Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:34][CH:35]([Cl:39])[C:36]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:37]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(Cl)Cl)[C@H]3SC2)s1
Yield: 65.9 %

Procedure:
7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (6.89 g) was suspended in methylene chloride (60 ml) and bis(trimethylsilyl)acetamide (8.12 g) was added to the suspension to give a solution. A solution of dichloroacetyl chloride (3.24 g) in methylene chloride (10 ml) was added to the solution obtained above at -20° C under stirring. The mixture was stirred at the same temperature for 20 minutes and methylene chloride was distilled off from the mixture after addition of a little water. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried. The solvent was distilled off from the solution under reduced pressure. The residue was pulverized by treating with ether and precipitates were collected by filtration and dried to give 7-dichloroacetamido-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (6.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31]C(Cl)=CC=1)[OH:26].[Li+].[CH3:35]C([N-]C(C)C)C.CC(C)CC=O>C1COCC1.C(Cl)Cl.O>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([OH:26])[CH2:27][CH:32]([CH3:35])[CH3:31]
Reactant: CC(C)[N-]C(C)C
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: CC(C)CC=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(O)c1c(Br)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 300 mg, 0.753 mmol) in THF (10 mL) at −78° C. was added LDA (1.8M in THF, 2.1 mL, 3.765 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (129.8 mg, 1.506 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 30 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1) to give 6-bromo-5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (65 mg, 17.8% yield) as a solid. LCMS: [M+-THP-OH] 382 and TR=2.155 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH:22]C(=O)OCC.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=[C:10]2[N:9]=[C:8]1[NH2:22]
Reactant: CCOC(=O)Nc1nc2cc(-c3ccccc3)cnc2n1Cc1ccc(OCc2ccc(OC)nc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(-c5ccccc5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 48 h
Yield: 34 %

Procedure:
To a stirred solution of ethyl (3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) was added potassium hydroxide (1.00 g, 17.82 mmol). The mixture was heated to 100° C. After 48 h, the mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×10 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to afford 0.027 g (34%) of the product as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (m, 3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90-6.77 (m, 4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H) ppm; (M+1)=468.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>>[N+:23]([C:5]1[S:1][C:2]([C:6]2[CH:7]=[CH:8][C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:10][CH:11]=2)=[N:3][CH:4]=1)([O-:25])=[O:24]
Reactant: c1csc(-c2ccc(N3CCOCC3)cc2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(-c2ccc(N3CCOCC3)cc2)s1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
To a mixture of 4-(4-(thiazol-2-yl)phenyl)morpholine (2.00 g, 8.13 mmol) and concentrated sulfuric acid (25 mL) was added concentrated nitric acid (0.60 mL) at −10° C. The reaction mixture was stirred at 0° C. for 4.5 h, then poured into ice water, and extracted with CH2Cl2 (60 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (0.70 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:16](Br)[CH:17]=[CH2:18].[OH-].[Na+].O>[Cl-].C[N+](CCCC)(CCCC)CCCC.C(OC)(C)(C)C>[CH2:18]([N:9]([C:4]1[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH:17]=[CH2:16]
Reactant: COC(CNc1cnc(Cl)c(Cl)c1)OC
Reactant: C=CCBr
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCN(CC(OC)OC)c1cnc(Cl)c(Cl)c1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To a mixture of (5,6-dichloro-pyridin-3-yl)-(2,2-dimethoxy-ethyl)-amine (190 g), allyl bromide (137.4 g), and methyl tributyl ammonium chloride (23.8 g) in methyl tert-butyl ether (1140 mL) was added 50% aqueous sodium hydroxide (665 mL). This was then stirred at 25-35° C. for about 24 hours. Then water (375 g) and methyl tert-butyl ether (280 g) were added and then the layers were separated. The organic layer was washed with 10 mM potassium phosphate dibasic/10 mM potassium phosphate monobasic aqueous solution (3×1000 mL), and then washed with 20% aqueous sodium chloride (1000 mL). The solution was concentrated to a small volume and then dissolved back up in tetrahydrofuran (1720 g). 1H NMR (400 MHz/CDCl3) δ 7.79 (d, J=3.02 Hz, 1H), 7.10 (d, J=3.02 Hz, 1H), 5.81-5.70 (m, 1H), 5.20 (ddd, J=1.78, 3.02 10.43 Hz, 1H), 5.09 (ddd, J=1.9, 3.2, 17.1 Hz, 1H). 4.48 (t, J=5.1 Hz, 1H), 4.00-3.95 (m, 2H), 3.43 (d, J=5.1, 2H), 3.41 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:36]=[CH:35][C:25]3[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 19.9 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.251 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (80 mg, 0.251 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 4 hours. Added CH2Cl2/MeOH/NH4OH, evaporated off solvent and purified with normal phase chromatography eluting with 1% to 3% MeOH in CH2Cl2 to yield a yellow solid, N-{(1R,2R)-2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (26 mg, 20%). mp 165° C.; LCMS: m/z=521.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.68 (m, 2H), 7.25 (s, 1H), 7.06 (d, 1H, J=8.6 Hz), 6.06 (d, 1H, J=6.6 Hz), 5.73 (d, 1H, J=7.3 Hz), 3.83 (m, 1H), 3.26 (s, 3H), 2.85 (s, 3H), 2.11 (m, 7H), 1.80 (s, 2H), 1.30 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[Cu][C:14]#[N:15].O.C(O)C>CC(O)COC(C(C)=C)=O>[C:14]([C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:12])[CH3:11])=[C:2]([F:1])[CH:7]=1)#[N:15]
Reactant: CC(=O)Nc1ccc(I)cc1F
Reactant: N#C[Cu]
Agent: C=C(C)C(=O)OCC(C)O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C#N)cc1F
Temperature: 153 °C
Yield: 75 %

Procedure:
N-(2-Fluoro-4-iodo-phenyl)-acetamide (63 g, 226 mmol) was dissolved in HPMA (100 mL). Copper(1) cyanide (20.6 g, 230 mmol) was added and the mixture heated to an external temperature of 153° C. for 5 h. The hot reaction mixture was poured into water (1 L) with stirring. A large amount of solid formed. The solid was filtered and washed with water (200 mL). The solid was extracted by heating in a flask with methylene chloride (500 mL) for 15 min. The solid was filtered off, washed with methylene chloride (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown-orange solid. Ethanol (100 mL) was added and the mixture heated to reflux. The solid did not all dissolve. The cooled mixture was filtered to give a light brown solid. The filtrate was concentrated to ½ volume and cooled overnight to give a further crop of solid. The combined solids were washed with cold ethanol (30 mL) and dried under vacuum to give 30 g (168 mmol). Yield: 75%; mp 173° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.3 (br s, 1H, NH), 8.3 (t, J=8.2 Hz, 1H), 7.9 (d, J=10.7 Hz, 1H), 7.67 (d, J=10.7 Hz, 1H), 2.16 (s, 3H, Me).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[NH:19][C:18]2=[O:30])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:32][CH3:33].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[N:19]([CH2:32][CH3:33])[C:18]2=[O:30])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]c2c(C(F)(F)F)ccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of NaH (40.9 mg), 3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) in DMF (dry) (3 mL) was added iodoethane (0.082 mL), and the mixture was stirred at room temperature for 3 h. To the mixture was added sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]1[CH:23]2[CH2:24][CH:25]([NH2:26])[CH:21]([CH2:22]2)[CH2:20]1>ClCCl>[CH:21]12[CH2:22][CH:23]([CH2:19][CH2:20]1)[CH2:24][CH:25]2[NH:26][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(C#N)c(NC2CC3CCC2C3)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a 0° C. solution of 10.0 g (53.9 mmol) of 4-chloro-2-(methylthio)-5-pyrimidinecarbonitrile in 100 mL of dichloromethane is added 9.0 mL (64.6 mmol) of triethylamine followed by dropwise addition of 7.0 mL (59.3 mmol) of exo-2-aminonorbornane. The reaction mixture is stirred at 0° C. for 2 hours. The resulting precipitate of triethylamine hydrochloride is filtered. The filtrate is washed three times with saturated aqueous solution of sodium bicarbonate. The aqueous phase is back extracted twice with dichloromethane. The combined organic phase is concentrated, and the residue is purified by filtering through a short column of silica gel eluted with dichloromethane to give 8.9 g (64%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[NH:24][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: Cc1ccccc1-c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Yield: 99 %

Procedure:
4-nitro-2-(2-tolyl)benzoic acid (1.72 g, 6.7 mmol) was coupled with (L)-leucine methyl ester in the presence of EDCI and HOBT to give the desired compound (2.55 g, 99% yield). 1H NMR (CDCl3) δ 8.29 (d, J=8.7 Hz, 1H), 8.10-8.16 (m, 2H), 7.18-7.42 (m, 4H), 5.76 (d, J=7.6 Hz, 1H), 4.49 (br m, 1H), 3.66 (s, 3H), 2.19 (s, 1H), 2.08 (s, 2H), 1.30-1.39 (m, 1H), 1.02-1.09 (m, 2H), 0.75-0.80 (dd, J=6.7 and 7.1 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 ml) was added to the reaction mixture followed by dropwise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The solvent was evaporated in vacuo. The residue was triturated with n-hexane. The resulting solid was collected by filtration, washed with hexane and dried in vacuo to give 21.0 g (98%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:23][CH:24]=3)[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63](Br)[CH3:64])(=[O:61])[CH3:60]>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]([C:12]([O:14][CH:63]([O:62][C:59](=[O:61])[CH3:60])[CH3:64])=[O:13])[N:10]2[C:15](=[O:52])[C@@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=[O:3])[NH2:2]
Reactant: CC(=O)OC(C)Br
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)C1C(COC(N)=O)=CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
(6R,7R)-3-Carbamoyloxymethyl-7-[(Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic acid (1.1 g) was stirred with potassium carbonate (105 mg) in N,N-dimethylformamide (5 ml) with ice water cooling under nitrogen. After five minutes, 1-acetoxy-1-ethyl bromide (300 mg) was added. After one hour at ice-bath temperature and 2.5 hours at 21°, the mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed with brine, dried with magnesium sulphate and evaporated to a foam. This was chromatographed on Sorbsil U30 (50 g) in ethyl acetate (10 to 70%) in petroleum ether (bp 40°-60°) to give the title compound (840 mg); νmax (CHBr3) 3583, 3403 (NH and NH2), 1785 (β-lactam), 1730 (ester and carbamate) and 1688 and 1513 cm-1 (amide); τ (CDCl3) includes 3.04 (NH and OCHCH3), 3.22 (thiazole proton), 4.19 and 4.70 (7-H and 6-H), 4.8 to 5.6 (3CH2 and NH2), and 5.90 (--CH2O).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[C:10]=2[F:23])=[C:4]([Cl:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]([CH:49]=[O:50])=[CH:35][C:36]3[N:40]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[N:38][C:37]=3[C:47]=2[F:48])=[C:28]([Cl:51])[CH:27]=1.C([O-])([O-])=O.[K+].[K+].S([CH2:68][N+:69]#[C-:70])(C1C=CC(C)=CC=1)(=O)=O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[C:10]=2[F:23])=[C:4]([Cl:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]([C:49]3[O:50][CH:70]=[N:69][CH:68]=3)=[CH:35][C:36]3[N:40]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[N:38][C:37]=3[C:47]=2[F:48])=[C:28]([Cl:51])[CH:27]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: Fc1c(Nc2ccc(Br)cc2Cl)c(-c2cnco2)cc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(-c3cnco3)cc21
Temperature: 25 °C
Yield: 4 %

Procedure:
(4-Bromo-2-chloro-phenyl)-(4-fluoro-6-oxazol-5-yl-1H-benzoimidazol-5-yl)-amine 10×: 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazole-5-carbaldehyde 10z (0.025 g, 0.053 mmol) is suspended in MeOH (2 mL) and K2CO3 (0.015 g, 0.105 mmol) is added followed by tosylmethyl isocyanide (0.011 g, 0.058 mmol). The reaction mixture is heated to reflux under N2 for 16 hours. After cooling, additional tosylmethyl isocyanide (0.011 g, 0.058 mmol) is added and the reaction mixture heated to reflux under N2 for 16 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure and dissolved in ethyl acetate. The organic solution is washed with water and brine. The combined aqueous washes are extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 20:1 methylene chloride:MeOH provides 4 mg (18%) desired product 10× and 1 mg (4%) (4-bromo-2-chloro-phenyl)-[4-fluoro-1-(2-methanesulfonyl-ethyl)-6-oxazol-5-yl-1H-benzoimidazol-5-yl]-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([S:14]([N:17]2[C:25]3[CH:24]=[C:23]([Cl:26])[CH:22]=[C:21]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31]([OH:33])=O)[C:19]([C:20]=34)=[C:18]2[C:34]([O:36][CH3:37])=[O:35])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C=O)C>[C:8]1([S:14]([N:17]2[C:25]3[CH:24]=[C:23]([Cl:26])[CH:22]=[C:21]4[CH2:27][CH2:28][CH:29]([CH2:30][C:31](=[O:33])[NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:19]([C:20]=34)=[C:18]2[C:34]([O:36][CH3:37])=[O:35])(=[O:15])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1c2c3c(cc(Cl)cc3n1S(=O)(=O)c1ccccc1)CCC2CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 111.9 %

Procedure:
A mixture of aniline (27.4 mg, 0.303 mmol), methyl 1-benzenesulfonyl-7-chloro-3-carboxymethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylate (120 mg, 0.275 mmol), 1-hydroxy-benzotriazole (46 mg, 0.303 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (47 mg, 0.303 mmol) in DMF (2.5 mL) was stirred for 20 h at room temperature, acidified to pH 1 by adding 1N HCl, and extracted with 1:1 toluene/ethyl acetate. The organic layer was washed successively with 1N HCl, water, saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and concentrated to give 161 mg of the title compound (quant): 1H NMR (CDCl3) δ7.95 (d, 2H, J=7.3 Hz), 7.90 (s, 1H), 7.85 (s, 1H), 7.58 (t, 1H, J=7.3 Hz), 7.52 (d, 1H, J=8.3 Hz), 7.46 (t, 1H, J=8.3 Hz), 7.30 (t, 1H, J=8.3 Hz), 7.15 (t, 1H, J=7.05 (s, 1H), 3.84 (s, 3H), 3.71 (m, 1H), 2.92 (ddd, 1H, J=17.2, 12.2, 3.6 Hz), 2.80 (md, 1H, J=17.2 Hz), 2.65 (dd, 1H, J=14.2, 4.0 Hz), 2.47 (dd, 1H, J=14.2, 9.6 Hz), 2.19 (md, 1H, J=13.6 Hz), 1.89 (m, 1H).
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C:15]1([C:21](O)=[O:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[BH4-].[Na+]>C1COCC1.O>[OH:22][CH2:21][C:15]1([NH:14][C:12](=[O:13])[O:11][C:7]([CH3:9])([CH3:8])[CH3:10])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.234 mL, 0.00245 mol) was added to a solution of 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 2.0 mmol) and triethylamine (0.341 mL, 2.45 mmol) in THF (6.8 mL) at −10° C. The mixture was stirred at RT for 30 min., filtered, and washed with THF. Sodium tetrahydroborate (0.15 g, 4.1 mmol) in water (1.0 mL) was added to the filtrate at 0° C., and then stirred at RT for 2 h. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc. The extract was washed with saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated to give the crude product which was directly used in next step without further purification. LCMS: (M+Na)=254.1; (M−100+H)=132.1.