Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:12][N:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1.CCOCC.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([S:52]([O:8][CH2:9][C@H:10]2[CH2:12][N:11]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])(=[O:54])=[O:53])=[CH:50][CH:51]=1)([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]1COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of tert-butyl (2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)aziridine-1-carboxylate (prepared following literature procedures: Travins, J. M.; Etzkorn, F. A. Tetrahedron Lett. 1998, 39, 9389-9392) in THF/Et2O (1/1) (0.17 M) was cooled in an ice bath and treated dropwise over 20 min with 1 M TBAF in THF (1.05 eq). The resulting solution was stirred in the ice bath for 30 min, before being quenched by the addition of sat. aq. NaHCO3 and extracted into Et2O/PE (4/1). The organic layers were collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was taken up in dry DCM (0.17 M) and TEA (1.3 eq) introduced prior to cooling to 0° C. DMAP (0.1 eq) and 4-nitrobenzenesulfonyl chloride (1.1 eq) were added and the resulting mixture left to stir at RT overnight. The reaction mixture was diluted with DCM and washed with sat. aq. NaHCO3, water and brine before drying over Na2SO4, filtering and concentrating in vacuo. The crude was purified by FC (PE/EtOAc 80:20) to afford the title compound as an off-white solid (57%). (ES+) m/z 359 (M+H)+
Reaction SMILES: C(N(C(C)C)CC)(C)C.CS(O[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]([O:34][C@@H:35]3[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]3[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])=[C:21]([CH3:58])[CH:20]=1)(=O)=O.[CH2:59]1[C:62]2([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]2)[CH2:61][NH:60]1>C(#N)C>[CH3:58][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[CH2:16][CH2:15][N:60]2[CH2:61][C:62]3([CH2:67][CH2:66][CH2:65][N:64]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:63]3)[CH2:59]2)[CH:24]=[CH:23][C:22]=1[CH2:25][C:26]1[C:27]([O:34][C@@H:35]2[O:52][C@H:51]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[C@@H:46]([O:47][C:48](=[O:50])[CH3:49])[C@H:41]([O:42][C:43](=[O:45])[CH3:44])[C@H:36]2[O:37][C:38](=[O:40])[CH3:39])=[N:28][NH:29][C:30]=1[CH:31]([CH3:33])[CH3:32]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC2(CNC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CC4(CCCN(C(=O)OC(C)(C)C)C4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 53.6 %

Procedure:
Add diisopropylethylamine (0.2 mL, 1.1 mmol) to a solution of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (200 mg, 0.28 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (77 mg, 0.34 mmol) in acetonitrile (3 mL). Heat the mixture at 80° C. for overnight. Concentrate under reduced pressure and purify residue by flash chromatography to yield the title compound (127 mg, 0.15 mmol). MS (m/z): 838.8, 839.6 (M+1), 836.8, 837.6 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O.[OH-].[Na+]>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2)(=[O:17])[CH3:16]
Reactant: Cn1c(=O)c(=O)[nH]c2cc(N)ccc21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 0.3 g (1.3 mmol) 6-amino-1-methylquinoxaline-2,3(1H,4H)-dione in a mixture of 15 ml water and 0.6 ml 4N sodium hydroxide was added 5 ml acetic acid anhydride. Stirring was continued at 25° C. for 2 h. The precipitate was filtered off and washed with water to give 0.21 g (68%) of 6-acetamido-1-methylquinoxaline-2,3(1H,4H)-dione. M.p. 390° C. NMR (DMSO-d6): 10.1 (1H, broad s), 9.7 (1H, broad s), 7.5-7.0 (3H), 3.43 (3H, s), 2.0 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[C:5]2[C:13]([OH:15])=O.CN(C=O)C.S(Cl)([Cl:23])=O.[N:25]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[Cl:23][C:7]1[CH:6]=[C:5]([C:13]([NH:32][CH2:31][CH2:30][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=C(O)c1cc(O)nc2ccc(Cl)cc12
Reactant: NCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cc(Cl)nc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a stirred suspension of 6-chloro-2-hydroxy-quinoline-4-carboxylic acid (preparation 8) (8.50 g, 38 mmol) in anhydrous DCM (250 ml), was added anhydrous DMF (2 ml) and thionyl chloride (11 ml, 152 mmol) at room temperature under argon. The mixture was refluxed for 3 h and then allowed to cool to room temperature. The solvents were removed under reduced pressure and the residue was dissolved in anhydrous THF (300 ml) under argon. 2-Pyrrolidin-1-ylethanamine (14 ml, 114 mmol) was added and the reaction was stirred at room temperature for 16 h. Solvents were removed under vacuum and the residue partitioned between NaHCO3 saturated aqueous solution (250 ml) and DCM (2×250 ml). The organic layers were combined, dried over MgSO4, filtrated and evaporated under reduced pressure. The crude was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: DCM, Solvent B: 10% MeOH—NH3 in DCM. Gradient: 2 min hold 100% A followed by 18 min ramp to 30% B and then 15 min hold at 30% B. The relevant fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as an off-white solid (5.6 g, 16.6 mmol, 43%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]([NH:36][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with isopropylamine (16 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 96 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH2:18].[C:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)([OH:21])=[O:20]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[NH:18][C:29](=[S:30])[NH:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 4-methoxy-3-amino-N-phenyl-benzamide (0.73 g, 3.0 mmol) and 3-carboxyphenyl isothiocyanate (0.54 g, 3.0 mmol) in ethyl acetate (60 mL) was warmed briefly to 50° C. and then allowed to stand overnight at room temperature. The mixture was then rewarmed to 50° C., filtered, and concentrated to dryness. Trituration of the residue in ethyl acetate followed by filtration afforded the product (1.083 g); m.p. 196-197° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]4=[O:36])[CH:19]=3)=[CH:11][C:10]=2[O:37][CH3:38])[CH:6]=[CH:5][N:4]=1)[CH3:2].[CH:39]([Mg]Br)(C)C.ClC1C=C(C2C=CC(C3N=NN(C4CCC5C=CC=CC=5N(CC(F)(F)F)C4=O)C=3)=CC=2OC)C=CN=1>>[CH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[N:17][N:18]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[N:22]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:21]4=[O:36])[CH:19]=3)=[CH:11][C:10]=2[O:37][CH3:38])[CH:6]=[CH:5][N:4]=1)([CH3:39])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: CCc1cc(-c2ccc(-c3cn(C4CCc5ccccc5N(CC(F)(F)F)C4=O)nn3)cc2OC)ccn1
Agent: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(Cl)c1
Product: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(C(C)C)c1

Procedure:
3-{4-[4-(2-Isopropylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was prepared by using the same procedure described for 3-{4-[4-(2-ethylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one with isopropyl magnesium bromide (1M in THF, 189 μl, 0.189 mmol), and 3-{4-[4-(2-chloropyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.095 mmol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]1([OH:46])[CH2:21][C@H:20]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][C@@H:18]2[C@H:14]1[CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH3:44])[CH3:36])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][C@@H:20]1[CH2:19][C@@H:18]2[C@@H:14]([CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[CH3:36])[CH2:17]2)[C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:46])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CN=[N+]=[N-])C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
1.68 g of sodium azide are added to a solution, which has been brought to 50° C., of 9.0 g (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethylperhydroisoindol-4-ol in 50 cm3 of dimethylformamide. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with 350 cm3 of water and subjected to extraction with 100 cm3 of ethyl acetate. The organic phase is washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 7.0 g of (3aS,4S,6R,7aR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[N:20]=[C:19]([C:21](OCC)=[O:22])[O:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]([CH3:38])[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:38][N:28]([CH3:27])[CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][N:35]([C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][N:13]([CH3:14])[S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:26])(=[O:12])=[O:11])[N:20]=2)=[O:22])[CH2:36][CH2:37]1
Reactant: CCOC(=O)c1nc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)no1
Reactant: CN(C)CCCN1CCNCC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2noc(C(=O)N3CCN(CCCN(C)C)CC3)n2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 3-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-5-carboxylate (30 mg, 0.08 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (27 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4n3)cc2)ccc1Cl
Yield: 55.5 %

Procedure:
2-(4-aminophenylthio) quinoline (3.9 mmoles, 1.0 g) and 4-chloro-3 -trifluoromethylphenylisothiocyanate (3.9 mmoles, 0.92 g) were reacted according to procedure A to yield 1.06 g, 56% of the title compound. Mass spec (FD) 490. Calculated for C23H15ClF3N3S2 : C, 56.38; H, 3.09, N, 8.58. Found: C, 56.60; H, 3.11; N, 8.42.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH2:33]Cl)=[CH:27][C:26]=1[Cl:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH2:33][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[Cl:35])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: COc1cc(CCl)cc(Cl)c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 h at this temperature and 2-benzyloxy-1-chloro-5-chloromethyl-3-methoxy-benzene (CAB02174, 1.49 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was separated and washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.76 g (79%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=2[C:20](O)=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]3[C:12]=2[C:20](=[O:21])[N:24]([CH:25]2[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]2=[O:27])[C:14]3=[O:16])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(C)c1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 89 %

Procedure:
A mixture of 3-(4-isopropylphenylamino)phthalic acid (0.64 g, 2.1 mmol) and rac-α-aminoglutarimide hydrochloride (0.35 g, 2.1 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 1:1 hexanes-ethyl acetate, eluting 0.74 g of the product, in 89% yield: mp 138-140° C.; 1H NMR (DMSO-d6) δ 1.21 (d, J=6.9 Hz, 6H), 2.04-2.08 (m, 1H), 2.52-2.64 (m, 2H), 2.84-2.94 (m, 2H), 5.13 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.19-7.30 (m, 5H), 7.35 (d, J=8.5 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 8.35 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 23.9, 31.0, 32.9, 48.7, 111.3, 113.0, 119.0, 122.5, 127.2, 132.4, 136.2, 136.9, 143.3, 144.5, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.27; H, 5.36; N, 10.64.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[C:30]([SH:31])=[N:29][N:28]=[N:27]1.CN(C)C=O.Cl.C(N([CH2:43][CH3:44])CC)C>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:7]([C:44]4[CH:43]=[CH:21][CH:14]=[CH:15][CH:16]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:22])=[C:15]([CH2:19][S:31][C:30]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)[O-])=C(CCl)CS(=O)[C@H]12
Reactant: CCN(CC)CC
Reactant: Sc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Temperature: 0 °C
Yield: 139.8 %

Procedure:
A mixture of benzyhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (70.0 g), 1H-tetrazole-5-thiol (15.6 g) and N,N-dimethylformamide (700 ml) was stirred to give a homogeneous solution and thereto was added triethylamine (32.1 g), keeping the temperature at 20° to 30° C. The resulting solution was stirred for 40 minutes at room temperature. After the reaction mixture was added to ice water (2.8 l), the mixture was adjusted to pH 2.0 with 10% hydrochloric acid and then filtered. The filter cake was washed with water and dried over phosphorus pentoxide under reduced pressure to give benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.8 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=3)=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: Brc1ccc2c(c1)CCO2
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCO3)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (2,3-dihydro-benzofuran-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.0 [M+H]+) was prepared from 5-bromo-2,3-dihydro-1-benzofuran instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:10]1[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Yield: 57.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (260 mg, 1.2 mmol), 2-nitrobenzene-1-sulfonyl chloride (597 mg, 2.69 mmol), DMAP (cat) and pyridine (0.3 ml, 3.67 mmol) in DCM (5 ml) gave the title compound (275 mg, 56%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Mg].[Cl:8][CH2:9][CH2:10][CH2:11]C(=O)C.[C:15]([O:18][C:19](=O)[CH3:20])(=[O:17])[CH3:16]>CCOCC.O>[Cl:8][CH2:9][CH2:10][CH2:11][C:19]([O:18][C:15](=[O:17])[CH3:16])([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CCCCl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(C)(CCCCl)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the Grignard reagent prepared from 1-bromopentane (4.8 g., 0.04 mole) and magnesium (0.96 g., 0.04 mole) in ether is added 5-chloro-2-pentanone (6.0 g., 0.04 mole). The reaction mixture is stirred at 25° C. for 1 hour and then cooled to 15° C. Acetic anhydride (6 ml., excess) is added carefully and the solution is allowed to stand for 20 hours. Water is added, and the ether layer is separated, washed with brine, and dried over sodium sulfate, Distillation affords the title compound in 4.3 g. (46%) yield, b.p. 88° C. (0.1 mm.).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.Cl[Si](C)(C)C.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1(OC)[O:35]C)=[O:27]>ClCCl>[C:30]1(=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27]
Reactant: COC1(OC)CCCCC1OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC2CCCCC2=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of gabapentin (2.56 g, 15 mmol) and chlorotrimethylsilane (3.7 mL, 30 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere was added triethylamine in portions. After having stirred for 15 min at 0° C. the chloroformate (45) was added dropwise into the reaction mixture. The mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was concentrated in vacuo and the residue was poured into cold water (50 mL) and then acidified to about pH 5.0 using 0.1 N HCl. The crude product was then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and the solvent removed in vacuo. The crude product was dissolved in acetone (25 mL) and treated using Amberlyst-15 (1.0 g) for 1.5 h (monitored by LC/MS). The reaction mixture was filtered and the filtercake was washed with acetone (2×15 mL). The combined extracts were evaporated under reduced pressure and the residue was purified using prep-HPLC/MS method to provide 1.71 g (55% yield) of compound 46 as a white solid. 1H NMR (CDCl3, 400 MHz): 5.42 (1H, t), 5.12 (1H, m), 3.35-3.16 (2H, m), 2.39 (4H, m), 1.80-1.40 (16H, m). MS (ESI): m/z=310.27 (M−H−), and 312.28 (M+H+).