude orange paste (0.361 g). MS (ESI/CI): mass calcd. for C23H23ClN4O5, 470; m/z found, 471 [M+H]+.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36]OS(C)(=O)=O)=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36][N:21]2[CH2:22][CH:23]3[O:25][CH:19]([CH2:18][N:17]([CH2:16][CH2:15][NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=4)(=[O:13])=[O:12])[CH2:24]3)[CH2:20]2)=[N:27]1
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Reactant: CS(=O)(=O)OCCc1noc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)NCCN2CC3CN(CCc4noc5ccccc45)CC(C2)O3)cc1
Temperature: 160 °C
Yield: 41.5 %

Procedure:
To 4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.123 g, 0.30 mmol, from prep E above), methanesulfonic acid 2-benzo[d]isoxazol-3-yl-ethyl ester (0.076 g, 0.315 mmol, from prep AD above) and potassium carbonate (0.145 g, 1.05 mmol; from Prep ) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 60 mg (41.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][CH:14]=2)[N:9]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([N:50]2[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]2=[O:51])[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1cc2ccc(F)cc2nc1-c1ccccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ccc(F)cc2nc1-c1ccccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethanol (0.7018 g, 2.326 mmol) in tetrahydrofuran (23.26 mL, 2.326 mmol) were added triphenylphosphine (1.220 g, 4.652 mmol), phthalimide (0.6844 g, 4.652 mmol), and diisopropyl azodicarboxylate (0.9159 mL, 4.652 mmol). The reaction mixture was stirred at room temperature. After 2 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc in hexane for 10 min as eluent to 2-(1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione as an off-white solid: LC-MS (ESI) m/z 431.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH3:14])([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:15][Mg+].[Br-].Cl>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[C:8]([CH:12]([OH:13])[CH3:15])([CH3:14])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=CCC(C)(C=O)C(C)C1
Reactant: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C)(C(C)O)C(C)C1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
4-Isobutyl-1,6-dimethylcyclohex-3-enecarbaldehyde 3c (4.5 g, 23 mmol) was dissolved in diethyl ether (40 ml). The solution was cooled to 0-5° C. under nitrogen and MeMgBr (3M, 12 ml, 35 mmol) added over 40 min with stirring. The temperature was allowed to rise to room temperature and stirring continued for 30 min. The reaction mixture was poured slowly onto a vigorously stirred mixture of 2M HCl and ice. After stirring for 10 min the phases were separated and the lower aqueous layer extracted twice with MTBE. The organic phases were combined and washed with sat. NaHCO3 solution and brine to pH 7. After drying (MgSO4) the organic phase was concentrated in vacuo to give 4.6 g of a light yellow oil. The crude oil was purified by flash chromatography (MTBE/hexane 3:7) to give 4d as a 1:2:3:5 mixture of diastereomers (2.7 g, 55% yield, >98% pure). Distillation of a 0.7 g sample gave 0.6 g of 4d (colorless oil, >99% pure) for olfactory assessment.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[N:8]2S(C)(=O)=O)=[CH:4][C:3]=1[F:22].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:15]([OH:21])([CH3:20])[CH2:16][S:17][CH2:18][CH3:19])[NH:8]2)=[CH:4][C:3]=1[F:22]
Reactant: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSCC(C)(O)c1cc2cc(F)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-chloro-5-fluoro-1-methanesulfonyl-1H-indol-2-yl)-1-ethylsulfanyl-propan-2-ol (0.30 g, 0.82 mmol) in methanol (10 mL) was added 4M sodium hydroxide solution (0.4 mL). The reaction was allowed to proceed overnight at room temperature. Complete reaction was not achieved, so additional 1 M sodium hydroxide solution (1 mL) was added and the reaction mixture was heated to 50° C. The reaction mixture was kept at 50° C. for two hours then allowed to stir overnight at room temperature. The reaction mixture was concentrated and to the concentrate was added 1N hydrochloric acid solution and water. The mixture was extracted twice with ethyl ether. The extracts were dried over Mg2SO4, filtered, and evaporated to yield a residue. The residue was purified by column chromatography eluting with dichloromethane to yield the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCc1ccc(C=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCCCc1ccc(C=CC(=O)O)cc1
Temperature: 100 °C

Procedure:
9.4 G. of p-n-hexylbenzaldehyde in 5 ml. of absolute pyridine are treated with 5.15 g. of malonic acid and 5 drops of piperidine. Then, the mixture is heated at 100° C. for 11 hours, and, subsequently, poured on to cold aqueous hydrochloric acid and extracted with ether. The p-n-hexylcinnamic acid obtained after recrystallization of the crude product from hexane/ether has a melting point of 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([O:11][Si](C(C)(C)C)(C)C)=[CH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.CS(N)(=O)=[O:21].S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[C@H:9]([OH:21])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC=C(O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 28 h
Yield: 86.2 %

Procedure:
Z-1-(3-Chlorophenyl-tert-butyldimethylsilyloxy-1-propene (12.0 g, 44 mmol) was added to a well-stirred mixture of AD-mix-P (80 g) and CH3SO2NH2 (4.2 g, 44 mmol) in tert-butyl alcohol/water mixture (220 mL/220 mL) maintained at 0° C. The reaction mixture was stirred at 0° C. for 28 hours. Solid sodium sulfite (40 g) was added. The mixture was stirred for an additional 45 minutes and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with NaHCO3 and brine, and evaporated. The residue was passed through a silica gel column to give the desired product (7.0 g). 1H NMR (CDCl3): δ 1.45 (d, 3H), 5.15 (q, 1H), 7.2-7.9 (m, 4H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Cc1ccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)cc1

Procedure:
Example 8 was prepared according to Example 2 except that in Step A 1-(p-tolyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 143°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)(=[O:14])[CH3:13].CCOCC>C(O)C>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:12](=[O:14])/[CH:13]=[C:3](\[OH:5])/[C:2]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
In a dry flask, under argon atmosphere, sodium (317 mg, 13.8 mmol, Eq: 1.00) was added portionwise to ethanol (9.0 ml). (The temperature increased to 60° C.). The reaction mixture was cooled at 0° C. Then Diethyl oxalate (2.01 g, 1.87 ml, 13.8 mmol, Eq: 1.00) was added dropwise followed by 4-acetylbenzonitrile (2 g, 13.8 mmol, Eq: 1.00) in Ethanol (3.00 ml). A white solid appeared. The reaction was stirred with mechanical stirrer overnight and monitored by TLC. Then the reaction mixture was concentrated in vacuo. The residue was cooled at 0° C. and water was added to the flask. 1M HCl was added to this solution (pH=3), then the solution was extracted two times with EtOAc. The organic layer was washed three times with 20 mL Brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid. This off-white solid was mixed with Ether at 0° C. The suspension was filtered to give a white solid (2.082 g, 61.6%).
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])=[O:10])=[C:7]([CH:20]([CH3:22])[CH3:21])[C:6](=[O:23])[NH:5][C:4]1=[O:24])[CH3:2].[H-].[Na+].Br[CH2:28][O:29][C:30](=[O:32])[CH3:31]>CN(C=O)C.O>[C:30]([O:29][CH2:28][N:5]1[C:6](=[O:23])[C:7]([CH:20]([CH3:21])[CH3:22])=[C:8]([C:9](=[O:10])[C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[N:3]([CH2:1][CH3:2])[C:4]1=[O:24])(=[O:32])[CH3:31]
Reactant: CC(=O)OCBr
Reactant: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl)-5-methylbenzonitrile (778 g, 2.39 mol) in anhydrous DMF (5 L) was added 60% NaH (115 g) portion-wise over 30 min at 0° C. The reaction mixture was stirred at room temperature for 3 hours and then the mixture was cooled to −10° C. Acetic acid bromomethyl ester (321 mL) was dropwise added to the reaction mixture for 2 hours at the same temperature and the reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (10 L). The precipitate was collected by filtration, washed with water (5 L) and then dissolved in dichloromethane (10 L). The organic solution was washed with water (4 L), dried with anhydrous magnesium sulfate (1 kg) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane, 1:20) to give (4-(3-cyano-5-methylbenzoyl)-3-ethyl-5-isopropyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)methyl acetate (745 g, 1.87 mol, 79%) as a white solid.