Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:19]3[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]3)[C:7]=2[CH:6]=1>C1C=CC=CC=1>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:19]3[CH2:24][CH2:23][N:22]([C:2]#[N:1])[CH2:21][CH2:20]3)[C:7]=2[CH:6]=1
Reactant: N#CBr
Reactant: CN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Solvent: c1ccccc1
Product: N#CN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 55 °C

Procedure:
A solution of cyanogen bromide (14.1 g., 0.133 mol) in benzene (200 ml) at 35° C. is treated with a solution of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine (31.2 g., 0.10 mol) in benzene (250 ml.) over 15 minutes. The solution is heated to 55° C. for four hours. The solvent is evaporated and the residue is recrystallized from ethanol to give 4-(2-chloro-9-xanthenylidene)-1-cyanopiperidine, m.p. 148°-150° C. A solution of the latter (27.2 g., 0.084 mol) in glacial acetic acid (450 ml.), water (250 ml.) and concentrated hydrochloric acid is refluxed for 18 hours, and the major portion of the solvent is evaporated. The residue is basified and extracted with ethylacetate. The extracts are washed with water and the solvent evaporated. The residue is triturated with ethanol, filtered and the filtrate is evaporated to leave 4-(2-chloro-9-xanthenylidene)piperidine. The free base is dissolved in acetonitrile and treated with one equivalent of methanesulfonic acid to yield 4-(2-chloro-9-xanthenylidene)piperidine methanesulfonate, m.p. 256°-260° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O.[CH2:8]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH2:8]([O:15][C:16]([CH2:17][CH2:18][NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: NCCC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)CCNCCC(=O)OCc1ccccc1

Procedure:
3-Aminopropionic acid (5 g, 56 mmol) was added to ethanol (50 mL), and TEA (7.8 ml, 56 mmol) and water (50 mL) were added and the mixture was refluxed under nitrogen. Acrylic acid benzyl ester ((9.1 g, 56 mmol) and more ethanol (50 mL) were added, and the mixture was refluxed for 16 h. The sample was concentrated under vacuum, adding toluene and reevaporating twice to yield 17.5 grams (product plus TEA).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][N:21]3[Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[C:13]([C:36]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:12]=1)C1C=CC=CC=1>[OH-].[K+].CO.O.O>[NH2:10][C:11]1[CH:12]=[C:13]([C:36]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:37])[CH:14]=[C:15]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)[CH:16]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cc(NC(=O)OCc4ccccc4)cc(C(=O)c4cccnc4)c3)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)c2cccnc2)cc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
[3-(Pyridine-3-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid benzyl ester (40 mg, 0.066 mmol) in 40% KOH in MeOH/H2O (5 mL/5 mL) was brought to reflux for 2 hours. After cooling down to room temperature, the mixture was diluted with water, and extracted with EtOAc. The organic layers were separated, dried and concentrated. Purification on silica gel afforded [3-amino-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone as a yellow solid (11.9 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 9.01 (d, J=1.6 Hz, 1H), 8.71 (dd, J=4.8, 1.7 Hz, 1H), 8.29 (s, 1H), 8.09 (dt, J=4.9, 2.6 Hz, 1H), 7.38-7.31 (m, 3H), 7.20-7.15 (m, 4H), 7.11-7.07 (m, 2H) 6.64-6.60 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:14][CH2:13]3)[NH:19][N:18]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A mixture of 2,4-dichloro-5-nitropyrimidine (2 g) and 5-cyclopropyl-1H-pyrazol-3-amine (2 g) in acetonitrile (20 mL) with diisopropylethylamine (2 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 2.1 g desired product. MS (electrospray): 281 (M+1) for C10H9ClN6O2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A suspension of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (400 mg) and potassium carbonate (300 mg) in DMF (5 ml) was mixed with 4-fluoronitrobenzene (290 mg). After 2 hours, the reaction mixture was poured into water, and the resulting precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified after concentration by chromatography. The product with the molecular weight of 319.36 (C16H21N3O4); MS (ESI): 320 (M+H+) was obtained in this way.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:18]([N+:27]([O-])=O)=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)[CH2:9][CH2:8]1.O.NN>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:18]([NH2:27])=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12]1
Reactant: NS(=O)(=O)c1cccc(CCCCN2CCN(c3ncccn3)CC2)c1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1c(CCCCN2CCN(c3ncccn3)CC2)cccc1S(N)(=O)=O
Reaction time: 0.5 h

Procedure:
0.06 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl-2-nitrobenzenesulphonamide is dissolved in 500 ml of MeOH, 2.4 g of 5% Pd-C are added, the mixture is heated to boiling and 0.17 mol of hydrazine hydrate in 50 ml of MeOH is added dropwise within 15 minutes. After boiling for a further 30 minutes, the mixture is filtered, the filtrate is evaporated, the residue is taken up in diethyl ether, washed with water, evaporated again and crystallised from isorpopanol/isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[N:47]([CH:49]=[O:50])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:49]([NH2:47])=[O:50]
Reactant: COc1cc2ncc(I)c(Cl)c2cc1OC
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Temperature: 100 °C

Procedure:
A stainless steel cylinder was charged with 4-chloro-3-iodo-6,7-dimethoxyquinoline (0.200 g, 0.572 mmol), palladium(II) acetate (0.013 g, 0.057 mmol), 1,3-bis(diphenylphosphino)propane (0.047 g, 0.11 mmol), DMF (2 mL), and 1,1,1,3,3,3-hexamethyldisilazane S (0.37 g, 0.48 mL, 2.3 mmol). The cylinder was sealed and pressurized with CO gas at 30 psi. The system was heated at 100° C. for 1.5 h and then cooled to RT. The mixture was concentrated to afford an orange solid. This material was triturated with dichloromethane and the resulting precipitate was filtered and dried to afford 4-chloro-6,7-dimethoxyquinoline-3-carboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 267.0 (M+H). Mass Calc'd for C12H11ClN2O3: 266.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved in dichloromethane (45 ml) and stirred at room temperature. Ethyl bromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (2.31 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (3.41 g, 77%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 3.25 g (73%); mp 126.5°-127° C.; [α]D22 -2.5° (c 1.01, EtoH). IR and 1H-NMR spectra, and Rf value of the product are completely identical with those of (1R,2S)-form mentioned in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 2,4-difluoro-phenylamine (1, 7.0 mL, 70.0 mmol) in 100 mL of dichloromethane, pyridine (11 mL, 140.0 mmol) and benzyl chloroformate (2, 11.9 mL, 83.4 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and potassium bisulfate solution. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum and crystallized from hexanes to give the desired compound (3, 15.6 g, 85%).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([OH:23])[C:20]([OH:24])=C(O)C=2)[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:30])[CH:12]1[CH:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]>CC(C)=O>[C:8]([N:11]1[CH:16]=[C:15]([C:17]2[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:20]([O:24][C:1](=[O:3])[CH3:2])=[C:21]([O:23][C:5](=[O:4])[CH3:6])[CH:22]=2)[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:13](=[O:30])[CH:12]1[CH:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]
Reactant: CC(=O)N1C=C(c2cc(O)c(O)c(O)c2)N(CC(=O)O)C(=O)C1C(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Oc1cc(C2=CN(C(C)=O)C(C(C)C)C(=O)N2CC(=O)O)cc(OC(C)=O)c1OC(C)=O

Procedure:
Acetic anhydride is added to a suspension of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (630 mg, Reference compound No. 62-2) in acetone (10 ml), and the mixture is stirred for one week. The reaction mixture is concentrated under reduced pressure to give the titled reference compound (790 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:29]([C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin4-amine and trans-2-phenyl-1-cyclopropanecarbonyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-(trans)-2-phenylcyclopropane-1-carboxamide as an off white solid, m.p. 77.0° C. 1H NMR (300 MHz, DMSO-d6) δ 7.90 (dd, J=8.1, 1.2 Hz, 1H), 7.81 (dd, J=8.1, 1.2 Hz, 1H), 7.78 (s, 1H)? 7.50 (dt, J=8.1, 1.5 Hz, 1H), 7.33-7.15 (m, 4H), 7.05-7.02(m, 2H), 5.84 (broad s, 1H), 5.51 (s, 2H), 4.52 (t, J=7.2 Hz, 2H), 3.32 (q, J=6.6 Hz, 2H), 2.49-2.43 (m, 1H), 2.07-1.95 (m, 3H), 1.64-1.51 (m, 3H), 1.25-1.18 (m, 1H); IR (KBr) 3304, 3179, 2939, 1640, 1582, 1527, 1479, 1396, 1250, 755, 735, 689 cm−1; MS (EI) m/e 399.2059 (399.2059 calcd for C24H25N5O).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[O:32])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCNCC3)c12
Reactant: COc1ccc(N=C=O)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of Example 20 (70 mg, 0.23 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-methoxyphenyl isocyanate (31 μL, 0.24 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 3% methanol in dichloromethane), yielding the title compound (61 mg) as a white powder. 13C NMR δ (75 MHz, CD3OD) 171.65, 162.60, 160.54, 159.64, 155.32, 154.73, 133.60, 127.71, 124.13, 121.41 (2C), 113.30 (2C), 106.19, 60.79, 54.73, 47.93 (2C), 43.38 (2C), 13.73. MS (m/z) 457 [M+H]+.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH3:26])[C:20]([CH3:27])=[CH:19][N:18]=1.[OH-].[Na+]>C(O)C.O>[CH2:25]([O:24][C:21]1[C:20]([CH3:27])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[C:22]=1[CH3:23])[CH3:26]
Reactant: CCOc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
5.82 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 200 ml of ethanol and the suspension was treated with 7.1 g 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×300 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from acetonitrile gave 6-[[(4-ethoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 184°-185°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:30])([CH3:29])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:17][C:18]1[CH:35]=[CH:34][C:21]2[N:22]([CH2:32][CH3:33])[C:23](=[O:31])[C:24]([CH3:29])([CH3:30])[C:25](=[O:28])[N:26]([CH3:27])[C:20]=2[CH:19]=1)[CH2:8][C:9]1[C:10]([CH3:16])=[N:11][C:12]([O:15][CH3:39])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(=O)[nH]c3C)C(=O)OC(C)(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc(OC)nc3C)C(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl)carbamic acid tert-butyl ester (536 mg) was dissolved in DMF(20 ml), and was cooled to 0° C. in ice water bath. Sodium hydride (60% in oil, 56.1 mg) was added thereto at the same temperature, and the mixture was stirred at 0° C. for 0.5 hours. Methyl iodide (0.081 ml) was added thereto, and the mixture was stirred at 0° C. for 0.5 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1). The purified product was condensed to dryness under reduced pressure to give the title compound(550 mg) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([O:18]C)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CC(C)=O.Cl>O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:18])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Reaction time: 3.5 h

Procedure:
To a solution of (±)-6-acetoxy-2-methoxy-2,5,7,8-tetramethylchroman in 2500 ml. of acetone was added 2000 ml. of H2O followed by 16.6 ml. of concentrated aqueous HCl. Solvent was distilled from the stirred mixture until the head temperature reached 90° centigrade. The suspension was cooled in an H2O bath to 50° centigrade. At 70° centigrade, 2000 ml. of acetone was added, giving a clear solution. The solution was seeded occasionally until crystallization began. After 3.5 hours, 1500 ml. of H2O was added and the suspension was cooled in an ice bath. The solid was removed by filtration, washed with H2O and dried at 50° centigrade/0.1 mmHg. to give (±)-6-acetoxy-2-hydroxy-2,5,7,8-tetramethylchroman as a granular yellow-tan solid, sintering from 114° centigrade, m.p. 127°-132° centigrade.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[OH:15][CH2:16][C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:25])=[O:18].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:35]1([CH2:34][NH:33][C:31]([N:27]2[CH2:28][CH2:29][CH2:30][C@H:26]2[C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[C:17](=[O:18])[CH2:16][O:15][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:25])=[O:32])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reaction time: 17 h

Procedure:
Triethylamine (0.59 ml), pivaloyl chloride (0.43 ml) were added, under ice-cooling, to a methylene chloride solution (25 ml) of (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.26 g) obtained in Example 5 and the mixture was stirred for 17 hours. The reaction mixture was poured into 5% potassium hydrogensulfate and extracted with methylene chloride. The extract was washed with saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.21 g) (see Table 1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH:7]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[N:16][N+:17]([O-:19])=[O:18])[CH2:6][O:5]1.[C:20](Cl)(=[O:22])[CH3:21]>C(#N)C>[CH3:21][C:20]([N:12]1[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][CH:7]2[CH2:6][O:5][CH:4]([CH3:3])[CH2:8]2)[C:11]1=[N:16][N+:17]([O-:19])=[O:18])=[O:22]
Reactant: CC(=O)Cl
Reactant: CC1CC(CN2CCCNC2=N[N+](=O)[O-])CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCCN(CC2COC(C)C2)C1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a suspension of 0.20 g of sodium hydride (60%, oily) in 30 ml of acetonitrile was added a solution of 1.00 g of 1-[(2-methyl-4-tetrahydrofuryl)methyl]-2-(nitroimino) hexahydropyrimidine in 5 ml of acetonitrile at room temperature, followed by stirring for 30 minutes. Next, to the mixture was added a solution of 0.39 g of acetyl chloride in 5 ml of acetonitrile under ice-cooling, and the mixture was then stirred under ice-cooling for 30 minutes and at room temperature for 3 hours. Afterward, insolubles were removed by filtration, and the filtrate was then concentrated under a reduced pressure. The resultant oily substance was purified by silica gel column chromatography (20:1 chloroform/methanol) to obtain 1.15 g of 1-(methylcarbonyl)-3-[(2-methyl-4-tetrahydrofuryl) methyl]-2-(nitroimino)hexahydropyrimidine as a yellow oil.
Reaction SMILES: [H-].[Na+].O1CCCC1.[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:18]([Sn:22]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23]I)[CH2:19][CH2:20][CH3:21]>C(OCC)(=O)C>[CH2:18]([Sn:22]([CH2:23][O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)COCCCN1CCOCC1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 150 %

Procedure:
To a mixture of sodium hydride (60%, 278 mg, 6.96 mmol) and tetrahydrofuran (20 ml) was added N-(3-hydroxypropyl)morpholine (963 μl, 6.96 mmol) at room temperature. Then, the reaction mixture was stirred at 45° C. (external temperature) for 10 minutes. To the reaction mixture was added tributyl-iodomethyl-tin (2.0 g, 4.64 mmol) at 0° C. (external temperature). Then, the mixture was stirred at 45° C. for 1 hour. The reaction mixture was cooled at room temperature, diluted with ethyl acetate, washed sequentially with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, heptane:ethyl acetate=9:1) to obtain the title compound (2.08 g, 6.96 mmol, 100%).