Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:45][CH:46]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc(-c2nccn2Cc2ccccc2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nccn2Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-benzyl-imidazol-2-yl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=20:1) C33H26N4O3
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:30])=[C:4]([CH:8]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:21])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:31][N+:32]([CH3:34])=[CH2:33].[I-].[C:36](O)(=O)C>>[CH3:33][N:32]([CH2:34][CH:9]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:30])[C:19](=[CH2:36])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])[CH3:31]
Reactant: CC(=O)O
Reactant: COc1cccc(C(=O)CC(CC(=O)c2ccccc2F)c2cccc(F)c2C)c1
Reactant: C=[N+](C)C
Agent: [I-]
Product: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1ccccc1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)pentane-1,5-dione (8.4 g, 20.6 mmol) and Eschenmoser's salt (17.6 g, 94.9 mmol) in acetic acid (86 mL) was stirred at 120° C. under nitrogen for 16 h. An additional 3.8 g (20 mmol) of Eschenmoser's salt was added and the mixture heated an additional 5 h. The solution was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (30 mL) and 9:1 hexanes/EtOAc, and then treated with 10% NaOH until the pH reached 11 (150 mL). After 30 min, the resulting brown solid was collected by filtration, triturated with EtOAc (3×50 mL), and dried under vacuum at 40° C. to give 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1-(2-fluorophenyl)-5-(3-methoxyphenyl)-4-methylenepentane-1,5-dione product (7.5 g, 76% crude yield) as a yellow solid (characterized by LCMS and 1H NMR, LRMS (M+H+) m/z=478.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)[CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)nn2C)cc1OC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OCc2cc([C@@H]3CCCN3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a CHCl3 (1.0 mL) solution of the compound (365 mg) obtained in Example 13-(2), TFA (5.0 mL) was added at 0° C. and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, saturated aqueous sodium bicarbonate (50 mL) was added and the organic layer extracted with CHCl3 (50 mL×2) was dried (Na2SO4), filtered and concentrated to give the titled compound (283 mg, pale brown oil.)
Reaction SMILES: [O:1]=[C:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-(3-oxobutyl)piperidine-1-carboxylate (3.7 g) in ethanol (40 mL) was added sodium borohydride (550 mg) at room temperature, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and water. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([C:13]([NH2:15])=[O:14])=[CH:5]2.[H-].[Na+].CN(C)C=O.[C:23](OCC)(=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[N:12]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:15][C:13](=[O:14])[C:6]1=[CH:5]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2cc(Cl)ccc2nc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2nc3ccc(Cl)cc3cc2c(=O)[nH]1
Reaction time: 0.25 h

Procedure:
A mixture of 6-chloro-2-aminoquinoline-3-carboxamide (2.2 g., 0.01 mole), sodium hydride (0.52 g. 0.012 mole as 56% dispersion in oil) and N,N-dimethylformamide (20 ml.) is added to a solution of diethyl oxalate (5 ml.) and N,N-dimethylformamide (5 ml.). The reaction mixture is stirred for fifteen minutes, a second portion of sodium hydride (0.52 g., 0.012 mole) added and stirred continued for an additional 15 minutes. Acetic acid (25.0 ml.) is cautiously added to the mixture followed by water (50 ml.). The tan precipitate is removed by filtration and dried (2.0 g. of crude ester). It is purified by chromatography on silica gel using chloroform:2B ethanol (99:1) as eluant. The product, recovered by concentration of the eluate, is recrystallized from acetic acid. Yield = 1.3 g. (37.3%). M.P. 260.5° C. (dec.). Mass spectra gave m/e = 303.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[OH:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.[OH-].[Na+]>O1CCOCC1>[OH:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: O[C@@H]1CCCC[C@H]1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN([C@@H]2CCCC[C@H]2O)CC1
Temperature: 105 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of (+/−)-trans-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-cyclohexanol (1.50 g, 6.25 mmol) in dioxane (45 ml) was treated with 5N hydrogen chloride (10 ml). The mixture was warmed to 105° C. and stirred for 4 h. After cooling to room temperature, water (9 ml) was added to the mixture, which was then basified to pH 14 by slow addition of 5N sodium hydroxide. The mixture was then extracted three times with ethyl acetate and the combined organic extracts were dried with anhydrous sodium sulphate and concentrated. The residual oil was purified by flash chromatography on silica gel, eluting with methanol 0–5% in dichloromethane. (+/−)-trans-1-(2-Hydroxy-cyclohexyl)-piperidin-4-one (0.830 g, 68%) was obtained as a white solid, MS (ISP): m/e=198.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](OC)=[CH:21][CH:20]=2)[N:3]=1.[H][H].C[OH:30]>[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[OH:30])[N:3]=1
Reactant: [H][H]
Reactant: COc1ccc(CCNc2nc(N)n3nc(-c4ccco4)nc3n2)cc1
Reactant: CO
Agent: [Pd]
Product: Nc1nc(NCCc2ccccc2O)nc2nc(-c3ccco3)nn12

Procedure:
A solution of the product of Example 161 (0.9 g) in methanol (150 ml) was hydrogenated at room-temperature and pressure using 10% palladium on carbon (0.9 g) catalyst. After the uptake of hydrogen was complete, the catalyst was filtered off and the solvent evaporated. The residue was crystallised from ethanol, and gave 7-amino-2-(2-furyl)-5-[2-(hydroxyphenyl)ethyl]amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine, m.p. 260°-263° C. microanalysis, found: C,57.2; H,4.8; N,28.6%; C16H15N7O2 (0.15) C2H5OH requires: C,57.0; H,4.7; N,28.5%; NMR: 2.81(t,2H, phenyl-H), 3.49(m,2H, CH2N); 6.71(d of d, 1H, furyl-4H), 7.03(d,1H, furyl-3H), 6.7-7.15 (complex, 4H, phenyl-H); 7.85(m,1H NH); 7.84(s,1H, furyl-5H); 8.09 (brs, 2H, NH2) and 9.31(s,1H, OH); m/e 338 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])/[CH:4]=[CH:5]\[CH2:6][OH:7].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[C:9]([Si:13]([CH3:15])([CH3:14])[O:7][CH2:6][CH:5]=[CH:4][CH2:3][O:8][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)C(=O)Cl
Reactant: OC/C=C\CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=O)OCC=CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 60% NaH (2.27 g, 56.75 mmoles) in tetrahydrofuran (15 mL) was cooled to 0° C. and to the solution cis-2-butene-1,4-diol (5.0 g, 56.75 mmoles) in tetrahydrofuran (10 mL) was added. The reaction was stirred at room temperature for thirty minutes and tert-butyl-chloro-dimethyl-silane (8.56 g, 56.75 mmoles) in tetrahydrofuran (15 mL) was added and stirred for another two hours. The reaction was quenched with 10% NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine (30 mL), dried with MgSO4, filtered, and evaporated in vacuo. The crude oil was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 50:50). The resulting product was dissolved in dichloromethane (25 mL) and pyridine (3.95 g, 50.6 mmoles) and isobutyryl chloride (2.68 g, 25.3 mmoles) were added. Then, the solution was stirred at room temperature for twelve hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water (50 mL), dried with MgSO4, filtered and evaporated in vacuo. The solvent was evaporated in vacuo and the product was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 70:30) to provide the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[N:6][CH:7]=1.FC1C=C(CN)C=CC=1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:3][C:4]=1[CH3:21]
Reactant: Cc1cc(-c2ccc(CN)cc2F)ccn1
Reactant: COc1ccc(CNCc2ncc(Br)cc2C)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CNCc2ncc(-c3ccnc(C)c3)cc2C)c(OC)c1
Temperature: 120 °C

Procedure:
To a round bottom flask was added 1-(5-bromo-3-methylpyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine 81-3 (1.5 g, 4.3 mmol), 2-methylpyridin-4-ylboronic acid 15-1 (589 mg, 4.3 mmol), Pd(PPh3)4 (248 mg, 0.22 mmol), saturated Na2CO3 (10 mL), ethanol (10 mL) and toluene (30 mL). The reaction was refluxed at 120° C. for 30 hours. After cooling to room temperature, the reaction was diluted into ethyl acetate and washed with brine. The solvent was removed by rotary evaporation. The crude product was purified by silica gel flash chromatography to give N-(2,4-dimethoxybenzyl)-1-(2′,5-dimethyl-3,4′-bipyridin-6-yl)methanamine 81-4. MS m/z 364.2 (M+1).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]=O.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(O)CCC>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[C:12]([CH2:20][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCNCC
Reactant: C=O
Reactant: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: CCCCO
Product: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccccc3n2)c1O
Temperature: 105 °C
Yield: 98.9 %

Procedure:
In 25 ml of n-butanol were dissolved 25.5 g (0.1 mols) of the purified product of 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 6, 5.2 g of 80% paraformaldehyde and 11.0 g (0.15 mols) of diethylamine. The solution was refluxed with heating at 105° C. for 24 hours. After completion of the reaction, the solvent and remaining raw materials were collected under reduced pressure, giving 34.7 g of objective 2-(2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol as a brown oil (yield 98.9%, purity 96.9%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)nc3C)c(C)nc12
Yield: 64.6 %

Procedure:
To a microwave pressure tube is added 0.070 g (0.178 mmol) of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.066 g (0.534 mmol) of pyridine-3-boronic acid, 0.103 g (0.089 mmol) of Pd(PPh3)4, 0.267 mL (0.534 mmol) of 2 M aqueous Na2CO3, and 1 mL 7:3:2 DME:H2O:EtOH, and the mixture is heated at 160° C. for 60 min. The reaction mixture is partitioned between 25 mL of ethyl acetate and 25 mL of water. The layers are separated and the aqueous is extracted 3×25 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes/Ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.045 g of the product, 64% yield. MS, ES+=392.2 (M+1); 1HNMR (DMSO-d6) δ 9.18 (s, 1H); 8.65 (m, 1H); 8.34 (d, 1H); 7.60 (m, 1H); 7.06 (s, 1H); 3.06 (m, 1H); 2.50 (s, 3H); 2.40 (s, 3H); 2.34 (s, 3H); 1.87-1.82 (m, 4H); 0.83-0.79 (m, 6H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.C(O)(=O)C.C(O[C:33]1(O[Si](C)(C)C)[CH2:35][CH2:34]1)C.[Na]>CO>[CH:33]1([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[N:19]=[C:12]4[N:13]([C:14](=[O:16])[NH:15][C:10]([C:4]5[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=5[Cl:2])=[CH:11]4)[N:17]=3)[CH2:21][CH2:22]2)[CH2:35][CH2:34]1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(C4CC4)CC3)nn12
Temperature: 25 °C

Procedure:
1.00 g (2.50 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride and 3 Å molecular sieve (1 g) were initially charged in 15 ml of dry methanol and acetic acid (1.43 ml, 25 mmol) of 3.01 ml (2.61 g, 15 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]-trimethylsilane and 690 mg (11 mmol) of sodium cyanoborhydride were then added. The mixture was stirred at reflux overnight. The mixture was cooled to RT and the reaction mixture was filtered. 50 ml of dichloromethane and 50 ml of water were added to the filtrate, and the mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 540 mg (53% of theory) of the product.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=3)[CH2:5][CH2:4]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 1 l capacity three-necked flask were added 4-{trans-4'-(hydroxymethyl)cyclohexyl}benzonitrile (75.6 g, 0.35 mol) and pyridine (150 ml), followed by cooling these down to 0° C., dropwise adding a pyridine solution (150 ml) of p-toluenesulfonyl chloride (70.3 g, 0.37 mol) over one hour, agitating these at room temperature for 2 hours, allowing them to stand overnight, adding water (500 ml), extracting with toluene, three times washing with water (300 ml), drying over magnesium sulfate, removing magnesium sulfate, concentrating the residue, passing it through a silica gel column using a chloroform solution, distilling off chloroform, recrystallizing from a mixed solvent of n-heptane with ethyl acetate and drying to obtain white crystals (103.5 g). The NMR spectra of this product accorded with those of the captioned compound and its M.P. was 108.1°-110.5° C.
Reaction SMILES: [OH:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.O1CCC[CH2:24]1.[H-].[Na+].CI>CN(C)P(=O)(N(C)C)N(C)C>[CH3:24][O:1][CH:2]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC(O)C(C)(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(CCC(C)=CCOc1ccc2c(c1)OCC2)C(C)(C)C
Temperature: 40 °C
Reaction time: 12 h

Procedure:
0.4 g. of 6-[(6-hydroxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 10 ml. of absolute tetrahydrofuran and, while stirring, warmed to 40° C. for 2 hours with 0.5 g. of a 55% by weight sodium hydride suspension in oil. Then 2 ml. of hexamethylphosphoric acid triamide and 1 ml. of methyl iodide are added and the mixture is stirred for 12 hours at room temperature. For the working up, the mixture is poured onto ice-water and extracted twice with diethyl ether. The ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/diethyl ether (19:1 parts by volume) there is obtained 6-[(6-methoxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran; nD25 = 1.5170.
Reaction SMILES: C([C@@H](O)[C@H](O)C([O-])=O)(O)=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH3+:26])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1.[N:27]([C:30]1[CH:39]=[C:38]2[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]2)=[CH:32][CH:31]=1)=[C:28]=[S:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([C@H:16]([NH:26][C:28]([NH:27][C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][C:36](=[O:40])[NH:37]4)=[CH:32][CH:31]=3)=[S:29])[CH2:17][C:18]([CH2:24][F:25])([CH2:22][F:23])[O:19]2)=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccc(N=C=S)cc2N1
Reactant: [NH3+][C@@H]1CC(CF)(CF)Oc2cc(Cl)ccc21
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCc2ccc(NC(=S)N[C@@H]3CC(CF)(CF)Oc4cc(Cl)ccc43)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a slurry of (R)-7-chloro-2,2-bis(fluoromethyl)chroman-4-aminium (2S,3S)-3-carboxy-2,3-dihydroxypropanoate (0.20 g, 0.51 mmol) in CH2Cl2 (1.3 mL) was added the product of Example 252A (0.10 g, 0.51 mmol) and diisopropylethyl amine (0.088 mL, 0.51 mmol). The mixture was stirred at ambient temperature overnight then placed directly onto a silica gel column. Elution with a 20-60% EtOAc/hexane gradient afforded the title compound (0.18 g, 76% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 9.63 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.3, 2.1 Hz, 1H), 6.99-6.92 (m, 2H), 6.90 (d, J=1.9 Hz, 1H), 5.84-5.73 (m, 1H), 4.77-4.62 (m, 2H), 4.58-4.50 (m, 2H), 2.83 (dd, J=8.4, 6.6 Hz, 2H), 2.43 (dd, J=8.4, 6.7 Hz, 2H), 2.34 (dd, J=13.5, 5.8 Hz, 1H), 2.12-2.00 (m, 1H); MS (ESI) m/z: 451.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH2:5][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1C=O
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC2CCCCO2)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a pre-stirred solution of 2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzaldehyde (2.14 g, 8.6 mmol) and piperidine (0.93 mL, 9.4 mmol) in DCM (35 mL) at 0° C. was added sodium triacetoxyborohydride (2.72 g, 12.8 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (30 mL) and ethyl acetate (75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.78 g, quantitative yield) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 6.51 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 5.40 (t, J=3.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s, 3H), 3.64-3.55 (m, 1H), 3.39 (s, 2H), 2.42-2.27 (m, 7H), 2.07-1.93 (m, 1H), 1.90-1.77 (m, 2H), 1.75-1.52 (m, 3H), 1.54-1.44 (m, 4H), 1.43-1.34 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[C:10]1([C@@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN1CCN(C)C1=O>[C:10]1([C@@H:16]([N:18]2[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]2)[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: C[C@@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Itaconic acid (650 g) and (S)-1-phenylethylamine (605 g) were suspended in 1,3-dimethylimidazolidinone (650 ml), and the suspension was stirred at 80° C. for 1 hr with heating, and further at 120° C. for 3 hr with heating. The mixture was cooled to room temperature, and water (4 l) was added. The precipitated crystals were collected by filtration and dried to give 950 g of 1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid. The crystals were recrystallized 3 times with isopropyl alcohol to give 156 g of (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid.