Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15]C)=[O:14])[CH3:8].O.[OH-].[Li+]>CO.O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([OH:15])=[O:14])[CH3:8]
Reactant: COC(=O)c1cc(C)cc(CN(C)Cc2ccco2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN(C)Cc2ccco2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(2-furylmethyl)(methyl)amino]methyl}-5-methylbenzoate (180 mg, 0.66 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (277 mg, 6.6 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. ESI MS m/z 258 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.[CH:17]([O:20]C)(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:13][C:7]1[C:6]2[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3][C:2]([CH3:16])([CH3:1])[C:11]=2[CH:10]=[C:9]([CH3:12])[C:8]=1[CH:17]=[O:20]
Reactant: Cc1cc(C)c2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C=O)C(C)(C)CCC2(C)C
Yield: 71.9 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1,1,4,4,5,7-hexamethylnaphthalene (5.0 g) of TiCl4 (7.32 g) in methylene chloride (40 ml) was treated with Cl2CHOCH3 (2.66 g) in methylene chloride (5 ml), at 0° and over 20 min. The temperature of the reaction mixture was allowed to reach 20° (20 min) and said mixture was then poured on ice water and extracted with ether. The organic phase was successively washed with a 10% aqueous solution of NaOH, water and an aqueous solution saturated with NaCl, then dried over Na2SO4, evaporated and recrystallized from methanol. 4.06 g (yield 72%) of 5,6,7,8-tetrahydro-1,3,5,5,8,8-hexamethyl-2-naphthalenecarbaldehyde were obtained, the product being identical in data to that described in b).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([C:11]([O:13]CC)=[O:12])[CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([F:8])([F:9])[F:10])=[C:4]([C:11]([OH:13])=[O:12])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)c(C(F)(F)F)o1
Yield: 93.5 %

Procedure:
To a solution of ethyl 5-methyl-2-(trifluoromethyl)-3-furancarboxylate (25 g, 113 mmol) in ethanol (200 ml) was added 2N aqueous sodium hydroxide solution (61.9 ml, 123.8 mmol) and the mixture was heated under reflux for 45 min. The reaction solution was concentrated, diluted with water (150 ml), and 6N hydrochloric acid was gradually added to adjust to about pH 5. The precipitated crystals were collected by filtration, washed with water to give 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (20.5 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH3:14][O:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C@H:29]3[CH2:31][C@H:30]3[CH2:32][CH2:33]O)[CH2:25][CH2:24]2)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:33][CH2:32][C@@H:30]2[CH2:31][C@@H:29]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([CH2:16][O:15][CH3:14])=[CH:22][N:21]=3)[CH2:24][CH2:25]2)=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an RT solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.60 g, 5.49 mmol) in 15 ml of anhydrous dichloromethane was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 4.32 g, 16.5 mmol), and di-tert-butyl azodicarboxylate (2.53 g, 11.0 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate:hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 458.3 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[BH4-].[Na+].Cl>O.CO.CC1C=CC=CC=1>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C1CCc2cc(C(O)c3ccccc3)ccc2N1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a suspension of 27.3 parts of intermediate 18, namely 6-benzoyl-3,4-dihydro-2(1H)-quinolinone, in 790 parts of methanol were added 115 parts of an aqueous sodium hydroxide solution 1N. After stirring for 10 min., there were added at once 4.54 parts of sodium tetrahydroborate. Stirring was continued over weekend at room temperature. Them were added 110 ml of HCl 1N and 1000 parts of water. The precipitate was faltered off, stirred in water for 15 min and then taken up in a mixture of methanol and methylbenzene. This solution was evaporated and the residue was co-evaporated with methylbenzene. The product was filtered off and dried at 70° C., yielding 21.9 parts (78.6%) of 3,4-dihydro-6-(hydroxyphenylmethyl)-2(1H)-quinolinone; mp. 175.0° C. (interm. 19).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)[CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])=[N:9]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)[CH:14]=2)[CH2:11][C:10]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)c2)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (350.0 mg, 0.58 mmol) prepared in Example 229 and trifluoroacetic acid (444.0 uL, 5.79 mmol) were slowly added to dichloromethane (5.8 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 400.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Br[C:2]1[C:3]2[N:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:20]=[N:19][C:4]=2[C:5]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:6][C:7]=1[CH3:8].[Li][CH2:28]CCC.CCCCCC.CI>C1COCC1>[CH2:23]([CH:22]([N:21]1[C:3]2[C:2]([CH3:28])=[C:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[C:4]=2[N:19]=[N:20]1)[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(CC)n1nnc2c(Oc3c(C)cc(C)cc3C)nc(C)c(Br)c21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCC(CC)n1nnc2c(Oc3c(C)cc(C)cc3C)nc(C)c(C)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a −78° C. solution of 7-bromo-1-(1-ethyl-propyl)-6-methyl-4-(2,4,6-trimethyl-phenoxy)-1H-[1,2,3]triazolo[4,5-c]pyridine (33 mg, 0.079 mmol) in 2 ml of dry THF was added 2.5 M nBuLi in hexane (0.047 ml, 0.019 mmol) and stirred at that temperature for 5 min. An excess of MeI (0.5 ml) was added and the mixture was stirred at that temperature for 15 min, then gradually warmed to room temperature for 1 hour. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 31 mg of a golden oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as white crystals. Mp 127–129° C.; 1H NMR (CDCl3) δ 6.91 (s,2H), 4.83(m,1H), 2.51(s,3H), 2.38(s,3H), 2.33(s,3H), 2.13(s,6H), 2.3–2.5(m,2H), 1.9–2.2(m,2H), 0.86(t,6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]1([CH2:15][CH:16]=O)[CH2:14][O:13][CH2:12]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH2:15][C:11]1([CH3:10])[CH2:14][O:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC1(CC=O)COC1
Solvent: ClCCl
Product: CC1(C/C=N/CC(=O)OC(C)(C)C)COC1
Yield: 100.6 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.92 g, 7 mmol) was reacted with (3-methyl-oxetan-3-yl)-acetaldehyde (0.8 g, 7 mmol) in CH2Cl2 at room temperature for 18 h to give [2-(3-methyl-oxetan-3-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.6 g, 100%).
Reaction SMILES: O.[OH-].[Li+].[Si:4]([O:11][CH2:12][C@H:13]([CH3:36])[O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[CH:24]=1)[C:18]([O:20]C)=[O:19])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>C1COCC1.O>[Si:4]([O:11][CH2:12][C@H:13]([CH3:36])[O:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[CH:24]=1)[C:18]([OH:20])=[O:19])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Lithium hydroxide monohydrate (346 mg, 8.24 mmol) was added to a solution of methyl 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]benzoate (3.70 g, 7.49 mmol) in THF (50 mL) and water (10 mL) and the reaction stirred for 2 h. A further portion of lithium hydroxide monohydrate (346 mg, 8.24 mmol) was then added and the reaction was heated at 45° C. for 1.5 h. The THF was then evaporated and water layer was extracted with diethyl ether (10 mL). The remaining aqueous layer was acidified with 5% w/v aqueous citric acid and extracted (2×50 mL) with ethyl acetate and the combined organic layers were dried (MgSO4), filtered and evaporated to afford the title compound as a gum (2.54 g, 71%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]([CH3:18])[CH:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.CN(C=O)C.[H-].[Na+].[C:31]([Si:35](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:34])([CH3:33])[CH3:32]>CCOC(C)=O>[CH3:34][C:31]([Si:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[O:1][C:2]1[C:7]2[CH:8]([CH3:18])[CH:9]([CH2:14][CH2:15][CH2:16][OH:17])[C:10]([CH3:12])([CH3:13])[O:11][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1)([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)C2C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCCO)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of 3.17 g (8.78 mmol) of rac-3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol in 60 mL of anhy. DMF (Aldrich) was added to a suspension of 383 mg (1 eq) of sodium hydride (Aldrich) in 20 mL of anhy. DMF (Aldrich) and the mixture stirred at RT under argon for 0.5 hr. 2.28 mL (1 eq.) of tert-butylchlorodiphenylsilane (Aldrich) was then added by syringe. After stirring for 2 hr at RT the reaction was diluted with EtOAc, washed with 0.1N aq. HCl, water, sat. aq. NaCl, dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 30% EtOAc-hexane. The fractions containing the product were combined and evaporated under reduced pressure to give 2.23 g (45%) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as a pale yellow oil. HR EI MS: Calc M+, 558.3530; Observed, 558.3516.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:10]([CH2:11][CH2:12][CH2:13][C:14](OC(C)(C)C)=[O:15])[C:9](=[O:21])[CH:8]([CH3:22])[N:7]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:6]1)=[O:4].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:59]1[C:61]2([CH2:66][CH2:65][NH:64][CH2:63][C@H:62]2[OH:67])[CH2:60]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[N:10]([CH2:11][CH2:12][CH2:13][C:14]([N:64]2[CH2:65][CH2:66][C:61]3([CH2:59][CH2:60]3)[C@H:62]([OH:67])[CH2:63]2)=[O:15])[C:9](=[O:21])[CH:8]([CH3:22])[N:7]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C(C)C(=O)N1CCCC(=O)OC(C)(C)C
Reactant: O[C@@H]1CNCCC12CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C(C)C(=O)N1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Reaction time: 2 h

Procedure:
To 0.15 g (0.3 mmol) of (S)-4-(3-tert-butoxycarbonyl-propyl)-6-methyl-5-oxo-piperazine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester in 5 ml of THF was added 1.5 ml of 37% hydrochloric acid. The reaction was stirred for 2 h after which time it was evaporated to dryness. The residue was redissolved in 2 m of DMF, 0.14 g (0.4 mmol) of HATU and 0.06 g (0.4 mmol) of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) were added followed by 0.2 ml (1.2 mmol) of triethylamine. The reaction was stirred for 1 h after which time the solvent was evaporated, the residue redissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to give after flash silica gel column (CH2Cl2/MeOH 95:5) the title compound in quantitative yield as a colorless foam. MS: 502.4 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]2=[N:6][C:5]=1[CH3:16].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:19][CH2:18]1.CC(NC(C)C)C>C(O)C>[N:23]1([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:7]4=[N:6][C:5]=3[CH3:16])[CH2:18][CH2:19]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: Cc1nc2n(C)c(C)cn2c(=O)c1CCBr
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1nc2n(C)c(C)cn2c(=O)c1CCN1CCC(n2ccc3ccccc32)CC1
Yield: 62 %

Procedure:
A mixture of 6-(2-bromoethyl)-1,2,7-trimethyl-1H,5H-imidazo[1,2-a]pyrimidin-5-one (8.85 g), prepared as described in EP-0,378,255, 1-(4-piperidinyl)-1H-indole (2 g) and N-(1-methylethyl)-2-propanamine (1.2 g) in ethanol (100 ml) was stirred and refluxed for 6 hours. The solvent was evaporated and the residue was stirred in water and subsequently extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/DIPE and the precipitate was filtered off and dried, yielding 2.5 g (62%) 6-[2-[4-(1H-indol-1-yl)-1-piperidinyl]ethyl]-1,2,7-trimethylimidazo[1,2-a]pyrimidin-5(1H)-one (compound 9; mp. 165.7° C.).
Reaction SMILES: CC(=CC)C.[C:6]([O:10][C:11]([C@@:13]1([CH2:36][CH:37]=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl([O-])=[O:40].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:6]([O:10][C:11]([C@@:13]1([CH2:36][C:37]([OH:40])=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [O-][Cl+][O-]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Yield: 83.2 %

Procedure:
2-Methyl-2-butene was added to a solution of (3S,4S)-4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 10.1 mmol) in tert-butyl alcohol (25.2 mL) under ice-cooling, and the mixture was stirred. Sodium chlorite (2.29 g, 25.3 mmol) was added to a solution of sodium dihydrogenphosphate dihydrate (4.10 g, 26.3 mmol) in water (20.2 mL) to separately prepare a solution. This solution was added to the above solution under ice-cooling, and the mixture was stirred at room temperature for one hour. The precipitated solid was collected by filtration, washed with water and hexane, and then dried under reduced pressure at 40° C. to give 3.93 g of the title compound as white powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Cl)cn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of 5-chloropicolinaldehyde (0.505 g, 3.57 mmol) in THF (7 mL) at 0° C. were added (trifluoromethyl)trimethylsilane (0.685 mL, 4.63 mmol) and tetra-N-butylammonium fluoride (1 M in THF, 0.036 mL, 0.036 mmol). The reaction mixture was stirred at 0° C. for 15 min and diluted with water (10 mL) and additional tetra-N-butylammonium fluoride (1 M in THF, 2.0 mL, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with EtOAc, the organic phase was separated and washed with water, brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (5% to 20% EtOAc in heptane) to give the title compound (0.643 g, 3.04 mmol, 85% yield) as a yellow oil. MS m/z=211.9 [M+H]+. Calculated for C7H5ClF3NO 211.0.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[N+:17]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[C:11]=1[NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])([O-:19])=[O:18]
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of beta-alanine ethyl ester hydrochloride (911 mg, 5.39 mmol), 2-chloro-1,3-dinitrobenzene (1.00 g, 4.94 mmol), triethylamine (2.07 mL, 14.9 mmol) and tetrahydrofuran (50 mL) was stirred at room temperature for 2 hr. To the reaction mixture were added beta-alanine ethyl ester hydrochloride (455 mg, 2.96 mmol) and triethylamine (1.03 mL, 7.39 mmol) at room temperature and the resultant mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on, silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.39 g, 4.92 mmol, 99.6%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31].Cl>C(Cl)Cl.CC(OC)(C)C>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2ccc(F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of methyl 2-(2,4-difluorobenzyl)piperidine-4-carboxylate (7.1 g, 26.37 mmol) in DCM (100 mL) was added DIPEA (6.5 mL, 37.32 mmol) followed by methyl carbonochloridate (2.3 mL, 29.21 mmol) dropwise. After completed addition the reaction mixture was stirred at room temperature for 4 h, then 2 M HCl was added. The organic layer was diluted with MTBE, the biphasic mixture was filtered to remove insolubles and after phase separation the organic layer was washed with brine and satd NaHCO3, dried over MgSO4 and evaporated to give dimethyl 2-(2,4-difluorobenzyl)piperidine-1,4-dicarboxylate (8.51 g, 99%) as a dark oil. MS m/z 328 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31](CC)[CH2:32]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[N:31]([CH3:32])[CH3:29])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
The aldehyde compound 2 (2.0 g, 5.2 mmol) was dissolved in CH2Cl2 (30 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.87 mL, 6.23 mmol) and BOP reagent (2.53 g, 5.7 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 13.0 mL, 26.0 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×10 mL), water (2×50 mL) and brine (1×50 mL). Drying and concentration of the organic layer gave the desired amide 10 (2.1 g, ˜98%). 1H NMR (400 MHz, DMSO-d6): 9.91 (s, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.57 (m, 1H), 2.94 (s, 3H), 2.75-2.91 (m, 5H), 1.31 (s, 9H).