Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1>CO.[Ni]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ni]
Solvent: CO
Product: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Yield: 90.9 %

Procedure:
A slurry of 1-(4,6-dimethyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine (27 g, 86.5 mmol) in methanol (1 L) was hydrogenated over Raney nickel (8 g) at 70-75 psi and room temperature in a Parr hydrogenation apparatus until no starting material was observed on TLC. The mixture was filtered through Celite and the filtrate concentrated in vacuo to afford 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl amine (22.2 g, 91%) as a solid which needed no further purification and was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH:28]C(OCC3C=CC=CC=3)=O)[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[O:42])[CH3:41].[H][H]>[Pd].CO>[C:40]([OH:43])(=[O:42])[CH3:41].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH2:28])[C:15]2=[O:39])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](N)C2=O)CC1
Reaction time: 3 h

Procedure:
A catalytic amount of 10% palladium on carbon was added to a solution of 4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.37 mmol) and acetic acid (100 μL, 1.7 mmol) in methanol (10 mL). Reaction vessel was placed on a Parr apparatus and charged with 30 psi of hydrogen gas. Mixture was allowed to shake at room temperature for 3 hours. Mixture was filtered. Filtrate was concentrated in vacuo. Crude compound was obtained as a dark oil in quantitative yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.06 (s, 1H), 7.36 (d, J=8.8, 1H), 7.12 (d, J=8.8, 1H), 4.92 (d, J=17.6, 1H), 4.67 (m, 1H), 4.49 (d, J=17.2, 1H), 4.26 (m, 1H), 3.98 (m, 2H), 3.05 (m, 1H), 2.83 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.45 (d, J=2.9, 9H), 1.25 (m, 2H). MS m/e (M−C4H8+H)+=344.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:27]C(OC(C)(C)C)=O)[C:11]([O:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 48 %

Procedure:
2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (2.05 g, 4.3 mmol) was treated with 4.0M HCl in 1,4-dioxane at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure and purified by prep-HPLC. The HPLC fractions were pooled, treated with 10 mL of 0.5N HCl, and dried by lyophilization to yield 0.85 g (48%) of the title compound as a white solid. 1H NMR (400 MHz, D2O): δ 3.11 (t, J=6.6 Hz, 2H), 4.38-4.44 (m, 6H), 6.60 (dd, J=2.2, 7.8 Hz, ½H), 6.61 (dd, J=2.4, 8.0 Hz, ½H), 6.70 (d, J=2.0 Hz, ½H), 6.71 (d, J=2.0 Hz, ½H), 6.77 (d, J=8.0 Hz, ½H), 6.78 (d, J=8.0 Hz, ½H), 7.46-7.52 (m, 2H), 7.60-7.68 (m, 1H), 7.96-8.02 (m, 2H); MS (ESI) m/z 376.15 (M+H)+.
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH:11]=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[C:11]([OH:1])=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: CC(C=O)c1ccc(-c2ccc(F)cc2)c(Br)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(Br)c1
Reaction time: 0.25 h

Procedure:
Silver nitrate (6.8 g.) in water (8 ml.) was stirred and treated dropwise with a mixture of 13.2 N potassium hydroxide (3.04 ml.) and water (7.3 ml.). The resulting slurry was diluted with ethanol (9 ml.) and a solution of 2-(2-bromo-4'-fluoro-4-biphenylyl)propionaldehyde (5.9 g.) in ethanol (17 ml.) was added slowly. After stirring for 15 minutes, a mixture of 13.2 N potassium hydroxide (1.8 ml.) and water (1.8 ml.) was added over 1 hour, the temperature being maintained at 43°-45°C. The reaction product was then stirred at 40°C. for 30 minutes, filtered, and the filtrate distilled in vacuo to remove the ethanol. The residue was acidified with dilute hydrochloric acid, the resulting oil isolated in ether, and the extract (after conventional washing) evaporated to dryness. Recrystallisation from light petroleum b.p. 80°-100°C. gave 2-(2-bromo-4'-fluoro-4-biphenylyl)propionic acid, m.p. 129°-131°C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:2]([CH3:3])[CH3:41])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC(C)C)c4)cc23)CC1
Yield: 22.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (21 mg, 0.42 mmol) for methanamine to afford 10 mg of the title compound (22.7%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:17][CH2:16][CH:15]([C:18](OC)=[O:19])[C:14]1=O.CO>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:14]2[N:1]=[C:2]([OH:3])[N:4]=[C:18]([OH:19])[C:15]=2[CH2:16][CH2:17]1
Reactant: NC(N)=O
Reactant: COC(=O)C1CCC(c2ccccc2OC)C1=O
Solvent: CO
Solvent: O
Product: COc1ccccc1C1CCc2c(O)nc(O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a melt of urea (6.07 g, 101 mmol) (bath temp 150° C.) was added methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 20.21 mmol) dropwise. After stirring overnight, the reaction was cooled to rt. Added MeOH (30 ml), and broke up the solid mass with a spatula and stirred for 1 h. Added water (600 ml), and stirred for 3 hr. The mixture was added to a Buchner funnel, and washed with water. Dried overnight in the vacuum oven (45° C.) to obtain 7-(2-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (4.03 g, 15.60 mmol, 77% yield) as a tan solid. LC-MS (M+H)+=259.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol) in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is then evaporated. To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) followed by portionwise addition of sodium cyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture is stirred overnight, and then the solvent is evaporated. The remaining residue is diluted with water (75 mL) and basified with Na2CO3. The mixture is extracted with ethyl acetate (3×75 mL). The combined organic extracts are washed with brine (50 mL), dried (Na2SO4), and the solvent is evaporated to give N-benzyl-D-alanine methyl ester.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=O>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:11]([C:13]1[S:17][C:16]([CH2:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:15][CH:14]=1)=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a stirred solution of isopropylamine (130 mg, 2.2 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.65 mL of a 2M solution in toluene, 1.3 mmol). After 1 h, a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (170 mg, 0.55 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. overnight. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 6% methanol in dichloromethane then heptane:ethyl acetate=100:0 to 1:4) gave the title compound (30 mg, 16%) as a white solid. MS: m/e=336.5 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6](O)[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH2:20][CH:21]=O)[CH3:19])[CH3:14]>>[CH3:19][CH:18]([CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH2:20][CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)=CCCC(C)CC=Cc1ccc(C(C)C)cc1
Yield: 82 %

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 = 1.5172
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:19].[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][CH:10]1[CH2:11][CH2:12][C:7]2([CH2:6][C:5](=[O:19])[C:4]3[C:16](=[CH:17][CH:18]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])[CH:3]=3)[O:15]2)[CH2:8][CH2:9]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 100 °C
Yield: 62.2 %

Procedure:
In a μwave vial was placed 6-bromo-4′-methoxyspiro[chroman-2,1′-cyclohexan]-4-one (48 mg, 0.148 mmol), 3-cyanobenzeneboronic acid (28 mg, 0.191 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and cesium carbonate (121 mg, 0.371 mmol). This solid mixture was dissolved in a Dioxane/water mixture (2.0 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 20 seconds. The vessel was placed in the μwave and heated to 100° C. for 5 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (10 mL) and water (10 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (5 mL). The combined organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4′-methoxy-4-oxospiro[chroman-2,1′-cyclohexane]-6-yl)benzonitrile (32 mg, 0.092 mmol, 62% yield).
Reaction SMILES: [Li+].[OH-].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:24][CH:23]([CH2:25][C:26]([O:28]C)=[O:27])[C:22](=[O:30])[N:21]([CH3:31])[CH2:20][C:19]=2[CH:32]=1>O1CCOCC1.O>[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22](=[O:30])[N:21]([CH3:31])[CH2:20][C:19]=2[CH:32]=1
Reactant: COC(=O)CC1Nc2ccc(CNCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1Cc2cc(CNCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
LiOH (14.6 mg, 0.34 mmol) was added at RT to a solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (133 mg, 0.31 mmol) in dioxane (3 mL) and H2O (1 mL). The reaction mixture was stirred at RT overnight then the organic solvent was removed in vacuo. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was purified by ODS chromatography (10% acetonitrile/H2O-0.1% TFA) to afford the title compound (65 mg, 51%): 1H NMR (DMSO-d6, 400 MHz) δ 2.51 (m, 1H), 2.73 (m, 1H), 2.91 (s, 3H), 3.69 (bs, 2H), 3.76 (d, J=16.6 Hz, 1H), 3.97 (br s, 2H), 4.97 (m, 1H), 4.45 (d, J=16.6 Hz, 1H), 5.77 (m, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.20 (m, 2H), 7.52 (m, 2H); MS (ES) m/e 394 (M+H)+. Anal. Calcd. for C21H23N5O3.2 CF3CO2H.H2O: C, 46.95; H, 4.26; N, 10.95. Found: C, 46.81; H, 4.00; N, 10.84.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])([OH:3])=O.Cl.[CH3:22][NH:23][CH3:24].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:22][N:23]([CH3:24])[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])=[O:3]
Reactant: CNC
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#CCn1c(-c2ccccc2)nc(C(=O)N(C)C)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.7 %

Procedure:
To a stirred solution of 0.87 g (3.2 mmol) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone, 0.32 g (3.9 mmol) of dimethylamine hydrochloride and 2 mL of pyridine in 10 mL of THF was added 0.74 g (3.6 mmol) of solid N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 4 days and filtered to remove insoluble material. The filtrate was diluted with 150 mL of ethyl acetate, washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate and dried over MgSO4. Removal of the solvent left 0.40 g of crude product which was purified by flash chromatography on a 30 g column of silica gel, eluted with 60, 80 and 100% ethyl acetate in hexanes to furnish 0.30 g (32%) of 6-dimethylaminocarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 19), mp 137°-140° C. 1H-NMR (CDCl3) δ 2.15(3H,s), 2.40(1H,t), 3.00(3H,s), 3.10(3H,s), 4.65(2H,d), 7.55(3H,m), 7.70(2H,m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>>[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]3[CH:3]=[C:4]([C:8]4([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: NC(=O)C1(c2cccc(O)c2)CCCC1
Agent: Cl
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCCC3)c2)cc1

Procedure:
1-(3-Hydroxyphenyl)cyclopentane-1-carboxamide was reacted with 4-(2-methyl-imidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound.
Reaction SMILES: [N:1]1([CH2:11][C:12]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.C=O.[C:33]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:12]([CH2:11][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:33])[CH2:3][CH2:2]1)([OH:30])[CH2:17][C:18]([C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[O:28][CH3:29])([CH3:20])[CH3:19]
Reactant: [BH3-]C#N
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCNc2ccccc21)C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCN(C)c2ccccc21)C(F)(F)F
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of 2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (Example 4) (18.6 mg) in acetonitrile (3 mL) was added formaldehyde solution (37% w/w aqueous, 300 μL) followed by sodium cyanoborohydride (13.8 mg). After 30 minutes at room temperature, acetic acid (50.4 μL) was added. The resulting mixture was stirred for 3 hours, quenched with saturated aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and the volatiles removed in vacuo. The residue was purified by preparative TLC (eluted with 25% EtOAc-hexanes) to give the title compound as a pale yellow oil (16.6 mg).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:13][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:17])=[O:16]
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, thermometer, and addition funnel, 25.3 parts of triethylamine, 17.2 parts of cyclopentanol, and 190.0 grams of methylene chloride were mixed under a nitrogen blanket and cooled to -40° C. with a dry ice-acetone bath. To this mixture 26.2 parts of methanesulfonyl chloride were added over one hour. The reaction mixture was stirred at -40° C. for an additional two hours and then allowed to warm to 0° C. and maintained at this temperature for eighteen hours. The mixture was vacuum filtered and then washed successively with chilled dilute sulfuric acid (twice with 200 part-portions), dilute sodium bicarbonate (three times with 200 part-portions), and water (twice with 200 part-portions). Subsequently the mixture was dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield cyclopentyl methanesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([NH:33][C:34]2[S:35][CH:36]=[N:37][N:38]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)Nc2nncs2)CCCC1)OCc1ccccc1
Yield: 63.8 %

Procedure:
10 g of N-benzyloxycarbonylcycloleucine, 3.9 g of triethylamine, 150 ml of chloroform, 4.1 g of ethyl chlorocarbonate and 3.9 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 8.4 g (yield: 64%) of 2-(N-benzyloxycarbonyl-cycloleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 229°-233° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([O:23]CC4C=CC(OC)=CC=4)=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]/[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=CC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 10.1 %

Procedure:
A stirred solution of 4-methoxybenzyl (6-R,7R)-7-phenylacetamido-3-(1-propenyl)-ceph-3-em-4-carboxylate (0.509 g, purity 9% E-isomer, 84% Z-isomer, 0.99 mmol) in dichloromethane (15 ml) was cooled to 2° C. Titanium tetrachloride (0.5 ml, 4.5 mmol) was added in 1 min. After 30 min the brown suspension was mixed with a chilled mixture of dichloromethane (50 ml) and a 2 M solution of hydrochloric acid in water (50 ml). The organic phase was separated and extracted with a 2 M solution of hydrochloric acid in water (3×50 ml) The aqueous phases were extracted with dichloromethane (25 ml). The combined organic phases were analyzed using HPLC: 0.036 g (6R,7R)-7-phenylacetamido-3-[(E)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.10 mmol, yield 10.2%); 0.301 g (6R,7R)-7-phenylacetamido-3-[(Z)-1-propenyl]-ceph-3-em-4-carboxylic acid (0.84 mmol, yield 84.8%). The overall yield is therefore 95.0%.