Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=S)[CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3]1.[BH4-].[Na+].O>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([N+:15]([O-:17])=[O:16])([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:3]1
Reactant: CN1CC(c2ccncc2)([N+](=O)[O-])CCC1=S
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCC(c2ccncc2)([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a solution of 105 mg (0.418 mmol) rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4′]bipyridinyl-6-thione in 2.1 ml methanol was added 144 mg (3.8 mmol) NaBH4. The mixture was stirred at room temperature for 20 minutes. Water (1.0 ml) was added. The mixture was stirred for 1 hour. The methanol was removed in vacuo. The residue was diluted with water and extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 53 mg (57%) of the title compound as a yellow oil. MS (m/e): 222.3 (M+H).
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[F:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.O.Cl>O1CCCC1.C(OCC)(=O)C>[OH:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[P:2]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccccc1-c1ccccc1P(c1cccc(F)c1)c1cccc(F)c1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
16.4 g (70 mmol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 80 ml of anhydrous tetrahydrofuran are introduced, in an argon atmosphere with stirring, and a 2M solution of 140 mmol of 3-fluorophenylmagnesium bromide in tetrahydrofuran is added dropwise. The temperature increases in the course of this from 25° to 45° C. The mixture is then stirred for 12 hours at 65° C., cooled to room temperature and 100 ml of water and 100 ml of ethyl acetate are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 25.8 g of colorless oil are obtained. By crystallization with methanol/water, 10:1, 19.8 g (71%) of colorless crystals having melting point 161° to 163° C. are obtained.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: Nc1ccccc1
Reactant: C/C(=C\Sc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of 2.5 g (12.8 mmol) of (E)-2-methyl-3-(phenylthio)-2-propenoic acid and 3.5 g (25.7 mmol) of thionyl chloride in 25 ml of toluene was refluxed for 1 hour and then concentrated under vacuum. The residue was dissolved in 25 ml of ethyl acetate and cooled in ice bath. To the solution was added dropwise 2.9 g (32 mmol) of aniline and stirred at room temperature for 30 minutes. The reaction mixture was washed sequentially with 1N HCl solution, a saturated NaHCO3 solution, and a saturated NaCl solution. The organic layer was dried over anhydrous MgSO4 and concentrated to obtain 3.0 g of (E)-2-Methyl-N-phenyl-3-(phenylthio)-2-propenamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[C:25]=1[Cl:27]
Reactant: Fc1cncc(Br)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1cncc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (0.48 mL, 0.0034 mol) in dry tetrahydrofuran (10 mL) was added 1.6 M n-butyl lithium in hexane (2.39 mL, 0.00369 mol) drop wise under nitrogen atmosphere at −78° C. and stirred for 30 min at −78° C. To the above stirred mixture was added a solution of 3-bromo-5-fluoropyridine (0.5 g, 0.00284 mol) in dry tetrahydrofuran at −78° C. and stirred for 45 min. After 45 min, a solution of hexachloroethane in dry tetrahydrofuran was added to the above reaction mixture at −78° C. and stirred for 30 min at −78° C. The reaction mixture was slowly warmed to RT and stirred for 1 h. The reaction was quenched with saturated solution of ammonium chloride (10 mL) and extracted with diethyl ether (25 mL x 3). The combined organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. The obtained crude was purified with silica gel chromatography by hexane to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.58 (s, 1H), 8.43 (s, 1H). MS (M+1): 209.9.
Reaction SMILES: [C:1]([N:4]1[CH2:23][CH2:22][CH2:21][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:39]([O:41][C:42](=[O:51])[C@:43]([C:46](=[O:50])[N:47]([CH3:49])[NH2:48])([CH3:45])[OH:44])[CH3:40]>C(Cl)Cl.O1CCCC1>[CH2:39]([O:41][C:42](=[O:51])[C@:43]([C:46](=[O:50])[N:47]([CH3:49])[NH:48][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6](=[O:7])[C@@H:5]1[CH2:21][CH2:22][CH2:23][N:4]1[C:1](=[O:3])[CH3:2])([CH3:45])[OH:44])[CH3:40]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@](C)(O)C(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@](C)(O)C(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Acetylprolylalanylproline (2 mmole) is dissolved in methylene chloride (5 ml) containing N-methylmorpholine (2 mmole) and diluted with dry tetrahydrofuran (400 ml). To this stirred solution at -20° to -25° is added isobutyl chloroformate (2 mmole) and the mixture is stirred for 15 minutes. A solution of 2-azaalanyl-l-lactic acid ethyl ester (2 mmole) in tetrahydrofuran (2 ml) is then added. The mixture is allowed to warm to room temperature over a period of 1 hour and stirred for a further 3 hours. The mixture is filtered, and the filtrate is evaporated to dryness. Chromatography on silica gel (38 gm) and elution with 5% methanol in chloroform gives acetylprolylalanylprolyl-2-azaalanyl-l-lactic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[CH2:7]([O:13][S:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:16])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:17]([S:14]([O-:16])(=[O:15])=[O:13])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: CCCCCCOS(=O)(=O)CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCS(=O)(=O)[O-]
Product: CCCCCCn1cc[n+](C)c1
Temperature: 80 °C
Reaction time: 25 h
Yield: 94.3 %

Procedure:
To a 50 ml four necked flask equipped with a stirrer, a dropping funnel, cooling tube and a thermometer, 41.05 g (0.5 mol) of 1-methyl imidazole and 50 ml of toluene were charged and, after heating at 80° C., 146.52 g (0.55 mol) of dihexyl sulfonic acid was dropped slowly taking one hour or more. They were stirred at a refluxing temperature for 25 hours. After cooling, solvent cleaning was conducted with toluene to obtain 156.83 g of 1-methyl-3-hexyl-imidazolium hexyl sulfonate salt by drying under a reduced pressure. Then, 99.13 g of the obtained 1-methyl-3-hexyl imidazolium hexyl sulfonate salt was dissolved in 80 ml of water, and a solution in which 139.24 g of lithium bis(trifluoromethane sulfonyl) imide was dissolved in 80 ml of water was added thereto at a room temperature and stirred. From separated two layers, the lower layer was fractionated and by-products were removed by adding 40 wt % of purified water and by water washing five times, and vacuum drying was applied to obtain 197.31 g of 1-methyl-3-hexyl imidazolium bis(trifluoromethane sulfonyl) imide. As a result of ICP analysis, the total alkali metal was 2.7 ppm or less, the chloride ion was 0.7 ppm and each of iodide and bromide ions was 0.1 ppm or less (less than ICP detection limit).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18](=[O:29])[N:19]([CH2:26][CH2:27][F:28])[CH:20]4[CH3:25])[C:12]([C:30]([F:33])([F:32])[F:31])=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45]>C1COCC1.C(OCC)(=O)C>[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18](=[O:29])[N:19]([CH2:26][CH2:27][F:28])[CH:20]4[CH3:25])[C:12]([C:30]([F:32])([F:33])[F:31])=[CH:11][N:10]=2)=[C:4]([O:34][CH3:35])[CH:3]=1)(=[O:46])[CH:44]=[CH2:45]
Reactant: COc1cc(N)ccc1Nc1ncc(C(F)(F)F)c(Nc2cccc3c2C(=O)N(CCF)C3C)n1
Reactant: C=CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(CCF)C4C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
311 mg (0.634 mmol) 2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 10 ml THF and combined with 115 μl (0.824 mmol) triethylamine and 62 μl (0.761 mmol) acrylic chloride. This mixture is stirred for 1 h at ambient temperature. Then it is diluted with ethyl acetate and extracted three times with water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1)([O-:3])=[O:2].[N:18]([C:21](OCC)=O)=C=S.[Cl-].O[NH3+].C([N:32](CC)C(C)C)(C)C>CO.C(O)C.CS(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:32]=[C:21]([NH2:18])[N:14]=[C:10]2[CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cc(Oc2cccc([N+](=O)[O-])c2)ccn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)N=C=S
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CS(C)=O
Solvent: CCO
Solvent: CO
Product: Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1
Yield: 38.6 %

Procedure:
In the same manner as in Example 17-1 and using 4-(3-nitrophenoxy)pyridin-2-amine (250 mg, 1.08 mmol), ethyl isothiocyanatoformate (184 mg, 1.41 mmol), DMSO (5 mL), hydroxylammonium chloride (525 mg, 7.56 mmol), N,N-diisopropylethylamine (940 μL, 5.40 mmol), ethanol (10 mL) and methanol (10 mL) as starting materials, the title compound (113 mg, 39%) was obtained as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:19][CH:18]=2)[CH:14]=[C:15]1[C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: BrCc1ccccc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3Cc2ccccc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and benzyl bromide. The title compound was obtained in 4% yield as white solid. MS (m/e): 462.2 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:27]#[C:28][C:29]([CH3:32])([OH:31])[CH3:30])=[CH:10][CH:11]=3)[N:6]=1.[CH3:33]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:31][C:29]([CH3:32])([CH3:30])[C:28]#[C:27][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(C#CC(C)(C)O)ccc2O3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3ccc(C)cc3)cnc1O2

Procedure:
A vial was charged with (S)-4-(2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)-2-methylbut-3-yn-2-ol (134.5 mg, 0.316 mmol), MeOH (3161 μL), and methanesulfonic acid (103 μL, 1.581 mmol). The vial was sealed and placed in a 70° C. oil bath for 4 hours. The mixture was poured into saturated aq. sodium bicarbonate solution (30 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column to give a impure material that was dissolved in methanol and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol, and the mixture was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-7-(3-methoxy-3-methylbut-1-ynyl)-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O.O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[N:18][N:17]=2)=[CH:14][CH:15]=1
Reactant: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
A mixture of methyl 4-[5-[4-(6-methoxy-n-hexyloxy)-phenyl]-1,3,4-thiadiazol-2-yl]benzoate (179.6 g), sodium hydroxide (25.3 g), water (250 ml), methanol (1 L), and tetrahydrofuran (750 ml) was heated under refluxing for 1 hour then cooled to room temperature and poured into water (7 L). The pH of the stirred mixture was adjusted to 2.0 with 6N-hydrochloric acid and the precipitate collected by filtration, washed thoroughly with water, followed by acetonitrile, then dried under hi-vacuum at 50° C. to give 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid (167 g) as a yellow powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=O.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:39]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
HATU (230 mg, 0.605 mmol) and aniline (0.063 mL, 0.691 mmol) was added to a solution of 3-aminobenzoic acid hydrochloride (100 mg, 0.576 mmol) and N,N-diisopropylethylamine (0.217 mL, 1.267 mmol) in 1.5 mL of DMF. The reaction solution was stirred at RT for 3 h. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 20% to 45%. Desired fractions were collected and the solvents were removed under reduced pressure. The residue was passed through 2 g SCX column and washed by 2M NH3 in MeOH to provide 3-amino-N-phenylbenzamide (42 mg, 0.198 mmol, 34.4% yield) as a light-yellow solid.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][C:20]1[C:25]([CH3:26])=[C:24]([NH2:27])[N:23]([CH3:28])[C:22](=[S:29])[N:21]=1.CO.N>C(#N)C.O1CCOCC1>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:29][C:22]3[N:21]=[C:20]([NH2:19])[C:25]([CH3:26])=[C:24]([NH2:27])[N+:23]=3[CH3:28])[CH2:7][S:8][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1c(N)nc(=S)n(C)c1N
Agent: N
Solvent: CO
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1c(N)nc(SCC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)[n+](C)c1N
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.1 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid and 1.70 g of 4,6-diamino-1,5-dimethyl-2-(1H)-pyrimidinethione suspended in a mixture of 10 ml of dry acetonitrile and 10 ml of dioxane was cooled to 0° C.; and 4.8 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 50° C.; the solution was stirred for five hours; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.7 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 3.02 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:17]([N:19](CC)CC)[CH3:18].[Cl:24]CC#N.Cl>C(O)C.C(O)(C)C>[ClH:24].[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:17]#[N:19])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: N#CCCl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: N#CCN1CC=C(c2cccc(C(F)(F)F)c2)CC1
Yield: 75 %

Procedure:
A mixture of 0.025 mole of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 3.5 ml of triethylamine and 0.025 mole of chloroacetonitrile in 40 ml of ethanol is heated to reflux for 5 hours. The reaction mixture is cooled, concentrated and the residue is taken up with diethyl ether. The ethereal solution thus obtained is filtered, washed with water and dried over anhydrous sodium sulfate. To the solution thus obtained is added a saturated solution of hydrogen chloride in isopropanol. In this way, the 4-(3-trifluoromethylphenyl)-1-cyanomethyl-1,2,3,6-tetrahydropyridine hydrochloride is obtained which, after crystallization in isopropanol, melts at 169°-172° C. Yield 75% of the theoretical.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[NH2:30][CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:30][CH:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32]3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)N(CC(=O)NC1Cc3ccccc3C1)CC2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-indane
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 118–120° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34–4.24 (m, 2 H), 4.09–4.01 (m, 1 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.93–1.74 (m, 2 H), 1.06–0.98 (m, 1 H), 0.95–0.81 (m, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.44 (m, 2 H), 0.34–0.22 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1099.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:31][CH3:30])=[O:9]
Reactant: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 3-[2,3-Dimethoxy-6-(1-oxo-indan-5-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 205) (100 mg, 0.260 mmol) in dichloromethane, were added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (75 mg, 3.90 mmol), 1-Hydroxybenzotriazole hydrate (HOBT) (80 mg, 0.520 mmol) and triethylamine (0.1 mL, 0.9814 mmol) and 1M methylamine solution (0.4 mL, 0.520 mmol) and the resultant reaction mixture was stirred at 16 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded the title compound as a solid.