Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O.[CH3:24][N:25]([CH:36]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37]1)[C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[ClH:21].[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:35][C:33]3[CH:32]=[CH:31][C:29]4[N:30]=[C:26]([N:25]([CH3:24])[CH:36]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37]5)[S:27][C:28]=4[CH:34]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:35][C:33]3[CH:32]=[CH:31][C:29]4[N:30]=[C:26]([N:25]([CH3:24])[CH:36]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37]5)[S:27][C:28]=4[CH:34]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(OCC2CCCCC2)cc1
Reactant: CN1CCC(N(C)c2nc3ccc(N)cc3s2)C1
Reactant: O=C(Cl)C(=O)Cl
Product: CN1CCC(N(C)c2nc3ccc(NC(=O)c4ccc(OCC5CCCCC5)cc4)cc3s2)C1
Product: Cl

Procedure:
The title compound is prepared by following Method C, using 4-cyclohexylmethoxy-benzoic acid (Crooks, S. L.; Merrill, B. A.; Wightman, P. D. WO 9603983 A1.) (0.46 g, 1.98 mmol), oxalyl chloride (0.66 mL, 7.62 mmol) and isomer-1 of N*2*-methyl-N*2*-(1-methyl-pyrrolidin-3-yl)-benzothiazole-2,6-diamine (0.40 g, 1.51 mmol) to afford 4-cyclohexylmethoxy-N-{2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-benzothiazol-6-yl}-benzamide (0.083 11%). The material is dissolved in EtOH and treated with 1.0 M HCl in EtOH (0.17 mL). Heptane is added and the resulting solid is collected to give 0.052 g (59%) of the hydrochloride salt. LC/MS: Retention time=5.38 min; (m/z): calcd for C27H34N4O2S (M+H)+: 479.7; found: 479.3.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:25][NH2:26])=O)=[CH:18][CH:17]=1.O1CCOCC1>C(O)(=O)C>[Br:1][C:2]1[N:11]=[C:10]([C:12]2[NH:13][C:23]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)=[N:25][N:26]=2)[C:9]([OH:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: N#Cc1nc(Br)c2cccnc2c1O
Reactant: NNC(=O)Cc1ccc(F)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Temperature: 200 °C
Yield: 21.2 %

Procedure:
A suspension of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carbonitrile (0.25 g, 9.99 mmol), 2-(4-fluorophenyl)acetic hydrazide (0.34 g, 2 mmol), 1,4-dioxane (2 mL) and acetic acid was heated at 200° C. for 10 minutes in a microwave chamber. The mixture was allowed to cool to room temperature, the precipitate was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo, 1 N sodium hydroxide and ethyl acetate were added and the aqueous layer was washed with ethyl acetate. The aqueous layer was then acidified to pH 5 and the solids formed were collected. This material was azeotroped with methanol to provide 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (0.17 g, 42%) as a yellow solid. 1H NMR (CDCl3/CD3OD): δ 9.07 (dd, J=4.0, 1.2 Hz, 1 H), 8.50 (dd, J=8.4, 1.2 Hz, 1 H), 7.65 (dd, J=8.4, 4.0 Hz, 1 H), 7.26 (m, 2 H), 6.95 (m, 2 H), 4.11 (s, 2 H); MS m/z 400 (M+1).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[NH2:21][CH2:22][CH:23]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:30][CH2:29]1)[C:24]([O:26][CH3:27])=[O:25].O>ClCCl>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:21][CH2:22][CH:23]([N:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:32][CH2:33]2)[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)C(CN)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CNS(=O)(=O)c1ccc(O)cc1)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 4.2 %

Procedure:
2.1 ml (15 mmol) of triethylamine and then 920 mg (5 mmol) of 4-hydroxybenzenesulfonyl chloride in 20 ml of dichloromethane are added dropwise to a solution of 1.1 g (3 mmol) of benzyl 4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate dihydrochloride in 30 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is then stirred at ambient temperature for 18 h. After the addition of water, the reaction medium is extracted with dichloromethane. The organic phase is with water and then dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 60 mg (46%) of benzyl 4-[2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazine-1-carboxylate are obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
As in Example 115, (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid (4.78 g) and 4-nitrophenol (3.14 g) in 20 mL of dichloromethane was treated with 1,3- dicyclohexylcarbodiimide (3.8 g) and the mixture was stirred at room temperature for 3 days. After the usual work up. crystallization of the crude ester from 2-propanol-hexane gave 4.86 g of (E,E)-5-(4-fluorophenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 71°-72,5° C.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]=[CH2:3].[NH2:14][C@H:15]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:14][C@@H:15]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1)=[O:10])[CH:2]=[CH2:3]
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: C=CCSc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Yield: 176.8 %

Procedure:
3-(Allylthio)benzoic acid (717 mg, 3.69 mmol), (2R,3R)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}butan-2-ol (247 mg, 0.685 mmol), and HATU (Aldrich, 2.1 g, 5.54 mmol) were dissolved in dichloromethane (35 mL), at ambient temperature, and treated with diisopropylethylamine (1.6 mL, 9.225 mmol). Upon completion, the reaction mixture was concentrated and chromatographed (SiO2, 2:1 to 1:1 Hexanes: EtOAc) to give the desired compound (650 mg). (LRMS (M+H) m/z=537.8)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:5]2[S:10](=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[C:5]3[S:10](=[O:11])[CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:26]4[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=4)[CH2:30][CH2:31]3)[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=S1CCc2nc(Cl)nc(Nc3cccc(Cl)c3)c21
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Temperature: 160 °C
Yield: 100 %

Procedure:
1.60 g (2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-(3-chloro-phenyl)-amine (prepared from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 3-chloroaniline as described in Example 28, see scheme 2), 2.30 g 1-(4-nitro-phenyl)-piperazine and 1.00 ml diisopropylethylamine are placed in 10 ml dioxane, then heated to 160° C. in the microwave for 0.75 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered. The precipitate is extracted first with water, then with ethanol. 2.47 g of the product are obtained as a powder.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:15]>CO>[Si:1]([O:8][C@@H:9]([CH2:13][CH2:12][OH:11])[C:10]([NH2:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Reactant: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Reaction time: 48 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) in methanol was added 7 N ammonia in methanol (20 mL, 140 mmol). The reaction was stirred in a sealed tube for 2 days. The solvent was removed in vacuo to yield (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) as a white solid. [M+H] calc'd for C10H23NO3Si, 234. found, 234.
Reaction SMILES: O=C(N(C1C=CC=CC=1)C1CCCCN1[CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])CC.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[C:14]([OH:16])(=[O:15])[CH2:13][CH3:12].[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30]
Reactant: CCC(=O)N(c1ccccc1)C1CCCCN1CCC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: CCC(=O)O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[(1-oxopropy])phenylamino]-piperidine (500 mg, 2.15 mmol) and t-butyl acrylate (0.37 ml, 2.58 mmol), in acetonitrile (2.5 ml) is stirred at room temperature for 24 hours. The solution is concentrated and the residue is chromatographed on silica gel (EtOAc) to give 4-[2-[(1-oxopropyl)phenylamino]-1-piperidine propanoic acid, t-butyl ester as an oil: 605 mg, 78%. To the ester (309 mg, 0.857 mmol) is added trifluoroacetic acid (4 ml). The homogeneous reaction mixture is stirred at room temperature for one hour and then concentrated to an oil which is triturated with ether to give a white solid, 3-[4-[(1-oxopropyl)phenylamino]-1-piperi]-dine]propanoic acid, trifluoroacetate: 316 mg, 88%; m.p. 187°-189° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:15])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:3].Cl>>[Cl-:14].[CH3:1][NH+:2]([CH:4]([CH3:15])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[CH3:3]
Reactant: CC(CCCc1ccc(Cl)cc1)N(C)C
Agent: Cl
Product: CC(CCCc1ccc(Cl)cc1)[NH+](C)C
Product: [Cl-]

Procedure:
7.6 Grams of 1-methyl-4-(4-chlorophenyl)butylamine was reacted with 9.9 ml. of ninety percent formic acid and 9.5 ml. of thirty-seven percent aqueous formaldehyde to provide 7.05 g. of N,N-dimethyl-1-methyl-4-(4-chlorophenyl)butylamine. The free amine was reacted with hydrogen chloride to form N,N-dimethyl-1-methyl-4-(4-chlorophenyl)butylaminium chloride. M.P. 109°-111° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11]O)=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].[Cl-].[Li+].N1C(C)=CC(C)=CC=1C.CS([Cl:33])(=O)=O>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH2:11][Cl:33])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: COCOc1ccc(C=CCO)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: COCOc1ccc(C=CCCl)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
Under a current of argon, a solution of 1.50 g of 4-methoxymethoxy-3-nitrocinnamyl alcohol in 15 ml of dimethyl formamide and 292 mg of anhydrous lithium chloride and 0.9 ml of 2,4,6-collidine added thereto as kept cooled with ice were stirred for 10 minutes and the produced mixture and 0.5 ml of methanesulfonyl chloride added as kept cooled with ice were stirred for four hours. The resultant reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. By concentrating the residue from drying under a vacuum, 1.62 g of 4-methoxymethoxy-3-nitrocinnamyl chloride was obtained in the form of a colorless oily substance. This product was put to use in its unpurified form in the following reaction.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22](O)[CH:21]=[CH:20]2.C(N(CC)CC)C>ClCCl.O>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=2)[CH:23]=1)(=[O:3])=[O:2]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Temperature: -10 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Triflic anhydride [(CF3SO2)2O, 1.8 ml, 3.03 g, 10.8 mmol] was added to a solution of 6-bromo-2-naphthol (2 g, 9.0 mmol) and triethylamine (NEt3) (1.52 ml, 1.09 g, 10.8 mmol) in dichloromethane (CH2Cl2) (40 ml) and under inert atmosphere at −10° C. After 2 h of stirring at −10° C., the reaction mixture was diluted in H2O (50 ml) and extractions with CH2Cl2 (3×40 ml) were carried out. The joined organic phases were washed with aq HCl (50 ml, 0.1 M), followed with H2O (50 ml) and were dried on Na2SO4. The filtration, evaporation and purification by column chromatography (SiO2, CH2Cl2) gave the title compound (3.25 g) as a colourless oil. IR (KBr) 3090, 1590, 1501, 1425, 1363, 1251, 1212, 1182, 1141, 1111, 1065, 960, 915, 882, 850, 801, 786, 767, 714, 653 y 609. M/Z (IQ, NH3) 356 [M+(81Br), 53%], 354 [M+ (79Br), 63], 223 [M-SO2CF3+ (81Br), 63] y 221 [M-SO2CF3+ (79Br), 100].
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6][C:7]([F:25])([F:24])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1.[CH3:26]I.O>CN(C)C=O>[CH:3]1([S:6][C:7]([F:24])([F:25])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])([O:15][CH3:26])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 60% sodium hydride (75 mg, 1.87 mmol) in N,N-dimethylformamide (50 ml), 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (0.50 g, 1.44 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (270 mg, 1.87 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[3-(cyclopropylthio)-2-(2,4-difluorophenyl)-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.31 g, yield: 60%) was obtained as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:32](OC=C)(=[O:34])[CH3:33]>>[C:32]([O:1][C@H:2]([CH3:24])[C@H:3]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)(=[O:34])[CH3:33].[OH:1][C@@H:2]([CH3:24])[C@@H:3]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Reactant: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C[C@@H](c2ccc([N+](=O)[O-])cc2)[C@@H](C)OC(C)=O)o1
Product: CCOC(=O)c1ccc(C[C@H](c2ccc([N+](=O)[O-])cc2)[C@H](C)O)o1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
6.35 g of ethyl 5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate [the compound prepared in Reference Example 4(2)] was dissolved in 64 ml of vinyl acetate, and 2.66 ml of triethylamine was added. Then, 635 mg of immobilized lipase (Toyothium LIP) was added, and the reaction solution was stirred at room temperature for 5 days. The insolubles were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=7/2→2/1] to give 2.93 g of ethyl 5-{(2S,3R)-3-acetoxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate and 2.81 g of the title compound as colorless oily substances, respectively. The absolute steric configuration of the title compound was determined by the Mosher method (J.Am.Chem.Soc.), vol. 113, p. 4092 (1991)).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH3:20])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([O:38][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][N:27]=3)[CH:40]=2)=[O:19])[N:7]([CH3:20])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c2cc1OC

Procedure:
The procedure in 138B was used to react the carbamate from Example 157A (123 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (78 μL, 0.45 mmol) and DMAP (3.6 mg, 0.03 mmol). The reaction was concentrated to dryness. The resulting oil purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 10-50% over 60 minutes. The main peak concentrated to a solid weighing 126 mg. 1H (DMSO-d6) 9.10 (s, 1H), 8.70 (s, 2H), 7.65 (m, 2H), 7.50 (m, 2H), 7.30 (m, 1H), 7.15 (s, 1H), 6.95 (m, 1H), 6.00 (s, 1H), 4.40 (s, 2H), 4.00 (s, 3H), 3.85 (s, 2H), 3.60 (s, 3H), 3.40 (s, 3H), 1.25 (s, 9H). LCMS (ESI) m/z 521 (M+H)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)C)(=[O:12])C.Cl.N1[CH:23]=[CH:22]C=CC=1>>[CH2:22]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:3][C:1](=[O:12])[CH3:2])[CH3:23]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ccccc1
Agent: Cl
Product: CCc1ccccc1NC(C)=O
Temperature: 25 °C

Procedure:
To the stirred solution of commercially available ethyl aniline (16, 20.3 g, 167.5 mmol, 1 eq.) in anhydrous pyridine (90 mL), at zero degree, under argon was added acetic anhydride (32 mL, 335.04 mmol, 2 eq). After the addition, the resulting solution was stirred with warming to room temperature overnight. The reaction solution was cooled (0° C.), pH adjusted between 4 and 5 with 10% HCl, and extracted with ethyl acetate (2×500 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated to provide the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=[O:2].[Cl-].[NH4+].C1COCC1.C(Cl)Cl>O.[Zn]>[OH:2][NH:1][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccccc1NO
Reaction time: 2 h
Yield: 50 %

Procedure:
To a stirring solution of ethyl 2-nitrobenzoate (32.0 g, 0.164 mol), ammonium chloride (22.28 g, 0.416 mol) in solvent mixture of water (240 mL) and THF (288 mL) was added zinc powder (26.8 g, 0.410 mol) slowly at 0° C. Reaction mixture was stirred at 0° C.-10° C. for 2 h. Reaction mixture was then diluted with water followed by DCM and filtered through Hyflow bed. The organic layer was separated and distilled out to get crude product which was column purified using 0-5% EtOAC in hexane to get titled compound as light yellow solid in 50% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][NH:27][CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:34](C)=O.[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19]4[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][C:18]=4[C:17]=3[CH:16]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1c2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc31)CNCC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3n2C)C1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in CH3OH (3 mL) was added formaldehyde (30 μL, 0.29 mmol) and NaBH(OAc)3 (110 mg, 0.52 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)pyridin-2(1H)-one (102 mg, 98%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (100 mg, 90%) as a yellow solid: mp 264-268° C. (decompose); 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.56-7.36 (m, 8H), 7.10 (dd, J=8.5, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 3.18 (m, 2H), 2.97 (s, 3H); ESI MS m/z 400 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.9 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2].[Br:24][CH2:25][C:26](Br)=O.C([O-])(=O)C.[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:26]([CH2:25][Br:24])=[N:15][N:14]=[C:12]3[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)([O-:3])=[O:2]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: O=C(Br)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2

Procedure:
In the manner given in Example 1, 7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with bromoacetyl bromide and after 1.5 hours with sodium acetate, then refluxed to give 8-nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.