Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=2[CH:36]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]5[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=5[CH:36]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(2-hydroxymethyl-3H-benzoimidazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow foam (37 mg, 26%). LCMS (m/e) 492 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.71 (bs, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 7.90 (d, 1H, J=7.8 Hz), 7.83 (d, 1H, J=7.5 Hz), 7.65-7.54 (m, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.08 (s, 1H), 6.96 (d, 1H, J=4.6 Hz), 6.82 (d, 1H, J=4.7 Hz), 6.73 (bs, 1H), 5.92 (bs, 1H), 4.89 (s, 2H), 2.62 (s, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[NH2:8][C:6]1[C:5]([OH:11])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(N)n1
Reaction time: 72 h
Yield: 98678.5 %

Procedure:
A mixture of 6-methyl-2-nitro-pyridin-3-ol (18.5 g, 0.120 mmol), 10% palladium on activated carbon (1.35 g), and ethyl acetate (240 mL) was hydrogenated for 3 days. The mixture was filtered through Celite and washed with methanol/ethylacetate (5%). The filtrate and washing were combined and concentrated to give the title compound (14.7 g, 99% yield) as a pale brown solid. 1H NMR (DMSO-d6) δ 9.19 (bs, 1H), 6.73 (d, 1H, J=7.6 Hz), 6.12 (d, 1H, J=7.6 Hz), 5.36 (bs, 2H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.B1([O-])O[O:19]1.O.O.O.O.[Na+].CCOC(C)=O>C1COCC1.O>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([OH:19])=[CH:5][N:4]=1
Reactant: [O-]B1OO1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (from step A) (1.167 g, 4.63 mmol) in THF/H2O (20 mL 1:1) at room temperature under argon was added sodium perborate tetrahydrate (2.137 g, 13.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was cooled to room temperature. EtOAc (10 mL) was added to the reaction mixture, which was washed with brine (15 mL×3). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was very insoluble, therefore it was used directly to next step. MS (ESI) 143 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:6]([N+:20]([O-])=O)[CH:5]=1.C(OP(OCC)OCC)C>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:11]1[NH:20][C:6]2[C:7]([CH:10]=1)=[CH:8][CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:23])[CH:5]=2
Reactant: COC(=O)c1ccc(/C=C/c2c(Cl)cccc2Cl)c([N+](=O)[O-])c1
Agent: CCOP(OCC)OCC
Product: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 162 °C

Procedure:
A mixture of 4-[(E)-2-(2,6-dichlorophenyl)-vinyl]-3-nitrobenzoic acid methyl ester (1.6 g, 4.5 mmol) and triethylphosphite (7.7 g, 6 equiv.) was heated at 162° C. for 3 h. Excess triethylphosphite was removed under reduced pressure and the redidual oil was purified by chromatography using methylene chloride as eluent to give methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 11.88 (s, 1H), 8.05 (s, 1H), 7.71-7.65 (m, 4H), 7.65-7.53 (m, 1H), 6.63 (s, 1H), 3.87 (s, 3H). MS (m/z) 320.07 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH:18]=[C:17]([NH:20][CH:21]=O)[NH:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14].[H-].[OH-].[Na+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl.CCOCC.O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH2:18][C:17]([NH:20][CH3:21])=[N:16]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=CNC1=CCN(c2ccc(Cl)c(Cl)c2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC1=NN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
To a stirred solution of 250 ml. of freshly distilled tetrahydrofuran under nitrogen is added cautiously 5.0 g. of lithium aluminum hydride, then 5.0 g. of N-[1-(3,4-dichlorophenyl)-3-pyrazolin-3-yl]formamide is added portionwise and the mixture is refluxed under nitrogen for 6 hours. The reaction mixture is cooled and the excess hydride is decomposed by the cautious dropwise addition of 5.0 ml. of water followed by 5.0 ml. of 15% sodium hydroxide solution and 15 ml. of water. The mixture is filtered and the filtrate is evaporated to give a gum and solid. This material is dissolved in dichloromethane and passed through a short column of a hydrous magnesium silicate. The effluent is evaporated to give a dark gum and solid. The mixture is dissolved in ether and treated as above with a hydrous magnesium silicate. The effluent is evaporated and the solid is recrystallized twice from ether-hexane to give 2.0 g. of the desired product as white crystals, m.p. 68°-70° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:13]([F:26])[CH:12]=1)C>C1COCC1>[F:26][C:13]1[CH:12]=[C:11]([CH2:10][OH:9])[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(OCCN2CCOCC2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To lithium aluminium hydride (0.03 g, 0.90 mmol) suspended in dry THF (1 ml) and cooled to 0° C. under an argon atmosphere was added a solution of 3-fluoro-4-(2-morpholin-4-yl-ethoxy)-benzoic acid ethyl ester (0.15 g, 0.5 mmol) in dry THF (1 ml). The cold bath was removed and the reaction mixture further stirred for 2 h at r.t. The reaction mixture was cooled (0° C.) and quenched with NaHCO3 (½ sat., 2 ml) and further stirred for 0.5 h at r.t., filtered and concentrated under reduced pressure. The filtrate was dissolved in ethyl acetate and washed with water (2×), brine, dried (MgSO4) filtered and concentrated under reduced pressure: 0.12 g (86%);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](O)=[O:34].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:33](=[O:34])[CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol) and pyridin-2-ylacetic acid hydrochloride (129 mg, 0.742 mmol) in N,N-dimethylformamide (4.0 mL) were added dropwise triethylamine (0.21 mL, 1.484 mmol) and diethyl cyanophosphate (0.12 mL, 0.816 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) and recrystallized from ethyl acetate to give the title compound (67 mg, 41%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH2:11][C@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(Cc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](O)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 5.6 %

Procedure:
To a solution of 1.8 g (5.6 mmol) (3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50 ml tetrahydrofuran were added at 0° C. 0.97 ml (6.2 mmol) diethyl azodicarboxylate and 0.75 g (6.2 mmol) benzoic acid. The reaction mixture was cooled to 0° C., followed by addition of 1.6 g (6.2 mmol) triphenylphosphine. The reaction mixture was stirred at 0° C. for 6 h. Addition of a saturated sodium carbonate solution was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with saturated sodium carbonate solution and brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. The residue was dissolved in a mixture of 50 ml dioxane and 18 ml 1 N aqueous sodium hydroxide solution. After stirring at 70° C. for 5 h the reaction mixture was diluted with tert-butyl methyl ether. The layers were separated and the organic layer was washed with a saturation aqueous sodium carbonate solution. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 0.1 g (6%) of the title compound as a light brown oil. MS m/e (%): 322 (M+H+, 100)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]=O)[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH:20]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cn(CCN)c(C)n1
Reactant: O=CCCc1cccc(Cl)c1
Product: Cc1nc(C)n2c1C(CCc1cccc(Cl)c1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3-chloro-phenyl)-propionaldehyde. LC-MS: tR=0.59 min.; [M+H]+=290 g/mol.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]1=[O:43]>CN(C)C=O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][C:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]2=[O:43])[C:16](=[O:20])[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)CCN1
Reactant: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(c2ccccc2)c2ccccc2)CCN1CCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of product from Example 64C (0.11 g, 0.4 mmol)) in N,N-dimethylformamide was added a 60% dispersion of sodium hydride in mineral oil (0.03 g, 0.75 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Then 1-(2-bromoethyl)-3,3-diphenylpyrrolidin-2-one (Example 64B, 0.142 g, 0.4 mmol) was added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated and partitioned in water/methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed, eluting first with 5% ethyl acetate/hexane and then eluting the title compound with 15% methanol/methylene chloride. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 20H), 3.48 (t, J=6.44 Hz, 2H), 3.42 (m, 2H), 3.28 (m, 2H), 3.12 (s, 2H), 2.70 (m, 2H), 2.66 (m, 2H), 2.42 (m, 2H); MS (ESI+) m/z 530 (M+H)+.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][C:17]1[CH:44]=[C:43]2[C:20]([CH2:21][CH2:22][C:23]3[C:24]2=[N:25][O:26][C:27]=3[C:28]2[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:30][N:29]=2)=[CH:19][C:18]=1O.CCCCCC>N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:18]1[CH:19]=[C:20]2[C:43](=[CH:44][C:17]=1[CH3:16])[C:24]1=[N:25][O:26][C:27]([C:28]3[C:32]([C:33]([F:34])([F:35])[F:36])=[C:31]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:30][N:29]=3)=[C:23]1[CH2:22][CH2:21]2)(=[O:8])=[O:9]
Reactant: Cc1cc2c(cc1O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Yield: 77.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.074 mL, 0.440 mmol) was added to a solution of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Preparation 64C, 0.121 g, 0.293 mmol) in pyridine (5 mL) at 0° C. over a period of 5 min. The reaction mixture was stirred at 0° C. for ten minutes and then at room temperature overnight. The reaction mixture was concentrated, and the yellowish-brown residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The ethyl acetate layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with a mixture of 15% ethyl acetate:85% hexane to yield 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate as a tan solid (0.123 g, 0.226 mmol, 77%). The product had an HPLC ret. time=4.52 min (condition B). LC/MS M+1=545.2.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:15]=1[O:14][CH3:13]
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: COc1cc(N(C)C)ccc1C=O
Product: COc1cc(N(C)C)ccc1C=NNC(=S)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.6 mmol) and 2-methoxy-4-dimethylaminobenzaldehyde (97 mg, 0.72 mmol) similar to Example 3 and isolated as a yellow solid (60 mg, 29%). 1H NMR (CDCl3): 9.08 (s, 1H), 8.05 (s, 1H), 7.65 (brs, 1H), 7.45 (brs, 1H), 6.27 (brs, 1H), 6.22 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 6.00 (s, 1H), 4.32 (m, 1H), 3.82 (s, 3H), 3.03 (s, 6H), 2.93 (s, 1H), 1.85 (m, 1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.41 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[CH3:17][O:18][N:19]=[C:20]([C:37](=[O:40])[CH2:38][Br:39])[C:21]([NH:23][CH:24]1[C:35](=[O:36])[N:26]2[CH:27]([C:32]([OH:34])=[O:33])C(O)C[S:30][C@H:25]12)=[O:22].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:20]([C:37](=[O:40])[CH2:38][Br:39])[C:21]([NH:23][CH:24]1[C:35](=[O:36])[N:26]2[CH:27]([C:32]([OH:34])=[O:33])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][S:30][C@H:25]12)=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(OC(C)=O)CS[C@H]12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (22.5 ml.) and boron trifluoride etherate (7.5 ml.) were added to a stirred solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer 31.8 g.) in dry tetrahydrofuran (150 ml.) at room temperature, and stirred at the same temperature for 30 minutes and at 50° C. for an hour. To the resultant solution was added a saturated aqueous solution of sodium chloride (100 ml.) and stirred for 30 minutes. Ethyl acetate (150 ml.) was added to the solution, and the ethyl acetate layer was separated, and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate (100 ml.). The ethyl acetate layer and the extract were combined, treated with activated charcoal and evaporated. After adding diisopropyl ether (500 ml.) to the residue, the solvent was decanted. The residue was pulverized with diisopropyl ether, and the precipitates were collected by filtration and dried to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-acetoxycepham-4 -carboxylic acid (syn isomer, 35.3 g.)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]([O:14][CH3:13])=[O:16])[CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:14][CH3:13])=[O:16]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccc2ccc(Br)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)cc3c2)c1
Yield: 72 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromonaphthalene (2.00 g, 6.99 mmol), 3-(methoxycarbonyl)phenylboronic acid (3.15 g, 17.48 mmol), CsF (4.00 g) and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen. 150 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen for 2 days. The solvent was removed on a rotary evaporator. 100 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was re-crystallized from the mixture solvent of ethyl acetate and hexane (v/v=1:9) to give a pure product with a yield of 72% (2.0 g) based on 2,7-dibromonaphthalene. 1H NMR (300 MHz, DMSO-d6): δ 3.92 (s, 6H), 7.70 (t, 2H), 7.93 (d, 2H), 8.01 (d, 2H), 8.13 (m, 4H), 8.39 (m, 2H), 8.45 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]1([CH2:20][O:21][NH:22][CH3:23])[CH2:19][CH2:18]1>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:22]([CH3:23])[O:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNOCC1CC1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC2CC2)n1
Yield: 99 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-cyclopropylmethyl-N-methyl-hydroxylamine hydrochloride (XC) as described in Example 13, yielding (XCI) in 99% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 6.91-6.77 (1H, m), 6.75-6.58 (1H, m), 3.77-3.64 (2H, m), 3.21-3.09 (7H, m), 1.54-1.41 (4H, m), 1.11-1.00 (1H, m), 0.88-0.80 (6H, m), 0.56-0.44 (2H, m), 0.32-0.20 (2H, m). ESI-MS (m/z) 295 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([NH:15][NH2:16])[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]2=[O:24])(=[O:3])[CH3:2].[CH:25]1(C(Cl)=O)CCC[CH2:26]1>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:25]([CH3:26])=[N:16][N:15]=[C:10]1[N:9]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:8]2=[O:24])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(=O)Nc1ccc2nc(NN)n(Cc3ccccc3)c(=O)c2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(C)n21

Procedure:
7.0 g (21.6 mmol) of 6-acetamido-3-benzyl-2-hydrazino-3,4-dihydro-quinazolin-4-one (synthesized according to a process described in patent application WO 00/66584) dissolved in glacial acetic acid are placed in a round-bottomed flask equipped with a stirrer and a condenser. Then, 3.15 g (23.8 mmol) of cyclopentylformyl chloride are added in a portionwise manner with stirring. The solution obtained is heated to reflux for 20 min. The solvent is evaporated off under vacuum and the residue is taken up in water.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13]([OH:15])=[O:14])=[O:4].[N:24]12[CH2:31][CH2:30][CH:27]([CH2:28][CH2:29]1)[C@@H:26](O)[CH2:25]2.O.N1(O)C2C=CC=CC=2N=N1.C(=NC1CCCCC1)=NC1CCCCC1>C1COCC1>[CH3:23][O:22][C:19]1[N:18]=[CH:17][C:16]([CH:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:13](=[O:15])[O:14][C@@H:26]2[CH:27]3[CH2:30][CH2:31][N:24]([CH2:29][CH2:28]3)[CH2:25]2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1NC(C(=O)O)c1ccc(OC)nc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-(methoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I79) (118 mg, 0.37 mmol), (R)-quinuclidin-3-ol (52.2 mg, 0.41 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (62.8 mg, 0.41 mmol), and N,N′-methanediylidenedicyclohexanamine (85 mg, 0.41 mmol) was dissolved in dry THF (10 ml) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain the title compound, which was used in the next step without any further purification.