Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of aniline (2.45 mL) and triethylamine (0.73 mL) in methylene chloride (30 mL) a solution of chloroacetyl chloride (2.56 mL) in methylene chloride (10 mL) was added dropwise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 1 hour. A 1M aqueous solution of KHSO4 was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to yield crude 2-chloro-N-phenyl-acetamide, which was subjected to the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]([C:17](=[O:31])[C:18]([C:20]1[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=1[CH2:29][CH3:30])=O)[N:9]=[C:10]([CH3:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([N:8]1[C:17](=[O:31])[C:18]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=2[CH2:29][CH3:30])=[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(Cc1ccccc1)N=C(C)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.7 %

Procedure:
To a 20 ml volume three-necked flask, 1-benzyl-1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(7)-39) (340 mg), toluene (3.0 ml), and potassium carbonate (0.18 g) were added at room temperature, then additional toluene (0.5 ml) was added. The resulting mixture was stirred at room temperature for 15 hours, then at the internal temperature of about 50° C. for 18 hours. To the resulting mixture, water was added was extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure, purified by column chromatography (hexane:ethyl acetate=5:1), further recrystallized from ethyl acetate to give 67.5 mg of 2-benzyl-4-(2,6-diethyl-4-methylphenyl)-6-methyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(7)-39).
Reaction SMILES: [Br-].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:11]=1[O:36][CH2:37][CH3:38])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li][CH2:40][CH2:41][CH2:42]C.[Si:44]([O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58]CC(=O)C)=[CH:54][CH:53]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].O>C1COCC1>[C:47]([Si:44]([O:51][C:52]1[CH:53]=[CH:54][C:55]([CH2:58][CH2:40][C:41]([CH3:42])=[CH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4])=[C:11]([O:36][CH2:37][CH3:38])[CH:12]=2)=[CH:56][CH:57]=1)([CH3:45])[CH3:46])([CH3:48])([CH3:49])[CH3:50]
Reactant: [Li]CCCC
Reactant: CC(=O)CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: CCOc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C=C(C)CCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (4-(tert-Butyldimethylsilyloxy)-3-ethoxyphenyl)methyltriphenyl-phosphonium bromide (28.7 g, 41.6 mmol, 1.0 equiv.) in THF (90 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 26 mL, 41.6 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 0° C. for 15 min. 4-(4-(Tert-butyldimethylsilyloxy)phenyl)butan-2-one (12.9 g, 41.6 mmol, 1.0 equiv.) in THF (30 mL) was added, and the mixture was stirred at 0° C.→70° C. for 16 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 98:2) to give tert-butyl(4-(4-(4-((tert-butyldimethylsilyl)oxy)-3-ethoxyphenyl)-3-methylbut-3-en-1-yl)phenoxy)dimethylsilane as a colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[C:18](=[O:19])[C:17]([CH:20](O)[C:21]([F:24])([F:23])[F:22])=[CH:16][NH:15][C:14]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.[Cl:29]CCl>C(#N)C>[ClH:3].[CH2:5]([O:12][C:13]1[C:18](=[O:19])[C:17]([CH:20]([Cl:29])[C:21]([F:24])([F:23])[F:22])=[CH:16][NH:15][C:14]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Reactant: ClCCl
Solvent: CC#N
Solvent: CO
Product: Cc1[nH]cc(C(Cl)C(F)(F)F)c(=O)c1OCc1ccccc1
Product: Cl
Temperature: 60 °C
Yield: 75 %

Procedure:
Thionyl chloride (7.5 mL, 102 mmol) was added to a suspension of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (8.0 g, 25.5 mmol) in acetonitrile (100 mL) at room temperature. The resulting mixture was heated to 60° C. for 1 h. The progress of the reaction was monitored by TLC (methanol/dichloromethane 5/100 v/v as eluant). The reaction mixture (suspension) was evaporated to dryness to afford a solid. After stirring in acetonitrile, the title compound was collected by suction filtration (7.1 g, 75% yield). 1H NMR (DMSO-d6+D2O) δ ppm: 7.88 (s, 1H), 7.33 (m, 5H), 6.03 (q, J=7.3 Hz, 1H), 5.02 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]1[NH:15][C:16](=[O:33])[C:17]([C:31]#[N:32])=[C:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[Br:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]1[N:15]=[C:16]([O:33][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:17]([C:31]#[N:32])=[C:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1c(Cc2cccc3ccccc23)nc(-c2cccc3c(Br)cccc23)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1nc(-c2cccc3c(Br)cccc23)nc(Cc2cccc3ccccc23)c1C#N
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, washed with hexane, 0.64 g, 16.1 mmol) in DMF (25 mL) was added a solution of 2-(5-bromo-1-naphthalenyl)-1,6-dihydro-4-[(1-naphthalenyl)methyl]-6-oxo-5-pyrimidinecarbonitrile (prepared in Step 3) (5.0 g, 10.7 mmol) in DMF (100 mL) at room temperature. After 30 minutes, t-butyl bromoacetate was added and stirring was continued for 18 hours. The reaction was quenched by the addition of water (10 mL) and the resulting mixture was partitioned between chloroform (200 mL) and water. The aqueous layer was extracted with chloroform (2×100 mL) and the combined organic layers were washed with water, brine, and dried (Na2SO4). The mixture was filtered through a short plug of Florosil and concentrated in vacuo to give a yellow solid (5.8 g, 48%). Recrystallization from acetonitrile/DMF gave 3.0 g of product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([O:11]C)=O)[CH:7]=1.F[C:17]1[C:26]([N+:27]([O-])=O)=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([CH3:13])[C:9](=[O:11])[NH:27][C:26]3[CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:19]([C:30]([F:33])([F:31])[F:32])=[CH:18][C:17]=3[O:14]2)[CH:7]=1
Reactant: COC(=O)C(C)(O)c1cc(Br)ccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C(F)(F)F
Product: COC(=O)c1cc2c(cc1C(F)(F)F)OC(C)(c1cc(Br)ccc1F)C(=O)N2

Procedure:
Using methyl 2-(5-bromo-2-fluorophenyl)-2-hydroxypropanoate and methyl 4-fluoro-5-nitro-2-(trifluoromethyl)benzoate, the title compound was obtained in a similar manner to Reference Example 22 and Reference Example 2.
Reaction SMILES: CO[CH2:3][N:4](CC1C=CC=CC=1)[CH2:5][Si](C)(C)C.[C:17](O)(C(F)(F)F)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=O)[CH:30]=[CH:29]2>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:32]2[CH:31]([CH3:17])[CH:30]3[CH2:5][NH:4][CH2:3][CH:29]3[C:28]=2[CH:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2c(c1)C=CC2=O
Solvent: ClCCl
Product: COc1ccc2c(c1)C1CNCC1C2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of 5-methoxy-inden-1-one (5.4 g, 33.8 mmol) in CH2Cl2 (165 mL) at 0° C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO3 (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C19H19NO2+H: 294, observed: 294.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:5]([N+:14]([O-])=O)[CH:4]=1.O1CCCC1>O>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: COc1ccc(-n2cccc2)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2cccc2)c(N)c1

Procedure:
A stirred solution of 33.5 g (0.154 mole) of 1-(4-methoxy-2-nitrophenyl)pyrrole in 684 ml. of tetrahydrofuran and 340 ml. of water is treated according to the manipulative procedure described in Example 13(b) to give 1-(2-amino-4-methoxyphenyl)pyrrole, m.p. 42°-43° C.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[S:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[CH3:25][C:26]1[S:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:33])=[O:32]
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)c(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,5-dimethyl-3-thienyl sulfonyl chloride (24 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,5-dimethyl-3-thienyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (4 mg). MS m/z 377 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](O)=[O:39])=[CH:34][CH:33]=2)[S:26]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)=[CH:4][C:3]=3[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:39])=[CH:41][CH:42]=2)[S:26]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 48.6 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridine-2-ylthio)phenyl]-N-methylcarbamate (0.78 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.06 g), diethyl cyanophosphonate (0.61 g), triethylamine (0.38 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.68 g).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH2:9][C:10](=[CH2:13])[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:27][CH2:11][C:10]([CH2:9][O:8][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:13]
Reactant: BrC(Br)(Br)Br
Reactant: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CBr)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.2 %

Procedure:
To a solution of 10 (2.56 g; 7.74 mmol) in CH2Cl2 (75 ml), CBr4 (3.63 g; 10.83 mmol) and triphenylphosphine (2.47 g; 9.31 mmol) were added respectively at 0° C. and the reaction was stirred at room temperature for 40 min. Cooled to 0° C., ethyl acetate (100 mL) and saturated aqueous NaHCO3 (30 mL) were added. The organic layer was separated and washed by saturated aqueous NaCl, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using CH2Cl2-hexane (1:5) as the eluent to afford 11 as white solid (3.02 g; 92% yield): 1H NMR (400 MHz, CDCl3) δ 7.42-7.48 (m, 6H, six of ArH), 7.27-7.33 (m, 6H, six of ArH), 7.20-7.27 (m, 3H, three of ArH), 5.37 (s, 1H, one of C═CH2), 5.31 (s, 1H, one of C═CH2), 4.01 (s, 2H, CH2Br), 3.75 (s, 2H, Ph3COCH2); 13C NMR (100 MHz, CDCl3) δ 143.6, 142.6, 128.4, 127.6, 126.9, 115.8, 86.9, 64.2, 33.5, (9).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1ccc(NC(=O)Cc2ccc(O)cc2)cc1

Procedure:
4-Hydroxyphenyl acetic acid (1.55 g, 10.2 mmol), 4-ethyl-phenylamine (1.28 ml, 10.3 mmol), TBTU (4.82 g, 15 mmol), and NMM (8.79 ml, 80 mmol) are stirred in DMF (30 ml) at rt for 5 h. The reaction mixture is taken up in AcOEt (0.2 L), washed with H2O (40 ml, 2×) and brine (40 ml, 2×), dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (silica gel, 3.5×25 cm, AcOEt/hexane=1:2→2:3) giving the title compound of Stage 16.1 as a colorless solid (1.68 g, 6.59 mmol; 66%) M+H=256.1; 1H-NMR (400 MHz, DMSO-d6): 10.0/9.24 (s/s, 1H, NH/OH), 7.46 (d, 8.5 Hz, 2H, phenyl), 7.09 (d, 8.5 Hz, 4H, phenyl), 6.66 (d, 8.5 Hz, 2H, phenyl), 3.47 (s, 2H, aryl-CH2), 2.53 (qu, 7.5 Hz, 2H, CH2), 1.13 (t, 7.5 Hz, 3H, CH3); R. (AcOEt/hexane=1:1): 0.66; m.p. =146-148° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[N:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[OH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2>>[NH2:13][C:12]1[O:15][CH:16]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]2[CH:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[C:11]=1[C:10]#[N:14])[CH:21]=[CH:22][N:23]=3
Reactant: Cc1cncc(C=O)n1
Reactant: Oc1cccc2cc[nH]c12
Reactant: N#CCC#N
Product: Cc1cncc(C2C3=CC=C4C=CN=C4C3OC(N)=C2C#N)n1
Yield: 82 %

Procedure:
The title compound was prepared from 6-methyl-pyrazine-2-carbaldehyde, malononitrile and 7-hydroxyindole by a procedure similar to Example 57 in 82% yield. 1H-NMR (DMSO-d6): 10.43 (brs, 1H), 8.50 (d, J=1.37 Hz, 1H), 8.38 (d, J=0.82 Hz, 1H), 7.35 (m, J=2.47, 2.20, 1.10, 0.83 Hz, 1H), 7.27 (d, J=8.24 Hz, 1H), 6.72 (dd, J=8.24, 0.55 Hz, 1H), 6.47 (m, J=2.20, 0.55 Hz, 1H), 6.11 (brs, 2H), 5.05 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:36])[C:7]=2[CH:37]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (251 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (74.8 mg, 33%) as a pale-brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[CH2:26]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>O>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:36][CH2:35]4)=[C:6]([O:24][CH3:25])[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[C:17]([F:23])[CH:18]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Solvent: O
Product: CCOC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(Cl)cc4F)c3cc2OC)CC1
Product: Cl
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (130 mg, 0.36 mmol), (prepared as described for the starting material in Example 62), in 1-ethoxycarbonylpiperazine (1.5 ml) was stirred and heated at 100° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (3×25 ml). The extracts were combined, washed with water (×2) and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was dissolved in acetone and 1M ethereal hydrogen chloride (2 ml) was added. The resulting precipitate was collected by filtration and then purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (94/5/1). The purified product was dissolved in acetone and 1M ethereal hydrogen chloride (2 ml) was added. The resulting precipitate was collected by filtration, washed with ether and dried to give 4-(4chloro-2-fluoroanilino)-7-(2-(4-ethoxycarbonylpiperazin-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (85 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2=[O:12].[C:13](Cl)([Cl:15])=[O:14]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]([Cl:15])=[O:14])[CH2:7][CH2:6][C:5]2=[O:12]
Reactant: O=C1CCNc2ccc(F)cc21
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)Cl)c2ccc(F)cc21
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
33.0 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline and 200 parts of dioxane were mixed, and 39.6 parts of phosgene were introduced to the stirred mixture over about 30 minutes while the temperature was maintained at 20°-25° C. After the introduction, the temperature was raised gradually, and the reaction was effected at 40°-45° C. for 2.5 hours, after which the temperature was further raised to 70° C., nitrogen gas was passed through the mixture, and the solvent (dioxane) was distilled off under reduced pressure. Petroleum ether was added to the residue followed by filtration, washing and drying, and there was obtained 43.7 parts of 6-fluoro-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]3=O)=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2].[Cl-:26].O>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[O:24][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([N:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[C:14]3[Cl:26])=[C:9]2[C:8](=[O:25])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2c3c(ccc2o1)C(=O)CC(C(=O)OC)=N3
Reactant: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(ccc3c(Cl)cc(C(=O)OC)nc32)o1
Yield: 66 %

Procedure:
The product of step (b) (1.3 g, 3.79 mmole) and phosporyl chloride (0.69 ml) in dry dichloroethane (80 ml) were heated to reflux for 15 minutes. The reaction mixture was then cooled and treated with water. The mixture was extracted with dichloroethane, the organic layer was washed with water, dried, and evaporated to give a brown solid. This was dried in vacuo over P2O5 at 50° C. to give the sub-title compound (0.9 g; 66%).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][C:19]3[O:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)(C)C>[OH:25][CH2:24][C:21]1[O:20][C:19]([CH2:18][N:17]2[C:16]3[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=3[N:14]=[C:13]2[N:9]2[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: OCc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 48 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (4 mmol) and sodium hydroxide (8 mmol) in isopropanol (20 mL). Heat to reflux. After 2 days, evaporate the reaction mixture in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.