Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].[S-2].[Na+].[Na+].Cl>O.CO.[N+](C)([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 30 °C

Procedure:
To 10 ml of nitromethane were added 2.72 g of 7-ACA, 11.2 g of ferric chloride and 2.1 g of methanol. The mixture was heated at 30° C. for 40 min while stirring to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture was added 50 ml of water. Then, the mixture was adjusted to pH 1.0 with sodium bicarbonate and, then, further adjusted to pH 7.5 with sodium sulfide while cooling on ice. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 7 with 1N HCl and applied to a column packed with HP-20 (a packing material for reversed phase adsorption chromatography manufactured and sold by Mitsubishi Chemical Industries, Ltd., Japan). Then, the elution was conducted using water as an eluent, thereby to obtain an eluate. Then, the eluate was adjusted to pH 3.5 with 36 % hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.02 g. The yield of the desired product was 42 %.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.C(Cl)(=O)C.Cl.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([N:36]1[CH2:39][C:38]3([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH2:37]1)[CH2:31][CH2:30]2.C(N(CC)CC)C>>[CH3:14][C:11]1[CH:12]=[CH:13][C:5]([CH2:4][C:1](=[O:3])[N:42]2[CH2:43][CH2:44][C:38]3([CH2:37][N:36]([CH:32]4[C:33]5[C:29](=[CH:28][C:27]([C:22]6[N:21]=[CH:26][CH:25]=[CH:24][N:23]=6)=[CH:35][CH:34]=5)[CH2:30][CH2:31]4)[CH2:39]3)[CH2:40][CH2:41]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: c1cnc(-c2ccc3c(c2)CC[C@@H]3N2CC3(CCNCC3)C2)nc1
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(-c5ncccn5)ccc42)C3)c(C(=O)O)c1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To 2-(carboxymethyl)-5-methylbenzoic acid (100 mg, 0.52 mmol, prepared according to the procedure described in Tetrahedron, 1975, 31(20), 2607-2619) in a microwave reaction vessel was added acetyl chloride (0.5 mL). The tube was sealed and irradiated (Biotage Inc., microwave) while stirring at 130° C. for 20 minutes. The reaction was cooled to room temperature and the excess acetyl chloride was removed in vacuo. Dichloromethane was added to azeotrope the excess acetyl chloride and the crude anhydride was dried under vacuum. The crude anhydride was dissolved in acetonitrile (2 mL) and 2-[(1S)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 220 mg, 0.52 mmol) was added followed by triethylamine (0.16 mL, 2.06 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the desired product was purified using reverse phase chromatography (Biotage SNAP (15 g), water/CH3CN=95/5% to 50/50%) to afford (176 mg, 69%) 5-methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid. MS (ES+) 497.6 (M+H)+. 1H NMR (CDCl3) δ 1.54-1.58 (m, 2H), 1.60-1.64 (m, 2H), 2.15-2.38 (m, 5H), 2.78-3.02 (m, 2H), 3.04-3.24 (m, 1H), 3.26-3.52 (m, 6H), 3.62-3.66 (m, 2H), 4.41-4.45 (m, 1H), 7.06-7.27 (m, 3H), 7.34-7.57 (m, 1H), 7.68 (s, 1H), 8.31 (s, 2H), 8.73-8.79 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(=O)COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: OCc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)COc1cccc(-c2cccc(CO)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
To a solution of (6-bromopyridin-2-yl)methanol (811 mg) in DME (20 mL) was added Pd(PPh3) 4 (453 mg) at ambient temperature under N2 gas atmosphere. After stirring for 20 minutes, ethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (1.20 g) and a solution of 2M Na2CO3 aqueous solution (5.88 mL) were added and the mixture was refluxed for 7 hours. The mixture was cooled to ambient temperature and partitioned between EtOAc (40 mL) and water. The organic layer was washed with saturated NaHCO3 aqueous solution, water and then brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=10:1) to give ethyl {3-[6-(hydroxymethyl)pyridin-2-yl]phenoxy}acetate (297 mg) as a colorless oil.
Reaction SMILES: [C:1](=O)(O)[O-:2].[Na+].C=O.[C:8]1([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C(O)=O>CS(C)=O>[C:15]([O:17][CH3:18])(=[O:16])[CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:1][OH:2]
Reactant: O=C([O-])O
Reactant: COC(=O)Cc1ccccc1
Agent: C=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 0.67 h

Procedure:
A nitrogen purged 500 mL three-neck flask was charged with sodium bicarbonate (1.05 g; 0.013 mole), paraformaldehyde (17.37 g; 0.55 mole) and dimethyl sulfoxide (100 mL). Methyl phenylacetate (75.09 g; 0.5 mole) was added and rinsed in with dimethylsulfoxide (50 mL). The slurry was stirred magnetically and the temperature rose from 22° C. to 34° C. over 40 minutes. The temperature remained at 33°-34° C. for about one hour, after which the temperature was raised to 45°-46° C. and held for 12 hours. The reaction mixture was allowed to cool with stirring for about seven hours. A solution of anhydrous oxalic acid (1.13 g; 0.013 mole) in dimethylsulfoxide (6 mL) was added, and the solvent was distilled at pot temperature 45° C. to 100° C. at 0.05 mm Hg. The distillate (153.6 g) was retained. The pale yellow oily residue of crude methyl tropate (112.82 g) contained a small amount of white solid (sodium hydrogen oxalate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[CH3:12])[CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O[C@@H](C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
Cool a solution of 3-((S)-1-tert-butoxycarbonyl-ethoxy)-benzoic acid methyl ester (0.80 g, 2.85 mmol) in methylene chloride (10 mL) to 0° C. and add trifluoroacetic acid (0.98 g 8.60 mmol). Warm the mixture to room temperature and stir overnight. Dilute the mixture with water and extract with methylene chloride. Concentrate the combined organic phase under reduced pressure and purify the residue by trituration with hexanes and methylene chloride to provide 0.40 g of 3-((S)-1-carboxy-ethoxy)-benzoic acid methyl ester as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:25][C@@H:26]4[CH2:30][O:29][C@@H:28]5[C@H:31]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:32][O:33][C@H:27]45)[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[Cl:42])=[CH:4][CH:3]=1.[C:43]([CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1)#[CH:44]>[Cu]I.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.C(N(CC)CC)C>[Si:35]([O:34][C@H:31]1[C@H:28]2[O:29][CH2:30][C@@H:26]([O:25][C:15]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:11]4[C:12]([N:14]=3)=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:44]#[C:43][CH:45]5[CH2:46][CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50]5)=[CH:7][CH:6]=3)=[C:9]([Cl:42])[CH:10]=4)[C@H:27]2[O:33][CH2:32]1)([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:37])[CH3:36]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O[Si](C)(C)C(C)(C)C)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a round bottom flask fitted with a reflux condenser under a nitrogen atmosphere was added 5-(4-bromophenyl)-2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (436 mg, 0.625 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (157 mg, 0.750 mmol), CuI (9.5 mg, 0.049 mmol), and Pd(PPh3)2Cl2 (70 mg, 0.100 mmol). Then triethylamine (4.0 mL) was added. The reaction mixture was cooled to −78°, evacuated and placed under an inert nitrogen atmosphere. Then the mixture was warmed to room temperature, and heated to 50° C. for 17 h. The mixture was allowed to cool to room temperature, and then filtered through Celite™ and rinsed with ethyl acetate until the filtrate was colorless. The filtrate was concentrated under reduced pressure. Flash silica gel chromatography of the resulting residue utilizing a Biotage™ 50 G SNAP cartridge and employing a linear gradient: 0-30% EtOAc in 1:1 Hexane/DCM over 20 column volumes afforded the desired product as a clear, colorless oil following concentration under reduced pressure. LC-MS: calculated for C42H61ClN4O7Si2 824.38, observed m/e: 825.60 (M+H)+ (Rt 3.32/4 min)
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1.[OH-].[K+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][CH:3]1[CH2:2][N:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([S:14][CH3:13])[CH:16]=2)[C:22](=[O:23])[N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4]1
Reactant: CSc1cccc(N=C=O)c1
Reactant: CC(CCl)CNc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1cccc(N2CC(C)CN(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
18.4 g of N-(3-chloro-2-methylpropyl)aniline was dissolved in 120 ml of toluene, and 16.5 g of 3-methylthiophenyl isocyanate was added at room temperature. Then, the mixture was stirred at 40° to 50° C. for 1 hour. A catalytic amount (0.2 g) of tetrabutyl ammonium bromide was then added. While maintaining the temperature of the mixture at 30° to 40° C., 34 g of a 50% by weight aqueous solution of potassium hydroxide was added dropwise to the mixture. After the addition, the mixture was well stirred at 40° to 50° C. for 1 hour to complete the reaction. The reaction mixture was cooled to room temperature. The toluene layer was separated and washed with 1% by weight HCl and water in this order. After dehydration, the toluene was distilled off under reduced pressure to give 20.3 g of the desired 5-methyl-1-(3-methylthiophenyl)-3-phenyl-tetrahydro-2-pyrimidinone as a viscous pale yellow liquid. nD20 1.6194
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Solvent: ClCCl
Product: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Yield: 70 %

Procedure:
The title compound was prepared as described in Example 25, but employing a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol) in CH2Cl2 (30 mL) resulted in a 70% yield (1.1 g); 1H NMR (CDCl3) δ 9.31 (s, 1H).
Reaction SMILES: ClS(O)(=O)=O.[N+:6]([C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[O:11]/[C:12](=[CH:17]\[C:18]([O:20]C)=O)/[C:13]([O:15][CH3:16])=[O:14])([O-:8])=[O:7].[N+](C1C=CC=CC=1O/C(=C/C(OC)=O)/C(OC)=O)([O-])=O>>[N+:6]([C:9]1[C:10]2[O:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18](=[O:20])[C:22]=2[CH:23]=[CH:24][CH:25]=1)([O-:8])=[O:7]
Reactant: COC(=O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: COC(=O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=S(=O)(O)Cl
Product: COC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 250 parts by weight of chlorosulfonic acid. Thereto, 50 parts by weight of a mixture (content: 82.1% by weight, fumaric acid/maleic acid ratio=58/42) of dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate was added dropwise at an inner temperature of 50° C. or below. After completion of addition, the inner temperature was raised to 70° C. and the mixture was stirred and kept at the same temperature for 6 hours to obtain a reaction solution containing 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield: 92%). After cooled to room temperature, the reaction solution was gradually added into 300 parts by weight of water. The mixture was kept at an inner temperature of 60° C. for 1 hour and then gradually cooled to an inner temperature of 0° C. Precipitated crystals were filtered and dried to obtain 30 parts by weight of a crystalline mixture of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 58.5% by weight; the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 39.8% by weight). The yield of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 32% and the yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 50%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23](Cl)=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Mg]Br.[Cl-].N.C(OCC)(=O)C>C1COCC1.CN1C(=O)CCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH3:27][C:23]1[N:24]=[CH:25][C:20]([N:17]2[CH2:18][CH2:19][CH:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH2:15][CH2:16]2)=[N:21][CH:22]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cnc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The tert-butyl-1′-(5-chloropyrazin-2-yl)-4,4′-bipiperidine-1-carboxylate (1.1 g, 2.9 mmol) was dissolved in 1:1 THF and NMP (30 mL) at r.t. Iron (III) acetylacetonate (512 mg, 1.45 mmol) was added under N2. Methyl magnesium bromide (3M, 3.9 mL, 11.6 mmol) was added dropwise and the mixture stirred for 15 min. An ice cooled solution of saturated ammonia chloride (30 mL, aq.) and ethyl acetate (30 mL) were added, the mixture shaken, and the phases separated. The organic phase was washed with brine (10 mL, ×1), dried over magnesium sulfate, filtered, and concentrated in vac. The residue was purified by chromatography on silica gel with 12.5% acetone: hexanes to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:32]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])=[CH:31][CH:30]=2)(=[O:34])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccccc1-c1ccc(S(=O)(=O)N[C@H]2CCN(Cc3cccc(C#N)c3)C2=O)cc1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2'-methoxybiphenyl-4-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: CN1CCC(N)CC1
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NC3CCN(C)CC3)nc21

Procedure:
The product of Example 44, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=440 (MH+). Rt=1.67 min.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1)[CH3:6])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[CH2:18]([O:17][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-propionic acid ethyl ester (1.4 g, 4.0 mmol) in 2:2:1 MeOH:THF:H2O was treated with 1N aqueous LiOH (3 mL) at room temperature overnight. The mixture was acidified with 10% aqueous HCl and extracted three times with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:17])[CH2:3]1.C1COCC1.C(O)C>C(O)C.[Pd]>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:17])[CH2:3]1
Reactant: CN1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CC(=O)Nc2ccc(N)cc2C1=O
Reaction time: 3 h
Yield: 29.8 %

Procedure:
Intermediate 1 (3.48 g, 15 mmol, preparation described in Example 1) was suspended in a 120 mL of 1:1 solution of THF/Ethanol. The suspension was treated with nitrogen followed by vacuum, before adding Pd/C 10% (0.7 g), suspended in ethanol. The reaction vessel was then fitted onto the Parr hydrogenator and left under hydrogen pressure (20 psi) for about 3 hours with stirring. The excess hydrogen gas was removed using vacuum and then nitrogen was purged through the solution. The catalyst was filtered off using celite and the filtrate was evaporated to the minimum amount of ethanol. A white precipitate formed which was separated by filtration and dried under vacuum to afford 918 mg of desired material 3 in 30% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:22]2[CH2:24][CH2:23]2)[C:11](N2[C@@H](C(C)C)COC2=O)=[O:12])=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O.O>[CH:22]1([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][O:12][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)[CH2:23][CH2:24]1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)C(c1ccc(Cl)cc1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1

Procedure:
Under a nitrogen atmosphere a suspension of 0.06 gram (0.0024 mole) of 97% sodium hydride in 2.2 mL of dimethylformamide was stirred, and a solution of 0.40 gram (0.002 mole) of stereoisomer (A) of 2-cyclopropyl-2-(4-chlorophenyl)ethyl ethanol in 1.0 mL of dimethylformamide was slowly added. Upon completion of addition, the reaction mixture was stirred for 1.5 hours, and then a solution of 0.46 gram (0.0019 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 1.0 mL of dimethylformamide was added. Upon completion of addition, the reaction mixture was stirred for one hour, and then 2-3 mL of water was added. The mixture was poured into 75 mL of aqueous, 10% hydrochloric acid and then was extracted with two 50 mL portions of hexane. The combined hexane layers were washed with 25 mL of a saturated, aqueous solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to rotating disk thin layer chromatography on silica gel using diethyl ether: hexane (19:1) as eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.55 gram of stereoisomer (A) of (4-fluoro-3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether as an oil. The nmr spectrum was consistent with the proposed structure. [α]D25 =(+)22.19°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:34]([CH:31]([CH3:33])[CH3:32])[C:35]2=[O:36])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N=C=O
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and isopropyl isocyanate to give the title compound as a colorless solid. MS: 485.2 ([M+H]+)