Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:13]2=[O:22])=[CH:8][CH:7]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](F)[N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[N:34]=[C:35]([N:19]2[CH2:18][CH2:17][C:14]3([C:13](=[O:22])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][C:4]([F:3])([F:23])[F:24])=[CH:7][CH:8]=4)[CH2:16][CH2:15]3)[CH2:21][CH2:20]2)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1cccc(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OCc3ccccc3)n1)CC2
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of NaH (9 mg, 0.24 mmol) in DMF (1 mL) at 0° C. was added a solution of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C, 50 mg, 0.16 mmol) and stirring was continued for 30 mins. A solution of 2-benzyloxy-6-fluoro-pyridine (39 mg, 0.19 mmol) in DMF (0.5 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine, 1N HCl and again with brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to yield the title compound as a light yellow solid (58 mg, 73%). MS (ESI): 498.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylethanolamine (5.02 ml, 50 mmol) was added dropwise over 5 minutes to an ice-cooled suspension of sodium hydride (2.2 g, 60% dispersion in mineral oil, 55 mmol) in tetrahydrofuran (100 ml), and the solution was stirred for 30 minutes. tert-Butyl bromoacetate (7.38 ml, 50 mmol) was added dropwise over 5 minutes, then the mixture was allowed to warm to room temperature and stirred for a further 18 hours. The mixture was pre-adsorbed onto silica gel, and purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate:methanol (50:50:0 to 0:100:0 to 0:80:20) to afford the title compound as a yellow oil, 1.46 g. 1H-NMR (CDCl3, 400 MHz) δ: 1.50 (s, 9H), 2.30 (s, 6H), 2.59 (t, 2H), 3.64 (t, 2H) 4.00 (s, 2H). LRMS: m/z (ES+) 204 [MH+]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(=O)(O)[O-].[Na+]>ClCCl.CO>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2cccnc2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCO)(c3cccnc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 5.2.2 using 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine, 3,4,5-trimethoxybenzoyl chloride, and sodium bicarbonate to give, after chromatography on silica gel eluting with dichloromethane/methanol 5/1, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[CH:23]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:23]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Reactant: CCOC([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NCc3nncn3-c3ccc(Cl)cc32)cc1

Procedure:
To a suspension of 1.6 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine prepared in Example 2 in 50 parts by volume of ethanol is added 3.0 parts of ethyl orthoformate, and then 0.5 part by volume of concentrated sulfuric acid is added dropwise with stirring. The whole mixture is stirred for a while and then neutralized with an aqueous slution of sodium bicarbonate, followed by evaporaton of the solvent. Water is added to the residue, whereby 8-chloro-6-(p-methoxyphenyl)-4H-s-triazolo (4,3-a) (1,4) benzodiazepine is yielded as crystals. Recrystallization from acetone and and then from ethyl acetate yields pale yellow flakes melting at 216° C to 217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2].CC(C)=[O:60].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[N+:1]([C:4]1[CH:57]=[CH:56][CH:55]=[CH:54][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([OH:60])=[O:17])[C@H:13]([CH:18]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[O:22])[CH3:19])[C:12]1=[O:34])=[O:9])([O-:3])=[O:2]
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-(o-Nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2'-hydroxyethyl)-2-azetidinone (0.1582 g, 0.20 mmol) (cf. Example 43, Step I) is dissolved in 5 ml acetone cooled to 0°. Jones Reagent (0.12 ml, 4N solution) is added dropwise over 3 minutes and the resulting solution is stirred at 0° for 10 minutes. Isopropanol (0.05 ml) is added and the mixture stirred for another 2 minutes. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl aqueous solution, dried and evaporated to give 0.132 g of crude acid which is used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:5][C:6]=1[CH3:7].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[S:5][C:6]=1[CH3:7]
Reactant: COC(CNCc1cc(Br)c(C)s1)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COC(CN(Cc1cc(Br)c(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-((4-bromo-5-methylthiophen-2-yl)methyl)-2,2-dimethoxyethanamine (14.5 g, 49 mmol) was dissolved in DCM (100 ml) and TEA (14 ml, 99 mmol) was added. The reaction was cooled to 0° C. with an ice bath and 4-tosyl chloride (8.5 ml, 59 mmol) was added portionwise. The reaction was allowed to warm up to RT and stirred overnight. The reaction was then diluted with DCM and water. The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate purified by column chromatography on silica gel using a gradient of 30 to 70% EtOAc in hexanes to give N-((4-bromo-5-methylthiophen-2-yl)methyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[NH:18]([C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[C:19]([NH2:21])=[NH:20].[OH-].[Na+]>CO.O>[N:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[NH:23][C:22]=1[N:18]=[C:19]1[NH:21][C:9]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:21][C:19](=[N:18][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[NH:20][C:8]2([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[NH:20]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccccc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccccc1C12NC(=Nc3nc4ccccc4[nH]3)NC1(c1ccccc1)NC(=Nc1nc3ccccc3[nH]1)N2

Procedure:
Following the procedure of Example 1, 1-(2-chlorophenyl)-2-phenylethanedione (0.25 g, 1.0 mmol) and 2-guanidinobenzimidazole (0.215 g, 1.2 mmol) in methanol (12 mL) was treated with a solution of sodium hydroxide (48 mg, 1.2 mmol) in 1.2 mL of water. The title compound was isolated as pale yellow crystals (130 mg, 39% yield). MS (ESI) m/z 559 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.ClCCl.[CH2:15](Br)[C:16]#[CH:17]>CO>[CH3:8][N:6]1[CH:7]=[C:2]([NH:1][CH2:17][C:16]#[CH:15])[C:3](=[O:11])[N:4]([CH3:10])[C:5]1=[O:9]
Reactant: Cn1cc(N)c(=O)n(C)c1=O
Reactant: C#CCBr
Solvent: CO
Solvent: ClCCl
Product: C#CCNc1cn(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Step 1 intermediate (1.4 g, 9.023 mmol) in 1:1 mixture of dichloromethane and methanol (28 mL) was added propargyl bromide (1.4 mL) and the mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give 500 mg of the product.
Reaction SMILES: [CH2:1]([C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[CH2:10][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:12][CH2:13][C:8]=2[C:7](=[O:27])[O:6]1)[CH:2]([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:27])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:9]=2[CH2:10]1)=[O:26]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1[N+](=O)[O-])CC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)CCc1ccccc1N)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of (E)-3-isobutyl-5-(3-(2-nitrophenyl)acryloyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (90 mg, 0.20 mmol) in ethanol/ethyl acetate/(3:1, 20 mL) was added Pd/C (10%, 20 mg). The reaction mixture was stirred vigorously under an atmosphere of H2(g) at room temperature for 1 h. The mixture was filtered through a pad of diatomaceous earth, the filtrate concentrated in vacuo, and the residue purified by column chromatography (4 g, SiO2, 0 to 50% ethyl acetate in hexanes) to provide 5-(3-(2-aminophenyl)propanoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 64%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-0.98 (m, 6H), 1.59-1.71 (m, 1H), 1.73-1.87 (m, 1H), 2.18-2.37 (m, 2H), 2.72 (d, J=6.78 Hz, 2H), 2.87 (d, J=6.78 Hz, 2H), 3.22-3.33 (m, 1H), 3.46-3.66 (m, 2H), 3.77-3.89 (m, 2H), 3.92-4.04 (m, 1H), 4.60-4.74 (m, 1H), 6.59-6.64 (m, 2H), 6.96-7.07 (m, 2H), 7.28-7.44 (m, 5H); MS m/z 419 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:12]N1C(=O)CCC1=O>O1CCOCC1.COCCO>[CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[C:8]([Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCCCc1nc(Cl)c(CO)[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
In a mixture of 70 ml of dioxane and 60 ml of methyl cellosolve was dissolved 4 g of 2-butyl-5-hydroxymethylimidazole, and 3.9 g of N-chlorosuccinimide was added to the solution, followed by stirring at 40° C. for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, and 100 ml each of water and ethyl acetate were added to the residue to shake for mixing. The ethyl acetate layer was evaporated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ether. The solution was allowed to cool, thereby yielding 2.4 g of 2-butyl-4-chloro-5-hydroxymethylimidazole deposited as colorless prisms, m.p. 147°-148° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([Cl:16])[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Sc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 0 °C

Procedure:
3-Benzyloxybenzenethiol (13) (75.0 g, 347 mmol) and 2-chloro-4-fluorobenzaldehyde (55.0 g, 347 mmol) were dissolved in dimethylformamide (DMF) (350 mL) while the solution was being stirred. The solution was then placed in a water bath at 30° C. and potassium carbonate (62.3 g, 451 mmol) and dimethylformamide (25 mL) were added. This mixture was stirred for 30 min at an internal temperature of 40 to 42° C. Tap water (125 mL) was then added and the mixture was cooled in ice water. To the cooled mixture, additional tap water (625 mL) was added dropwise for crystallization. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 10% aqueous 2-propanol (188 mL). The moist crystals were dissolved in ethyl acetate (750 mL) and the solution was washed twice with tap water (375 mL×2). The organic layer was concentrated under reduced pressure and acetone (900 mL) was added to the resulting residue. Purified water (386 mL) was then added dropwise at an internal temperature of 23° C. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 50% aqueous acetone (400 mL). The washed crystals were air-dried overnight. Subsequently, the product was dried by blowing an air stream at 45° C. for 1 hour. This gave 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde (1) as a colorless prism crystals (115 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1OC)([O-:3])=[O:2].[CH3:15][NH2:16].Cl>>[CH3:15][NH:16][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN
Agent: Cl
Product: CNc1cc(C(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture comprising 4-nitro-3-methoxybenzoic acid (5.0 g, 25.4 mmol) and aqueous methylamine (40%, 15 mL) is a sealed tube was heated in an oil bath at 100° C. for 12 hours, allowed to cool to room temperature, and then poured into a stirring slurry of 1M aqueous hydrochloric acid and ice to give an orange precipitate. The precipitate was collected by filtration, rinsed with water and recrystallized from hot ethanol to provide 3-methylamino-4-nitrobenzoic acid as a bright red crystalline solid (3.6 g, 73% yield); 1H-NMR (300 MHz, DMSO-d6): 13.5 (s), 8.3 (q), 8.2 (d), 7.4 (s), 7.1 (d), 3.0 (d).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:26][CH:25]([CH3:24])[O:29][C:28]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC1CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)OC4=O)nc3)CC2)c(C)c1
Yield: 29.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (93 mg) described in Preparation Example 73 and 5-methyloxazolidin-2-one (30 mg), the title compound (29 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-6-methylpyridine (723 mg, 3.47 mmol) in N,N-dimethylformamide (11.5 ml) was added sodium hydride (mineral oil 55% dispersion) (0.18 g, 4.2 mmol) in portions under ice cooling. After stirring at room temperature for 30 minutes, tert-butyl bromoacetate (0.62 ml, 4.2 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=10:1→5:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.14 g) substantially quantitatively as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 4-ethoxyaniline by a procedure similar to example 28 (32%). 1H NMR (CDCl3): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13]1[O:14][C:15]3[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=3[C:17]=1[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7]2.[H-].[Na+].Br[CH2:31][C:32]#[N:33].Cl>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][C:6]([C:13]3[O:14][C:15]4[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=4[C:17]=3[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5][CH:4]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:31][C:32]#[N:33]
Reactant: N#CCBr
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
To an ice-cooled solution of 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.2 g, 2.8 mmol) in dry DMF (12 mL) was added sodium hydride (0.315 g, 7.88 mmol of a 60% dispersion on mineral oil) in three portions. Bromoacetonitrile (0.49 mL, 7.0 mmol) was added and the mixture was stirred at room temperature for 1.5 hours, then poured into excess water and acidified with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 15% tert-butyl methyl ether in hexane as an eluant to afford 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile as a yellow solid (0.776 g, 60%), mp 98-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]([NH:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2.1 mmol) and benzoic acid (2.1 mmol, 1 equiv.) were dissolved in DMF (10 mL). EDC.HCl (1.5 equiv.), DIPEA (3 equiv.) and HOBT (1.5 equiv.) were added to the reaction mixture and stirred at room temperature for 5 h. The reaction mass was concentrated under reduced pressure to remove excess of solvent present. Diluted the residue with EtOAc and washed water followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated to get N′-benzoyl-6-chloro-4-(isopropylamino)nicotinohydrazide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:36]2[CH:37]=[CH:38][C:39]([Cl:51])=[C:40]3[C:44]=2[N:43]([CH3:45])[N:42]=[C:41]3[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:5]([C@@H:8]([NH:18][C:19](=[O:35])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([CH:32]([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.NC1C=C(C2C=CC([Cl:92])=C3C=2N(C)N=C3NS(C)(=O)=O)C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:36]2[CH:37]=[CH:38][C:39]([Cl:51])=[C:40]3[C:44]=2[N:43]([CH3:45])[N:42]=[C:41]3[NH:46][S:47]([CH3:50])(=[O:48])=[O:49])[C:5]([C@@H:8]([NH:18][C:19](=[O:35])[CH2:20][N:21]2[C:25]3[C:26]([F:31])([F:30])[C@@H:27]4[CH2:29][C@@H:28]4[C:24]=3[C:23]([CH:32]([F:34])[F:33])=[N:22]2)[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][C:7]=1[Cl:92]
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)Cn3nc(C(F)F)c4c3C(F)(F)[C@@H]3C[C@H]43)c21

Procedure:
Compound 53B was prepared according to the method presented for the synthesis of compound 49C in Example 49 substituting 53A for 49A to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ 7.17-6.94 (m, 2H), 6.87-6.54 (m, 2H), 6.53-6.19 (m, 3H), 4.96 (s, 1H), 4.72 (dd, 2H), 3.41 (s, 2H), 3.24 (d, 3H), 3.16-2.88 (m, 3H), 1.38 (dt, 1H), 1.13-0.99 (m, 1H). MS (m/z) 787 [M+H]+.