Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)OCC[Si](C)(C)C

Procedure:
1 g. of 10% palladium on carbon catalyst is added to a solution of [(phenylmethoxy)carbonyl]-L-leucine, 2-(trimethylsilyl)ethyl ester (9.1 g., 24.9 mmole) in ethyl acetate (200 ml.) cooled in an ice-bath under nitrogen. The reaction mixture is subjected to a steady stream of hydrogen gas for 2.5 hours at room temperature, then filtered and concentrated in vacuo to remove volatiles and yield 5.8 g. of L-leucine, 2-(trimethylsilyl)ethyl ester as a liquid product. TLC (silica gel, 3:1 hexane:ethyl acetate) Rf =0.08.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:32][C:31]1[C:26]([NH:25][C:11]([C:10]2[N:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[CH:8]=[CH:7][CH:6]=[CH:5]3)=[O:13])=[CH:27][C:28]([F:39])=[C:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=1
Reactant: Cn1nc2ccccc2c1C(=O)O
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2c3ccccc3nn2C)cc1F
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To 2-methylindazole-3-carboxylic acid (650 mg, 3.69 mmol) and DMF (29.0 μl, 0.37 mmol) was added benzene (20 ml). Under stirring at room temperature, oxalyl chloride (0.39 ml, 4.43 mmol) was added dropwise to the resulting mixture. After completion of the dropwise addition, the reaction mixture was stirred for further 1 hour at room temperature. A solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (855 mg, 3.69 mmol) and triethylamine (3.09 ml, 22.1 mmol) in benzene (3.0 ml), which had been prepared in advance, was added dropwise to the reaction mixture, and the mixture was heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (5:1, v/v) eluate fractions, ethyl (5-chloro-2-fluoro-4-((2-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (390 mg, 27%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=O)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[S:26])[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[C:4]([Cl:16])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12
Solvent: C1CCOC1
Product: S=C1Nc2c(Cl)cc(Cl)cc2C2CCCC12

Procedure:
6,8-Dichloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.39 mmol) is heated with Lawesson's reagent (412 mg, 1.02 mmol) for 2 hours in THF (20 ml). The batch is concentrated by evaporation and purified by column chromatography (SiO2) with ethyl acetate-hexane: 100 mg (94%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][CH2:24][C:25]([O:27]CC)=[O:26].Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C@@H:11]([CH3:21])[C@H:12]([OH:20])[C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:5]=[C:4]([Cl:22])[C:3]=1[NH:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)CNc1c(Cl)cc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NCCc1cc(Cl)c(NCC(=O)O)c(Cl)c1)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Ethyl N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]aminoacetate (500 mg) was dissolved in 1N aqueous sodium hydroxide solution (5.0 ml), and the solution was stirred for 1 hour at room temperature. To the reaction mixture was added 1N hydrochloric acid (5.0 ml) under ice-cooling with stirring, and collection of the resulting precipitates by filtration gave N-[2,6-dichloro-4-[2-[[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-aminoacetic acid (464 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:13]=O)[CH2:10][C@H:9]([CH3:11])[CH2:8][C@H:7]([CH3:12])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[N:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][C@H:7]([CH3:12])[CH2:8][C@H:9]([CH3:11])[CH2:10]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)C1(C=O)C[C@H](C)C[C@H](C)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)C[C@H](C)C[C@H](C)C1
Yield: 56.9 %

Procedure:
A mixture of (3S,5R)-1-formyl-3,5-dimethyl-cyclohexanecarboxylic acid methyl ester (5.5 g, 27.8 mmol), sodium acetate (4.57 g, 55.6 mmol) and O-benzylhydroxylamine hydrochloride (8.88 g, 55.6 mmol) were stirred in methanol (100 mL) for 18 h. The methanol was removed in vacuo, water (100 mL) was added and the aqueous phase was extracted with EtOAc (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. The residue was purified by flash column chromatography using an eluting system of hexane/EtOAc (99:1) to yield the title compound as a clear yellow oil (4.8 g, 57%). MH+304.
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[O:4]=[S:5]1(=[O:17])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]([CH2:15][Cl:16])N1>>[O:17]=[S:5]1(=[O:4])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]([CH2:15][Cl:16])[N:1]1[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: O=S1(=O)NC(CCl)=Nc2ccccc21
Product: CN1C(CCl)=Nc2ccccc2S1(=O)=O

Procedure:
The title compound is prepared by diazomethane methylation of 1,1-dioxo-3-(chloromethyl)-2H-benzo[e][1,2,4]thiadiazine (CAS#37162-65-5, Enamine #EN300-62803) by the method published in Farmaco, Edicione Scientifica 1966, 21, 430-442 (see compound XVI).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)=[O:13])=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)=[O:13])=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 85 %

Procedure:
(E)-3-[4-(2,3,4,5-Tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-acrylic acid methyl ester from Example E65.2 (485 mg, 1.44 mmol) was dissolved in methanol (60 ml) and hydrogenated over 10% Pd/C catalyst (214 mg) for 2 h. The mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to yield the title compound (415 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[C:25]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:25]3[C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=[C:29]([CH3:30])[C:24]=3[CH3:23])[CH2:34][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 64 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:13]1[C:12]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=2[N:10]=[C:9]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[O:8][CH2:29][CH:30]1[CH2:32][CH2:31]1
Reactant: BrCC1CC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(Cc3cccc(Cl)c3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and bromomethyl-cyclopropane (CAS Reg. No. 7051-34-5). Colorless powder (22%). MS (Turbo Spray): m/z=459.3 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NCCOCCO
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-[(2-aminoethyl)oxy]ethanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, br t), 8.51 (1H, s), 7.74 (1H, s), 7.31 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 4.59 (1H, t, J=5 Hz), 4.11 (2H, s), 3.57-3.38 (8H, m), 3.12 (3H, s), 2.82 (3H, s); HRMS calcd for C24H27FN4O6+H: 487.1993. Found: 487.2007.
Reaction SMILES: [ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH2:11].Cl.[N:13]1([C:18](=N)[NH2:19])C=CC=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[ClH:1].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[NH:11][C:18]([NH2:19])=[NH:13]
Reactant: NC1Cc2ccccc2C1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Stir a solution of 2,3-dihydro-1H-inden-2-amine hydrochloride (197 g; 1.08 equiv; 1.16 moles), 1H-pyrazole-1-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74 mL) in acetonitrile (2 L) at 62° C. for 2 hours, during which time a white solid precipitates. Cool the mixture to 25° C., then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25° C. for 1 h to afford the title compound (200 g, 87%) as a white solid. MS (m/z): 176 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]=[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]=[C:11]3[N:12]=[C:13]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:14]=[C:15]([NH2:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3cccc(F)c3)nc2n1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Nc1nc(N2CCNCC2)nc2nc(-c3cccc(F)c3)nn12
Temperature: 25 °C

Procedure:
18 mmol of 2-(3-fluoro-phenyl)-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (prepared as described Caulkett et al., J. Chem. Soc. Perkin Trans I. 801-808 (1995)) was suspended in 50 mL of CH3CN along with 5 eq. of piperazine. The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with H2O, brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (95% CH2Cl2, 4% MeOH, 1% Et3N) to afford 2-(3-fluoro-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13].C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.[Li]CCCC.OS(O)(=O)=O>C1(C)C=CC=CC=1.C1COCC1>[BH:18]([OH:19])[OH:17].[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: COc1cc(F)c(C(C)C)cc1Br
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OBO
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
A 500 mL dry flask was charged with 2-bromo-5-fluoro-4-isopropylanisole (compound of formula 4, Scheme 3) (24.6 g, 0.1 mol) and dissolved in toluene (80 mL) and THF (80 mL). The resulting solution was flushed with argon, and tri-isopropylborate (32 mL, 0.14 mol) was added. The mixture was cooled to −80° C. Then 10 M n-BuLi in hexanes (12.5 mL, 0.125 mol) was added slowly, maintaining a temperature below −55° C. Thirty minutes after completion of the n-BuLi addition, the reaction was warmed to −35° C. and quenched into 3 M H2SO4 solution (75 mL, 0.225 mol). DIPE (200 mL) was added to the mixture to dilute the organic layer. The mixture was stirred (15 min) and the aqueous layer was cut away. The organic layer was washed with 3.0 M H2SO4 (75 mL). The organic phase was extracted three times with 1M NaOH (200 mL first and then 50 mL and 50 mL). The three NaOH extractions were combined, diluted with 2-propanol (85 mL), and cooled to 15° C. Then the solution was slowly acidified to pH ˜2 using 3 M H2SO4 (70 mL) while maintaining temperature at 15-20° C. The resulting slurry was stirred for 1 hour and then filtered. The filter cake was washed with water (3×30 mL) and dried under an air flow for 1 day. The white crystalline solid was isolated to yield boronic acid of formula 5 (Scheme 3) (19.23 g, 91%): mp 100-102° C.; 1H NMR (CDCl3) δ 1.25 (d, J=6.9 Hz, 6H), 3.17 (sept., J=6.9 Hz, 1H), 3.88 (s, 3H), 5.83 (s, 2H), 6.59 (d, J=12.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]([C:21]1[C:26]([NH2:27])=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:20]>>[C:19]([C:21]1[CH:22]=[C:23]([O:30][CH3:31])[C:24]([O:28][CH3:29])=[CH:25][C:26]=1[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)(=[O:20])[CH3:18]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c(C(C)=O)cc1OC

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-amino-4,5-dimethoxyacetophenone (56 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (24 mg, 30%). 1H NMR (CDCl3): 12.49 (s, 1H), 9.65-9.64 (m, 1H), 8.86 (s, 1H), 8.74-8.70 (m, 2H), 7.45-7.41 (m, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 4.12 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:16]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[C:3]([O:17][CH3:18])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=3[CH:16]=2)=[N:21][CH:22]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(=O)N(C)c2cc(N)c(OC)cc2C1
Product: CCN1CC(=O)N(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-4-ethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to example 730 (0.062 g, 46%) Mp 214-216° C.; LCMS (m/e) 552 (M); 1H-NMR (DMSO, 400 MHz) δ 8.23 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.22-7.20 (d, 1H, J=8.84 Hz), 7.04 (s, 1H), 6.88-6.86 (d, 1H, J=8.34 Hz), 3.89 (s, 3H), 3.88-3.79 (m, 1H), 3.50 (s, 2H), 3.28 (s, 3H), 2.99 (s, 2H), 2.89 (s, 3H), 2.58-2.53 (q, 2H, J=6.82 Hz), 2.05-1.90 (m, 2H), 1.68-1.58 (m, 2H), 1.40-1.17 (m, 3H), 1.08-1.04 (t, 3H, J=7.33 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:22]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][C:5]([Br:22])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: Nc1nccnc1C(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Br)nc1C(=O)c1cccnc1
Reaction time: 1 h

Procedure:
(3-Amino-pyrazin-2-yl)-pyridin-3-yl-methanone (1.00 g, 4.99 mmol) is dissolved in glacial acetic acid (10 ml). Na2CO3 (0.583 g, 5.49 mmol) is added. After evolution of gas has finished, a solution of bromine (0.192 ml, 3.74 mmol) in acetic acid (5 ml) is added dropwise. Na2CO3 (0.583 mg, 5.49 mmol) is added, followed by a second solution of bromine (0.192 ml, 3.74 mmol) in acetic acid (5 ml). The resulting orange suspension is left to stir for 1 hour. The reaction is quenched by pouring onto ice water (150 ml), and the orange solid formed is collected by filtration, washed with water and dried in vacuo at 40° C. overnight to yield the title compound. [M+H]+ 279.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][CH2:7][C:8](=[O:16])[C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=O.Cl.[NH2:18][CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[Br:6][CH2:7][C:8](=[O:16])[C:9](=[N:13][O:14][CH3:15])[C:10]([NH:18][CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30][CH:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)=[O:12]
Reactant: CON=C(C(=O)O)C(=O)CBr
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Yield: 83.3 %

Procedure:
Vilsmeir reagent, which was prepared from N,N-dimethylformamide (0.48 g) and phosphorus oxychloride (1.0 g), was suspended in ethyl acetate (20 ml), and thereto was added 4-bromo-2-methoxyiminoacetoacetic acid (syn isomer) (1.34 g) under ice-cooling, followed by stirring at the same temperature for half an hour to prepare the activated acid solution. This solution was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (2.15 g) and trimethylsilylacetamide (3.93 g) in ethyl acetate (30 ml) at -20° C., and the mixture was stirred at -20° to 0° C. for 1.5 hours. To the reaction mixture was added ethyl acetate (100 ml) and water (100 ml), and the separated ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4 -carboxylate (syn isomer) (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH:12]1[C:11]2[NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[C:15]=2[CH2:14][CH2:13]1)[CH3:21]
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: Nc1ccc(F)cc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Temperature: 115 °C
Yield: 53.1 %

Procedure:
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ehtyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:14]2[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])c(N)c1

Procedure:
A mixture of 2.5 G. of 2-amino-4-chloro-1-nitrobenzene, 3.4 g. of 1-methyl-2-mercapto-imidazole and 4.2 g. potassium carbonate in 20 ml. dimethylformamide is heated overnight at 110°-120°C., then cooled, and poured into water. The product is filtered off and recrytallized from aqueous methanol to give 2-amino-4-(1-methylimidazol-2-ylthio)-1-nitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2O.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[Cl:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
1-(6-bromo-4-hydroxyquinolin-3-yl)butan-1-one (3.73 g, 12.7 mmol) was added to phosphoryl chloride (37 mL) and the reaction was stirred at 75° C. for 2 h. After this time the reaction mixture was cooled to room temperature and slowly poured into a solution of satd. aq. sodium carbonate that was cooled to 0° C. The resultant mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica, ethyl acetate) afforded the desired product (3.90 g, 98%) as an off-white solid. ESI MS m/z 312 [C13H13BrClNO+H]+