Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:5][C:4]=1[CH:21]=[CH2:22].[H][H]>O1CCCC1.[Pd]>[CH2:21]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:3]=1[O:2][CH3:1])[CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])[CH3:22]
Reactant: C=Cc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(CN2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 92.1 %

Procedure:
2.75 g of N-(4-methoxy-3-vinylbenzyl)phthalimide was dissolved in 50 ml tetrahydrofuran, 0.1 g of 10% Pd-C was added thereto, and the mixture was stirred for 40 min in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulting residue was purified by silica gel column chromatography to give 2.55 g of N-(3-ethyl-4-methoxybenzyl)phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH2:9])=[N:6][CH:7]=1.[C:10]([N+:14]#[C-:15])([CH3:13])([CH3:12])[CH3:11]>CO.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:9][N:8]=2)[CH:7]=1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: C=Nc1ccc(Br)cn1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Nc1cnc2ccc(Br)cn12
Temperature: 25 °C
Yield: 78 %

Procedure:
To a suspension of 5-bromo-N-methylenepyridin-2-amine (0.85 g, 4.6 mmol) in methanol (20 mL) was added tert-butyl isocyanide (1.14 mL, 10.1 mmol) and trifluoroacetic acid (˜3 drops). The reaction mixture was heated at reflux for 2 h, after which point a clear solution was obtained. The mixture was allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient ethyl acetate in hexanes to afford 6-bromo-N-(tert-butyl)imidazo[1,2-a]pyridin-3-amine as a beige solid in 78% yield (0.956 g): 1H NMR (300 MHz, CDCl3) δ8.31 (br s, 1H), 7.41-7.33 (m, 1H), 7.29 (s, 1H), 7.17-7.10 (m, 1H), 2.70 (br s, 1H), 1.16 (s, 9H); MS (ES+) m/z 267.9 (M+1), 270.0 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[C:3]=1[F:23]>CO.[Pd].C>[F:10][C:5]1[C:6]([F:9])=[C:7]([F:8])[CH:2]=[C:3]([F:23])[C:4]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(Br)c2F)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2c(F)cc(F)c(F)c2F)cc1
Reaction time: 4 h
Yield: 40.8 %

Procedure:
1-Bromo-2,4,5,6-tetrafluoro-3-[(4-methoxyphenyl)aminosulfonyl]benzene (250 mg, 0.6 mmol) (Example 5) was dissolved in methanol (25 ml) and placed in a closed vessel. A catalytic amount of 10% Pd/charcoal (25 mg) was added and the mixture was hydrogenated at 60 psi H2 for 4 h. The mixture was filtered through celite, the solvent was evaporated and the residue was purified by chromatography (silica; EtOAc/Hexane, 1:4) to yield 82 mg of the title compound. 1H-NMR (CDCl3): δ 7.10 (2H, dd, J=9.0 and 2.0 Hz), 6.94 (1H, br s), 6.85 (1H, m). 6.79 (2H, dd, J=9.0 and 2.0 Hz), 3.75 (3H, s). MS(EI): 335 (20, M+), 122 (100). Anal. Calcd. for C13H9F4NO3S: C, 46.57; H, 2.71; N, 4.18; S, 9.56. Found: C, 46.46; H, 2.67; N, 4.17; S, 9.52.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10]/[C:9](=[CH:13]\N(C)C)/[C:8]1=O)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]1[C:8]2[N:45]=[C:43]([NH:42][C:32]3[CH:33]=[CH:34][C:35]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:30]([O:29][CH3:28])[CH:31]=3)[N:44]=[CH:13][C:9]=2[CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(O[Si](C)(C)C(C)(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O[Si](C)(C)C(C)(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-(tert-butyl-dimethyl-silanyloxy)-6-[1-dimethylamino-meth-(E)-ylidene]-cyclohexanone (80 mg, 0.28 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (74 mg, 0.20 mmol) using in analogous manner the procedure described in example 45b). Obtained as an orange gum (27 mg, 29%). MS ISP (m/e): 466.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.49 (s, 1H), 8.32 (s, 1H), 7.72 (d, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.18 (d, 1H), 7.02 (s, 1H), 4.60 (m, 1H), 3.78 (s, 3H), 2.60-2.70 (m, 1H), 2.14 (s, 3H), 1.86 (m, 3H), 1.72 (m, 1H), 0.85 (s, 9H), 0.20 (s, 3H), 0.05 (s, 3H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH:15][C:26](=[O:27])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(N)c2cc([N+](=O)[O-])ccc2n1
Reactant: CC(C)(C)N=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCNc1nc(NC(=O)NC(C)(C)C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To 5 ml of a solution of 165 mg (0.67 mmol) of 2-allylamino-4-amino-6-nitroquinazoline in THF was added 17 mg (10.7 mmol) of sodium hydride. After the mixture was stirred under ice cooling for 0.5 hour, 76 mg (0.77 mmol) of t-butylisocyanate was added, followed by stirring for 1.5 hours at room temperature. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 79 mg (yield: 34.2%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:24][CH2:25][CH:26]([O:29][N:30]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:27][OH:28]>>[OH:24][CH2:25][CH:26]([O:29]/[N:30]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH2:27][OH:28]
Reactant: O=C1c2ccccc2C(=O)N1OC(CO)CO
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OC(CO)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 54 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propane-1,3-diol (intermediate B) in 54% yield using the same procedure as described in the synthesis of example 22 and example 7A. 1H-NMR (400 MHz, CD3OD), δ ppm 9.40 (s, 1H), 8.86 (dd, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.22 (s, 2H), 4.46 (t, 1H), 3.87 (d, 4H), 2.42 (s, 3H). LCMS (method B): [MH]+=394, tR=1.86 min.
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](C)([CH3:28])[O:25][C@@H:24](CC(N(OC)C)=O)[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].S(=O)(=O)(O)[OH:41]>C(#N)C>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](=[O:41])[CH2:28][C@H:24]([OH:25])[CH2:23]2)=[C:9]([CH:37]([CH3:39])[CH3:38])[N:8]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(-c3ccc(F)cc3)nc(N(C)S(C)(=O)=O)nc2C(C)C)OC(C)(C)O1
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 3 h
Yield: 82 %

Procedure:
E-(6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (5.0 g), acetonitrile (30.0 mL), and sulfuric acid (0.47 mL) were added to a reactor and then the reaction mixture was stirred at 50˜60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and then ethyl acetate (30.0 mL) and water (30.0 mL) were added thereto. The separated organic layer was dried under reduced pressure to obtain E-6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (3.4 g, yield 82%).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:28][CH2:27][CH2:26][CH2:25][OH:24])[CH2:11][CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCCCCBr
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.05 g of 4-(diphenylmethoxy)piperidine was dissolved in 10 ml of N,N-dimethylformamide; 0.57 ml of 4-bromobutyl acetate and 652 mg of potassium carbonate were added, followed by stirring at 50 9 for 3 hours. Ice water was added, followed by extraction with ethyl ether; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 15 ml of ethanol; 8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 1 hour. After the mixture was concentrated under reduced pressure. The residue was neutralized with 1 N hydrochloric acid, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure, the crystal precipitate was collected, washed with ethyl ether and dried to yield 1.21 g of the title compound.
Reaction SMILES: [CH2:1](I)[CH3:2].[F:4][C:5]1([F:49])[CH2:10][CH2:9][CH:8]([C:11]2[C:20]3[CH:19]([OH:21])[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15]=3[N:14]=[C:13]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=4)[CH2:26][CH2:25]3)[C:12]=2[CH:37]([F:48])[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH2:7][CH2:6]1>>[F:49][C:5]1([F:4])[CH2:6][CH2:7][CH:8]([C:11]2[C:20]3[CH:19]([OH:21])[CH2:18][C:17]([CH3:22])([CH3:23])[CH2:16][C:15]=3[N:14]=[C:13]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:35]=[CH:34][C:33]([O:36][CH2:32][C@@H:33]([O:36][CH:2]5[CH2:1][CH2:17][CH2:18][CH2:19][O:21]5)[CH3:34])=[CH:32][N:31]=4)[CH2:28][CH2:29]3)[C:12]=2[CH:37]([F:48])[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=2)[CH2:9][CH2:10]1
Reactant: CCI
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: C[C@@H](COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1)OC1CCCCO1

Procedure:
Reactions similar to those of Example 13 were performed except for using (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methyl benzene sulfonate which was synthesized by the method described in P. Huszthy et al., Journal of Organic Chemistry, 1992, Vol. 57, pp. 5383-5394, instead of ethyl iodide, and from 50 mg (77 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 49 mg (62 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5-{[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH:3]=[C:4]([C:7]#[N:8])[C:5]#[N:6].[Na+].[Cl-].[BH4-].[Na+].Cl>C(OCC)(=O)C.C(O)C>[CH2:3]([CH:4]([C:7]#[N:8])[C:5]#[N:6])[C:2]([CH3:10])([CH3:9])[CH3:1]
Reactant: CC(C)(C)C=C(C#N)C#N
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)CC(C#N)C#N
Reaction time: 0.5 h

Procedure:
To the 500 mL round bottom flask with the product from Example 10A was added 100 mL ethanol. The mixture was cooled in an ice bath (NaCl was added to the bath to keep the temperature below 0° C.) and sodium borohydride was added. The mixture was stirred for 30 minutes. 160 mL 0.5 N HCl solution was added carefully and ethyl acetate was used to extract the mixture twice. Brine was added to help the layers to separate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude title compound was used directly in the following steps without further purification. MS (ESI) m/z 135.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=4)[CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Reactant: Cc1cc(Cl)cc(C)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2cc(C)nc(C)c2)CC1
Temperature: 150 °C
Reaction time: 25 h
Yield: 92.7 %

Procedure:
To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) were added triethylamine (0.05 ml) and 4-chloro-2,6-dimethylpyridine (Journal of Heterocyclic Chemistry, vol. 27, p. 1841 (1990)) (45 mg) and the mixture was stirred at 150° C. for 25 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (160 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.O.NN>[Ni].C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCc2cc(N)ccc21

Procedure:
Approximately 400 mg of Raney nickel is added to a mixture of 2.84 g (15.9 mmole) of −1-methyl-5-nitroindoline and 4 ml (80 mmole) of hydrazine hydrate in 60 ml of absolute ethanol. The reaction mixture is heated to reflux for 5 hours. After returning to 23° C., a little silica is added to the flask and the solvent is evaporated off under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a Heptane/AcOEt mixture (3/7). A violet powder is obtained (65%) which is used directly in the following stage.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1>O.O.CC1C=CC(S(O)(=O)=O)=CC=1>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][C:10]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:11]1
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: N#Cc1ccccc1NC1=CC(=O)CCC1
Yield: 92.8 %

Procedure:
A mixture of 2-aminobenzonitrile (120 g) and 1,3-cyclohexandione (120 g) in water (400 ml) was heated to 40° and 4-methylbenzenesulfonic acid monohydrate (6.2 g) was added, with stirring. The mixture was stirred at 40° for 1 hr. The mixture was filtered, and the filter cake was washed with water to provide 200 g (93%) of 2-(3-oxocyclohexen-1-yl)aminobenzonitrile, mp 191.4°.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][N:16]([C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][N:16]([C@@H:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH3:21])[CH2:15]3)=[CH:12][CH:13]=2)[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC3CCCCC3)cc2)C1
Agent: C=O
Agent: [Na+]
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)C3CCCCC3)cc2)C1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of (S)-2-(4-(cyclohexylamino)phenyl)-4-((R)-1-phenylethyl)morpholine (6.95 g, 19.1 mmol) and formalin (35%, 8.18 ml, 95.4 mmol) was added sodium triacetoxyborohydride (12.1 g, 57.2 mmol) at room temperature. After stirring for 30 minutes, the resulting suspension was partitioned between ethyl acetate and 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-20% ethyl acetate in hexane to furnish (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)-4-((1R)-1-phenylethyl)morpholine (7.27 g, quant.) as a pale yellow oil.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH2:45]1[C:55]2=[C:56]3[C:51](=[CH:52][CH:53]=[CH:54]2)[C:50]([CH2:57][NH:58][CH3:59])=[CH:49][CH:48]=[C:47]3[CH2:46]1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH2:45]1[C:55]2=[C:56]3[C:51](=[CH:52][CH:53]=[CH:54]2)[C:50]([CH2:57][N:58]([CH3:59])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]2[CH:18]=[N:19][C:13]4[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]5[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[CH2:15][C:14]=4[CH:16]=2)=[CH:49][CH:48]=[C:47]3[CH2:46]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1ccc2c3c(cccc13)CC2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2c3c(cccc13)CC2)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting acenaphthen-5-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (175 mg, 43%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.15-10.11 (m, 2H), 8.41-8.33 (m, 1H), 7.98-7.96 (m, 1H), 7.88-7.74 (m, 1H), 7.60-7.44 (m, 2H), 7.38-7.12 (m, 4H), 5.23-5.01 (m, 2H), 4.55-4.46 (m, 2H), 4.00-3.96 (m, 2H), 3.86-3.36 (m, 10H), 3.12-2.89 (m, 7H); MS (ESI) m/e 512 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21]Br)[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].[S-:26][C:27]#[N:28].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:24])[CH2:19][C:20](=[O:23])[CH2:21][S:26][C:27]#[N:28])[C:15](=[O:25])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2]
Reactant: N#C[S-]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2SC1
Agent: [K+]
Solvent: CC#N
Product: N#CSCC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
A mixture of 3-carbamoyloxymethyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (0.52 g.) and potassium thiocyanate (0.174 g.) in acetonitrile (10 ml.) was stirred for 6 hours at room temperature, and then acetonitrile was distilled off therefrom. To the residue were added ethyl acetate (50 ml.) and a saturated aqueous solution of sodium chloride (20 ml.), and the mixture was adjusted to pH 2 with 50% phosphoric acid with stirring, and then ethyl acetate layer was separated therefrom. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off therefrom. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(3-oxo-4-thiocyanatobutyramido)-3-cephem-4-carboxylic acid (0.36 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N+:26]([O-])=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.CO.[H][H]>[Ni].O1CCCC1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:29]=[CH:30][C:2]([Cl:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCNc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 70.5 %

Procedure:
A mixture of 64 parts of 5-chloro-1,3-dihydro-1-{1-[3-(2-nitrophenylamino)propyl]-4-piperidinyl}-2H-benzimidazol-2-one in 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 10 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanol and ethanol. The product is filtered off and dried, yielding 42 parts (70.5%) of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][O:26][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (95.4 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(pyridin-3-yloxy)propanamide (91.3 mg).