Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:30])([F:29])[F:28])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH2:26])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:27]([F:29])([F:28])[F:30])[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH3:24])=[C:21]([CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1CN
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C
Reaction time: 3 h

Procedure:
Propionyl chloride (0.17 ml) is added to a solution of C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-yl}-methylamine (816 mg) and DIPEA (1 ml) in dichloromethane (10 ml) at room temperature. After 3 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC and by crystallization in a diethylether/petroleum ether mixture to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophen-3-ylmethyl}-propionamide (compound 1.6, 122 mg) as white crystals. MS (HPLC/MS): 465 (MH+). Retention time: 1.96 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26]2)=[CH:21][CH:20]=1>>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][CH:13]=3)=[O:17])=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(-c4ccc(F)cc4F)cc3)cc2)C1

Procedure:
2′,4′-Difluorobiphenyl-4-carboxylic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 421.20 (C25H25F2N3O); MS (ESI): 422 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5](C(OCC)=O)[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[CH:7](C(OCC)=O)[C:8]([O:10]CC)=[O:9])C>Cl.C(O)(=O)C>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][C:4]([OH:30])=[O:3])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(Br)cc1)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC(CC(=O)O)c1ccc(Br)cc1

Procedure:
A solution of 3-(4-bromo-phenyl)-2,4-bis-ethoxycarbonyl-pentanedioic acid diethyl ester in concentrated hydrochloric acid (100 ml) and acetic acid (100 ml) was refluxed for 8 h. Removal of the solvent in vacuo and recrystallization of the residue from acetonitrile yielded 3-(4-bromo-phenyl)-pentanedioic acid (22.84 g in 1st crop, 65%, 3.84 g in 2nd crop, 11.05% from 4-bromobenzaldehyde).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccccn1
Reactant: NCc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1ccc(CNc2ccccn2)cn1
Temperature: 230 °C

Procedure:
A mixture of 2-fluoropyridine (1.4 g, 15 mmol) and 6-chloro-3-pyridinemethanamine (alternatively named 5-aminomethyl-2-chloropyridine) (2.55 g, 18 mmol) in N-methylpyrrolidinone (5 mL) was heated at 230° C. in a microwave reactor for 30 min. This reaction was repeated four times using the same amounts of starting materials for each repetition. All five of the reaction mixtures were then poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel using 10% ethyl acetate in hexanes as the eluent to provide the title compound as an oil (5.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[NH4+].C(OCC)(=O)C>O.[Zn]>[NH2:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ncc1N
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of 2-cyano-4-methyl-5-nitropyridine (1.86 g) and ammonium chloride (3.05 g) in water (50 mL) was added zinc (7.46 g) under ice-cooling over 10 minutes, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added ethyl acetate (50 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the organic layer of the filtrate was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=1/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (0.7 g).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH2:9][NH:10][C@@H:11]([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])[N:6]([CH3:8])[CH:7]=1.C[O:19][CH:20](O)[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].[NH4+].[OH-]>CC#N.CC(O)C>[OH:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH2:9][NH:10][C@H:11]([C:12]([NH:14][CH3:15])=[O:13])[CH3:16])[N:6]([CH3:8])[C:7]=1[CH:20]([OH:19])[C:21]([F:24])([F:23])[F:22]
Reactant: COC(O)C(F)(F)F
Reactant: CNC(=O)[C@H](C)NCc1cc(=O)c(O)cn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CC#N
Product: CNC(=O)[C@H](C)NCc1cc(=O)c(O)c(C(O)C(F)(F)F)n1C
Temperature: 77.5 °C

Procedure:
A mixture of (S)-2-((5-hydroxy-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (3.13 g, 13.1 mmol), trifluoroacetaldehyde methyl hemiacetal (3.6 mL, 38.0 mmol) and potassium carbonate (2.62 g, 19.0 mmol) in CH3CN (35 mL) was heated at 75-80° C. for overnight. Analysis of the reaction mixture by TLC using a solvent mixture of 28-30% conc. NH4OH in IPA as eluant indicated incomplete consumption of the starting material. A further portion of trifluoroacetaldehyde methyl hemiacetal (4 mL) was added, and the mixture was heated at 95-100° C. for another 24 h. On cooling to room temperature, the mixture was purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). Thus, the title compound N2-{[5-hydroxy-1-methyl-4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-1,4-dihydropyridin-2-yl]methyl}-N-methyl-L-alaninamide, Apo7033, was obtained as a yellowish solid (1.53 g) in 35% yield. 1H NMR (DMSO-D6) δ (ppm): 7.79 (t, J=4.4 Hz, 1H, NH), 6.30 (s, 1H), 5.87 (q, J=8.7 Hz, 1H, CHCF3), 3.82 (s, 3H, NCH3), 3.61-3.65 (dd, 2J=14.5 and 4J=1.9 Hz, 1H, 0.5 NHCH2), 3.47-3.52 (apparent t, J=15.2 Hz, 1H, 0.5 NHCH2), 3.08 (q, J=6.8 Hz, 1H, CHCH3), 2.59 (d, J=4.2 Hz, 3H, NHCH3), 1.12 (dd, 2J=6.8 and 4J=2.3 Hz, 3H, CHCH3); 13C NMR (DMSO-D6) δ (ppm): 175.0 (C═O), 169.6 (C═O), 149.2, 147.3, 125.6, 125.0 (q, J=283 Hz, CHCF3), 113.1 (CH), 65.2 (q, J=33 Hz, CHCF3), 56.9 (CH), 48.9 (CH2), 36.6 (NCH3), 25.8 (NHCH3), 19.6 (CH3); MS m/z 360 [M+Na]+, 338 (100%) [M+1]+, 236.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:10][CH2:11]1
Reactant: Nc1nccnc1Cl
Reactant: C1COCCN1
Product: Nc1nccnc1N1CCOCC1

Procedure:
A solution of compound 1a (10.0 g, 76.9 mmol) in morpholine (42.3 g, 486 mmol) was stirred at 120° C. overnight. The mixture was concentrated under reduced pressure. The residue was then treated with DCM (200 mL). The solids were collected by filtration and washed with Et2O. Compound 1b was obtained as a white solid (11.0 g, 74% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H12N4O: 181.1 (M+H). found: 181.2.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[Na].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O>O>[N:16]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[C:5]([CH3:14])[C:6]([Cl:13])=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2ccc(Cl)c(C)c2nc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ccc(Cl)c(C)c2nc1-n1cncn1
Temperature: 100 °C
Reaction time: 25 h
Yield: 96 %

Procedure:
A mixture of 2.26 g of 2,7-dichloro-3,8-dimethyl-quinoline, 1.1 g of the sodium salt of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 25 hours. The reaction mixture is poured into 100 ml of water and the precipitated product is filtered. Thus 2.48 g of the desired compound are obtained, yield 96%. Mp.: 147°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.C[O-].[Na+].CO.Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:15][CH2:16][CH2:17][Cl:18])=[N:6][CH:7]=1
Reactant: Sc1ccc(Cl)cn1
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ClCCCSc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
5-Chloropyridine-2-thiol (600 mg, 4.12 mmol) synthesized in Example (119a) was dissolved in methanol (15 mL), and 28% sodium methoxide/methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, followed by stirring at 60° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and vacuum drying was carried out to afford the desired compound (849 mg, yield 92%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24]=[O:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].C(O)(=O)C>CO.O>[CH3:1][C:2]1[NH:3][C:4]([CH2:24][OH:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1c1ccccc1C#N
Yield: 72.2 %

Procedure:
To a cold solution of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.3 g) in methanol (46 ml) at -5° C. was added portionwise sodium borohydride (140.7 mg) for 10 minutes, during which the temperature was kept at -4° to -5° C. with stirring. The mixture was stirred for additional 15 minutes at -6° C. The reaction mixture was diluted with water (20 ml) and acidified to about pH 5 with 50% actic acid, and then condensed under reduced pressure to separate out crystalline product. After adding water (30 ml), the crystals were collected by filtration, washed thoroughly with water and dried. Thus obtained crystals (2.05 g) were recrystallized from methanol (15 ml) to give pure crystals of dimethyl 2-methyl-4-(2-cyanophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.67 g), mp 177° to 178° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[S:24][N:23]=[C:22](O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[S:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Reactant: COC(=O)c1cc(O)ns1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (458 mg, 2.2 mmol) in THF (10 mL) was added 3-hydroxy-isothiazole-5-carboxylic acid methyl ester (350 mg, 1.9 mmol) and triphenylphosphine (692 mg, 2.6 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.05 mL, 2.4 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1) afforded the title compound (488 mg, 64%) as a white solid. MS: m/e=350.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:26][CH3:27])=[CH:14][CH:13]=3)[CH:25]=2)[CH:21]=[N:22]1)[CH3:34]
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3cn[nH]c3c2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Temperature: 90 °C
Yield: 80.1 %

Procedure:
6-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole (0.15 g, 0.331 mmol), ethyl bromoacetate (0.055 g, 0.331 mmol), cesium carbonate (119 mg, 0.364 mmol) in 6 mL DMF was stirred at RT overnight and then heated to 90° C. for 35 min. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-30% ethyl acetate in hexanes to yield [6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indazol-1-yl]-acetic acid ethyl ester as a white solid (120 mg, 80.1%).
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CNC
Product: CN(C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
A mixture of tert-butyl 3-iodoazetidine-1-carboxylate (EP 1176147, prep 18) (5 g, 17.6 mmol) and dimethylamine (27 mL, 33% in ethanol, 176 mmol) was heated to 80° C. for 28 hours in a sealed vessel. The cooled mixture was evaporated in vacuo and the residue pre-adsorbed onto silica gel. This was then purified by column chromatography on silica gel using ethyl acetate:hexane (50:50) as eluant to afford the title compound as a yellow oil, 1.07 g.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH3:24])=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+].C(O)C.O>C(#N)C>[C:25]([C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=1[O:23][CH3:24])([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC#N
Product: COc1c(C(C)(C)C)cc(C#Cc2ccc(CC(=O)O)cc2)cc1C(C)(C)C

Procedure:
Following General Procedure I and using [4-(3,5-di-tert-butyl-4-methoxy-phenylethynyl)-phenyl]-acetic acid methyl ester (Compound 142, 0.114 g, 0.29 mmol), 5M aqueous sodium hydroxide solution (2 mL) and ethanol (4 mL), followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a white solid (0.097 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][CH2:26][C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:8]([NH:10][CH:11]2[C:22](=[O:23])[N:13]3[C:14]([C:19]([O-:21])=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:44]([O:50][CH2:51]I)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46].C(OCC)(=O)C.O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:24][O:25][CH2:26][C:27]([O:29][CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:28])[C:8]([NH:10][CH:11]2[C:22](=[O:23])[N:13]3[C:14]([C:19]([O:21][CH2:51][O:50][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[S:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CC1=C(C([O-])=S)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=S)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (4.0 g) in dimethylformamide (40 ml) was added a solution of pivaloyloxymethyl iodide (1.5 g) in dimethylformamide (4.5 ml) at 0° C. and the mixture was stirred for 15 minutes at the same temperature. Ethyl acetate (150 ml) and water (100 ml) were added to the reaction mixture. The separated organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer) (3.22 g).
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([O-])=O>CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(O)CC1(C[N+](=O)[O-])CCCCC1
Agent: [Pd]
Solvent: CO
Product: NCC1(CC(=O)O)CCCCC1
Yield: 75.9 %

Procedure:
A solution of 2.01 g (0.01 mol) of 1-(nitromethyl)-cyclohexyl-acetic acid in 50 ml of methanol is hydrogenated in the presence of 0.2 g of palladium oil activated carbon at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated to 10 ml. 20 ml of tetrahydrofuran is added to the residue and the precipitated crystals were filtered off and dried to yield 1.3 g (80%) of the title compound. Mp: 164-169° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 87 %

Procedure:
A solution of trimethylsilyldiazomethane (2M in hexane, 50 ml, 4 eq) is slowly added to a solution of 3-fluoro-4-nitrobenzoic acid (4.7 g, 1 eq) in methanol (70 ml) until the gas evolution ceases. The excess trimethylsilyldiazomethane is consumed by the dropwise addition of acetic acid until the solution becomes discoloured. The mixture is then concentrated under reduced pressure at a temperature of approximately 40° C. Water (200 ml) and dichloromethane (300 ml) are added to the residue. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is washed with petroleum ether and dried (4.4 g; 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C=O)C>[NH2:39][C:37](=[O:38])[CH2:36][N:22]1[C:23]2[N:24]=[CH:25][N:26]=[CH:27][C:28]=2[C:20]([C:18]([C:16]2[CH:17]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[N:14][CH:15]=2)=[O:19])=[CH:21]1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 50 mg, 0.13 mmol) in DMF (1 ml) was added Cs2CO3 (75 mg, 0.23 mmol) followed by 2-bromoacetamide (21.3 mg, 0.154 mmol). The reaction was then stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×5 mL). The organics were combined, washed with water (5 mL) then brine (5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 59% yield, 34 mg.
Reaction SMILES: [CH2:1]([C:4](=[CH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([CH:4]([CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH:5]([OH:7])[CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCC(=CCC(C)C)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CC=C(C)C)C(C)O
Temperature: -15 °C
Yield: 83 %

Procedure:
3-allyl-6-methylheptenone (20.0 g, 120 mmol) was dissolved in anhydrous THF (100 ml) and the solution cooled to −15° C. under stirring. A 3.5M solution of LiAlH4 (in THF/toluene, 12.0 ml, 42 mmol, 0.35 mol. eq.) was added dropwise under argon over 30 min. The reaction mixture was then stirred at −15° C. for 1 hour. The temperature was raised to 0° C., and the mixture carefully hydrolyzed by successive dropwise additions of water (1.60 g), 15% aqueous NaOH (1.60 g) and water (4.80 g), while keeping the reaction mixture at 0° C. The mixture was allowed to warm to room temperature, and the precipitate filtered. Evaporation of the solvent afforded the crude product. Fractional distillation though a 10 cm Vigreux column afforded the desired compound (16.94 g (83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]>>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[O:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1
Reactant: OCc1cccc(F)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 55 %

Procedure:
Prepared in analogy to example 1a) from 2,4,5-trifluoronitrobenzene and 3-fluoro-benzyl alcohol. Colorless solid. Yield=55%. MS: m/e=283.1 (M+).