Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].CC#N.[OH2:19]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[C:6]1=[O:19])=[O:4]
Reactant: COC(=O)N1CCc2nc(Cl)ccc2C1
Reactant: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)N1CCc2nc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (226.7 mg, 1 mmol) was dissolved in CCl4 (3.57 mL) and MeCN (0.357 mL) at room temperature before adding NaIO4 (0.643 g) in 1 mL of H2O, followed by RuCl3.hydrate (62.2 mg). The reaction mixture was stirred vigorously at room temperature for 2 hours. After dilution with DCM, it was filtered through Celite and the filter cake was washed three times with DCM. The combined organic solution was concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 20% EtOAc in hexane) then afforded the tile compound (143 mg, 60%) as a white solid. MS: 241.1 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[CH3:39].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[C:31]([CH3:39])[CH:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-methoxy-3-methylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.31 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:8])=[CH:5][S:6][CH:7]=1.[C:9]([C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([C:14](=[CH:20][NH:8][C:4]1[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Reactant: COc1cscc1N
Product: CCCC(=O)C(=CNc1cscc1OC)C(=O)OCC

Procedure:
4-Methoxy-3-thiopheneamine (11 g, 0.085 mol) and ethyl 2-butyryl-3-ethoxyprop-2-enoate (20 g, 0.093 mol) was heated in an inert atmosphere at 120° for 30 minutes. Addition of petroleum ether, b.p. 40°-60°, 200 ml, gave a solid which was collected by filtration and dried, 17.58 g, m.p. 89°-91°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][C@H:35]5[CH3:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C[C@@H]1CN(C)CCN1
Product: C[C@@H]1CN(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,3-(R)-Dimethyl-piperazine following general procedure C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35].C(O)C(N)(CO)CO.CCN(CC)CC>C1COCC1>[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:35]
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1cc(F)ccc1Cl
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine (80 mg, 0.20 mmol) in 2 mL THF was added 2-chloro-5-fluorobenzoyl chloride (26 μL, 0.22 mmol). When LC/MS indicated the reaction was complete, several equivalents of PS-trisamine were added and the mixture was stirred for 16 h. Et3N was added if necessary to get the reaction into solution. The mixture was filtered and the resin washed well with THF. The filtrate was concentrated and triturated with DCM to give the title compound (51 mg, 46%). 1H NMR (400 MHz, d6-DMSO) δ 10.66 (s, 1H), 9.78 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 8.45 (d, J=8.8 Hz, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.80-7.74 (m, 2H), 7.61-7.42 (m, 5H), 7.39-7.32 (m, 2H), 7.26-7.20 (m, 1H), 7.11 (t, J=6.4 Hz, 1H), 6.72-6.67 (m, 1H), 6.57 (d, J=5.2 Hz, 1H) ppm. MS (ESI) m/z=553 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:5][C:6](=[O:25])[C@H:7]([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:8][C:9](OC(C)(C)C)=O>Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[NH:5][C:6](=[O:25])[C@H:7]([CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:8][CH2:9][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141.3 %

Procedure:
N-[N-(tert-Butoxycarbonyl)-O-benzyl-L-seryl]-D-leucine methyl ester (545 mg) was dissolved in 4N HCl-AcOEt (5 ml), and the solution was stirred at ambient temperature for 1.5 hours. The solvent was evaporated in vacuo. The resulting oil was dissolved in dry MeOH (5 ml). Benzaldehyde (205 mg) and sodium cyanoborohydride (NaBH3CN, 97 mg) were added to this solution, and the reaction mixture was stirred at ambient temperature for 3 hours. Benzaldehyde (60 mg) and NaBH3CN (30 mg) were added to the reaction mixture and the mixture was stirred at ambient temperature for 1.5 hours. After evaporation of the solvent in vacuo, the residue was partitioned by dissolving same in AcOEt and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated sodium chloride (NaCl) solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: CHCl3) to give 376 mg of N-(N,O-dibenzyl-L-seryl)-D-leucine methyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12](O)=[O:13])[CH2:8][CH2:7]1)[CH3:2]>C1COCC1>[OH:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](CO)CC1
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid (385.6 mg, 1.80 mmol) in THF (20 mL) was added BH3 (2.7 mL of a 1M solution in THF, 2.70 mmol). After 2 hours, the reaction was quenched by careful addition of H2O (10 mL). The mixture was extracted with EtOAc (80 mL) and the organic layer was washed with water and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 60% EtOAc/hexanes) afforded ethyl [trans-4-(hydroxymethyl)cyclohexyl]acetate. Rf=0.26 (40% EtOAc/hexanes). 1H NMR (CDCl3, 600 MHz) δ 4.12 (q, J=7.1 Hz, 2H), 3.45 (d, J=6.5 Hz, 2H), 2.19 (d, J=7.0 Hz, 2H), 1.72-1.82 (m, 5H), 1.45 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.96-1.05 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>CO>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]([CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:24][C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:8]1)[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(N(CC1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(pyrrolidin-3-ylmethyl)acetamide (165 mg, 0.528 mmol) in methanol (3 mL) were added tert-butyl acrylate (0.103 mL, 0.703 mmol) and potassium carbonate (110 mg, 0.792 mmol), and the mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes and then 10% MeOH/EtOAc) to give 68 mg of product as colorless oil. MS: (M+H)+=441.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.36-1.69 (m, 11H), 1.89-2.08 (m, 1H), 2.21-2.88 (m, 10H), 3.10-3.21 (m, 1H), 3.47-3.75 (m, 2H), 7.05-7.40 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH2:34][O:35][CH3:36])([CH2:31][O:32][CH3:33])[C:28]3=[N:37][N:38]=[N:39][N:27]3[C:26]=2[CH:40]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[CH3:33][O:32][CH2:31][C:29]1([CH2:34][O:35][CH3:36])[C:28]2=[N:37][N:38]=[N:39][N:27]2[C:26]2[CH:40]=[C:22]([NH:21][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[CH2:17][C@H:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)[CH:23]=[CH:24][C:25]=2[O:30]1
Reactant: COCC1(COC)Oc2ccc(N)cc2-n2nnnc21
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COCC1(COC)Oc2ccc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)cc2-n2nnnc21
Temperature: 100 °C

Procedure:
A mixture of (7R,8aS)-N-(2-choro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (36 mg, 0.12 mmol, 1 equiv), 8-amino-4,4-bis(methoxymethyl)-4H-tetrazolo[5,1-c]-[1,4]-benzoxazine (40 mg, 0.14 mmol, 1.2 equiv) and pTsOH.H2O (46 mg, 0.24 mmol, 2.0 equiv) in isopropanol (1.0 mL) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed and the residue was purified by column chromatography using a mixture of DCM/2N NH3 in MeOH (95:5) to give the product as a solid.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18].C(N(CC)CC)C>C(#N)C>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg, 1.49 mmol) and 2-amino -N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL of acetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The suspension was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The resulting residue was chromatographed over 50 g of flash silica using dichloromethane/methanol 9:1 as the eluant to provide the desired product as a light yellow solid (310 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H), 0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m, 2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m, 1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:11]([C:12]2[C:21]3[O:20][CH2:19][CH:18]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[N:17]4[C:28](=O)[NH:29][C:15]([C:16]=34)=[C:14]([F:31])[CH:13]=2)=[C:10]([CH3:32])[O:9][N:8]=1>>[Cl:3][C:28]1[N:17]2[CH:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][O:20][C:21]3=[C:16]2[C:15](=[C:14]([F:31])[CH:13]=[C:12]3[C:11]2[C:7]([CH3:6])=[N:8][O:9][C:10]=2[CH3:32])[N:29]=1
Reactant: Cc1noc(C)c1-c1cc(F)c2[nH]c(=O)n3c2c1OCC3c1cccnc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Phosphoryl chloride (1.5 mL, 16 mmol) was added to a vial charged with 7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (32 mg, 0.087 mmol) and the mixture was stirred overnight at 90° C. The mixture was quenched with ice-cold water, diluted with NaHCO3 and extracted with ethyl acetate. The organic extracts were collected and evaporated to afford the title compound. LCMS calc. for C19H15ClFN4O2 (M+H)+: m/z=385.1. found: 385.1.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]C1CC(C(C)C)CCC1=O>>[Br:20][CH:11]1[CH2:12][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CC1Br

Procedure:
The bromination of 4,4-diphenylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14]([F:23])([F:22])/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[CH3:12][O:11][C:8]1[C:9]([CH3:10])=[C:2]2[C:3]([CH:4]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]([C:14]([F:13])([F:23])[F:22])[O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1C
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(OC)c(C)c2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of benzaldehyde from Step 1 (3.0 g, 18.07 mmole) and ethyl 4,4,4-trifluorocrotonate (4.5 g, 27.11 mmole) was dissolved in anhydrous DMF (20 mL), warmed to 60° C. and treated with anhydrous K2CO3 (4.99 g, 36.14 mmole). The solution was maintained at 90° C. for 24 hours. LCMS analysis indicated that the reaction was complete. After the reaction was cooled to room temperature, the solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford brown solid, that was dissolved in MeOH (40 mL) and was precipitated upon adding 13 mL water. The suspension was filtered and dried on vacuum yielding a light brown solid: (4.37 g, 76.6%): LCMS m/z339.10 (M+Na). 1H NMR (CDCl3/400 MHz) 7.68 (s, 1H), 7.03(d, 1H, J=8.7 Hz), 6.50 (d, 1H, J=8.7 Hz), 5.70 (q, 1H, J=6 Hz), 4.29 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 2.09(s, 3H), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([CH3:23])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2)[CH3:3].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:2]([C:4]1[CH:5]=[C:6]([CH3:23])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:15])([F:16])[F:17])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9]2)[CH3:3]
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C(C)O)c2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(C)cc(CC)c2OC1C(F)(F)F
Reaction time: 18 h

Procedure:
The ethyl 8-(1-hydroxyethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 6051, Step 1 (0.30 g, 0.91 mmole) was dissolved in trifluoroacetic acid (5 mL). Triethylsilane (0.32 g, 2.73 mmole) was added dropwise to the above solution, which was allowed to stir for 18 hours. The reaction was quenched with saturated sodium bicarbonate (15 mL) and extracted with Et2O (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give a yellow oil which solidified upon standing (0.28 g, 98%): GCMS m/z 314.0 (M+). 1H NMR (CDCl3/400 MHz) 7.66 (s, 1H), 6.98 (s, 1H), 6.85 (s, 1H), 5.70 (q, 1H, J=7.0 Hz), 4.30 (m, 2H), 2.61 (m, 2H), 2.25 (s, 3H), 1.32 (m, 3H), 1.15 (m, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[O:13]1CCC[CH2:14]1.[Na]>CO>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([O:13][CH3:14])[N:3]=[CH:4][C:5]=2[N:11]=1
Reactant: Brc1ccc2nc(Br)ncc2n1
Reactant: C1CCOC1
Agent: [Na]
Solvent: CO
Product: COc1ncc2nc(Br)ccc2n1
Temperature: 40 °C

Procedure:
A 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromopyrido[3,2-d]pyrimidine (10.7 g, 37.04 mmol). To this was added tetrahydrofuran (500 ml) and methanol (150 ml). A solution of sodium (89 mg, 3.87 mmol, 0.10 equiv) in methnaol (60 ml) was then added dropwise with stirring, while warming to a temperature of 40° C. The resulting solution was allowed to react, with stirring, for 1.5 hours while the temperature was maintained at 40° C. The reaction progress was monitored by TLC. The reaction mixture was then quenched by adding 1.5 L of water. The mixture was concentrated under reduced pressure. The resulting slurry was filtered and the solids collected. The solids were then dissolved in 2 L of ethyl acetate. The resulting mixture was washed once with 500 ml of brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified recrystallization from 2:1 tetrahydrofuran:methanol to afford the title compound.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[CH:24]([NH:25][C:26](=[O:56])[C:27]([C:40]4[N:41]=[C:42]([NH:45]C(OCC5C=CC=CC=5)=O)[S:43][CH:44]=4)=[CH:28][CH2:29][C:30]([O:32]CC4C=CC=CC=4)=[O:31])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:58][S:59][C:60]2[N:64]([CH3:65])[N:63]=[N:62][N:61]=2)=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[NH2:45][C:42]1[S:43][CH:44]=[C:40]([C:27](=[CH:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]([NH:25][CH:24]2[C:23](=[O:57])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH2:58][S:59][C:60]4[N:64]([CH3:65])[N:63]=[N:62][N:61]=4)[CH2:19][S:20][C@H:21]23)=[O:56])[N:41]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=CCC(=O)OCc3ccccc3)c3csc(NC(=O)OCc4ccccc4)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=CCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of 7-[2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester in anisole (12 parts) is added aluminum chloride (9 equivalents). After stirring for 4 hours at 0° C., the mixture is neutralized with aqueous 5% sodium hydrogen carbonate, filtered to remove solid, and washed with ethyl acetate. Aqueous layer is acidified with hydrochloric acid, washed with ethyl acetate, and passed through a column of HP 20 or SP 207 (synthetic adsorbent produced by Mitsubishi Chemical K.K.). Adsorbed material is eluted with 80% methanol to afford 7-[2-(2-amino-4-thiazolyl)-4-carboxy-2-butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylic acid. Yield: 65%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C>[CH3:16][O:15]/[N:14]=[C:9](\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[CH3:17])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CCl
Reactant: Cc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 60 °C
Reaction time: 45 h
Yield: 53.1 %

Procedure:
A mixture of (E)-2-(2-chloromethylphenyl)-2-methoxyimino-N-methylacetamide (500 mg), 2,5-dimethylphenol (700 mg), potassium carbonate (700 mg) and acetone (5.0 ml) was stirred in a sealed tube at 60° C. for 45 hours. After the mixture was cooled by allowing it to stand, ethyl acetate was added thereto. The mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue was subjected to column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound (360 mg, 53%). In this chromatographic separation, some of the starting compound was recovered.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+:22]>>[NH2:22][C:13]1[CH2:14][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:17])[CH3:1])=[CH:4][CH:5]=2)[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CC(=O)[O-]
Product: CN(C)c1ccc(C2CC(=O)C=C(N)C2)cc1

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-(4-dimethylamino-phenyl)-cyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.