Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[C:18](=O)[CH3:19].C(N(CC)C(C)C)(C)C.ClC(Cl)=O>C(O)C>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C:17]1[S:14][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:11][CH:10]=2)=[N:15][C:18]=1[CH3:19]
Reactant: NC(=S)Nc1ccc(-n2cncn2)cc1
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Agent: O=C(Cl)Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2ccc(-n3cncn3)cc2)sc1Cc1cccc(Cl)c1
Temperature: 170 °C

Procedure:
A suspension of 55 mg (0.25 mmol) 4-(1,2,4-triazol-1-yl)phenylthiourea, of 60 mg (0.28 mmol) 3-chloro-4-(3-chlorophenyl)-2-butanone and of 65 mg (0.5 mmol) N,N-diisopropyl ethyl amine in ethanol (2.5 ml) was refluxed over night. The same amount of chloro ketone was added and the reaction was heated to reflux over night. Again 1.1 equivalent of chloro ketone was added and the reaction was heated for 10 minutes in a microwave oven to 170° C. The solvent was evaporated and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 27 mg (28%) [5-(3-chloro-benzyl)-4-methyl-thiazol-2-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine as a yellow solid. MS ISP (m/e): 382.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=8.48 (s, 1H), 8.09 (s, 1H), 7.60 (d, 2H), 7.46 (d, 2H), 7.25-7.18 (m, 3H), 7.09 (d, 1H), 3.96 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]([F:28])([F:27])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([Cl:22])[CH:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[N:12]=1.[C:29](=[O:31])=[O:30].Cl>COCCOC.O>[F:28][C:10]([F:9])([F:27])[C:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([Cl:22])[C:14]([C:29]([OH:31])=[O:30])=[C:13]([C:23]([F:24])([F:25])[F:26])[N:12]=1
Reactant: O=C=O
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)O)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a -78° C. solution of LDA (0.128 mol) in 85 ml of DME was added a solution of 18.28 g (0.057 mol) of product of Example 9 in 20 ml of DME. The reaction mixture was stirred at -78° C. for 1 hour. To the above solution was added excess of dry ice. After stirring at -78° C. the reaction mixture was warmed to room temperature in 1 hour and poured into 250 ml of water containing 50 ml of concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with saturated NaHCO3. The basic extract was made acidic with concentrated HCl. The oil precipitate was extracted into ether. The ether solution was dried (MgSO4) and concentrated in vacuo to give 7.81 g (37.6%) of product as a solid; mp 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.C(O)(=[O:20])C>O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:20])[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1
Reactant: CC(=O)O
Reactant: COC(=O)CCCCCc1ccc(C#N)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 11 %

Procedure:
The compound (620 mg) obtained in the above (1) is dissolved in a mixture of acetic acid (30 ml) and water (5 ml), and thereto is added chromic anhydride (1.3 g)/acetic acid (2 ml), and the mixture is stirred at room temperature for 17.5 hours. The mixture is diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution, and purified by silica gel column chromatography (n-hexane/ethyl acetate=5:1→2:1) to give the title compound (70 mg, 11%), and the starting compound (365 mg, 59%) is also recovered.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]>C1COCC1>[C:18]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[O:28])[CH:23]=[CH:24][CH:25]=1)#[N:19]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCCCN1CCC(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCCCN2CCC(Cc3ccccc3)CC2)c1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
4-benzyl-1-(3-amino-n-prop-1-yl)piperidine (300 mg, 1.29 mmol, 1 eq) was dissolved in THF at 25° C. under N2 then 3-cyanophenyl isocyanate (186 mg, 1.29 mmol, 1 eq) was added. TLC after 30 minutes shows the reaction complete. The solvent was removed in vacuo then the residue was purified over silica gel in 100% EtOAc to 8:2 chloroform/MeOH to yield 437 mg of an amber oil as product. NMR (300 MHz, DMSO-d6) δ 9.90-9.50 (m, 1H); 9.32 (s, 1H); 7.93 (s, 1H); 7.59 (d, 1H, J=7Hz); 7.43 (t, 1H, J=7Hz); 7.40-7.24 (m, 3H); 7.24-7.10 (m, 3H); 6.68 (t, 1H, J=7 Hz); 3.50-3.25 (m, 2H); 3.25-3.07 (m, 2H); 3.07-2.90 (m, 2H); 2.90-2.60 (m, 2H); 2.60-2.40 (m, 2H); 2.00-1.60 (m, 5H); 1.60-1.30 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][CH:9]=[C:10]([NH:11][NH2:12])[C:4]=2[O:3]1.C(N(CC)C(C)C)(C)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24]([NH:12][NH:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([CH3:13])=[CH:8][CH:9]=1)=[O:25]
Reactant: Cc1ccc(NN)c2c1CC(C)O2
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)NNc1ccc(C)c2c1OC(C)C2
Temperature: -5 °C
Reaction time: 2 h

Procedure:
15.6 g of 1E was mixed with 150 ml of THF and 11.3 g of N,N-diisopropylethylamine. The mixture was cooled to -5° C. and 9.1 g of methyl chloroformate was added drop-by-drop to the stirred mixture, which then was stirred at 0° C. for two hours. The mixture then was poured over ice water and extracted with ether. The extract was dried (MgSO4), filtered and the solvent was evaporated. The residue was column chromatographed on silica gel, using a 1:4:20 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane as eluent, to give 1, as a tan solid, m.p.: 90°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([Cl:22])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2cc(C(=O)O)c(C)n2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C(=O)Cl)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
According to Scheme 2, Step 2: To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol, 9.30 g) and five drops of DMF in DCM (94 mL) was added oxalyl chloride (76 mmol, 6.66 mL) dropwise, at 0° C. The reaction mixture was allowed to warm up to room temperature and was stirred for 3 hours. After concentration, the residue was treated with toluene and was co-evaporated to dryness to yield 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride. To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride (37.8 mmol) in acetonitrile (94 mL) was added a solution of TMSCHN2 (41.5 mmol, 83.0 mL) dropwise, at 0° C., and then the reaction mixture was allowed to warm up to room temperature and was stirred overnight. After cooling the reaction mixture to −10° C., HBr 48% (14.8 mL) was added dropwise and the reaction mixture was stirred for 2 hours at −10° C. At 0° C., 10% NaOH solution was added to the reaction mixture to reach pH=7. The reaction mixture was diluted with water and EtOAc and the aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (30.6 mmol, 9.90 g, 81%) which was used without any purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([C:11]3[C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[CH:8]=[C:7]([CH3:30])[C:6]2=[O:31])[CH2:3][CH2:2]1.[CH2:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[CH:1]1([CH2:4][N:5]2[C:6](=[O:31])[C:7]([CH3:30])=[CH:8][C:9]([C:11]3[C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])=[CH:15][N:14]=[C:13]([NH:37][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[N:12]=3)=[CH:10]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(CC2CC2)c1=O
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cc(C)c(=O)n(CC3CC3)c2)n1

Procedure:
The title compound of Example 248, step 3 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 248, step 4 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.09 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.04-6.96 (m, 2H), 6.91-6.89 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.64 (q, J=7.2 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J=7.2 Hz, 3H), 1.25-1.23 (m, 1H), 0.62-0.60 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 477.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[Br:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH3:26])=[CH:18][CH:17]=1.C(O)(=O)C(O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Br:15][C:16]1[C:21]([C:22]([O:8][C:7]2[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]=2[F:9])=[O:23])=[C:20]([F:25])[C:19]([CH3:26])=[CH:18][CH:17]=1
Reactant: CCCCCc1ccc(Br)c(O)c1F
Reactant: Cc1ccc(Br)c(C(=O)O)c1F
Agent: CN(C)c1ccncc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Product: CCCCCc1ccc(Br)c(OC(=O)c2c(Br)ccc(C)c2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
43.2 g (0.165 mol) of 6-bromo-2-fluoro-3-pentylphenol, 40.5 g (0.173 mol) of 6-bromo-2-fluoro-3-methylbenzoic acid and 3.52 g (29 mmol) of 4-(dimethylamino)pyridine were initially introduced in 300 ml of dichloro-methane, and a solution of 35.7 g (0.172 mol) of N,N-dicyclohexyl-carbodiimide in 80 ml of dichloromethane was added. The batch was stirred overnight at room temperature, and 4.16 g (33 mmol) of oxalic acid were subsequently added. After 1 hour, the precipitated solid was filtered off, and the filtrate was evaporated under reduced pressure. The crude product was filtered through silica gel with n-heptane/1-chlorobutane (1:1), giving 72.7 g (91% of theory) of 6-bromo-2-fluoro-3-pentylphenyl 6-bromo-2-fluoro-3-methylbenzoate as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2)[C:29]([CH3:30])=[O:31]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 14 (200 mg, 1.25 mmol), dimethylaminopyridine (20 mg) and triethylamine (0.94 mL) in THF cooled to 0° C. was added a solution of acetyl chloride (0.30 mL, 4.16 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 3 h. THF was removed in vacuo and ethyl acetate (40 mL) was added. The solution was washed with water (20 mL×2). The solution was dried using sodium sulfate and solvent was removed in vacuo. The residue was dissolved in methanol (5 mL) and 3N NaOH solution(1 mL) was added. The reacted was allowed to proceed overnight. The reaction mixture was evaporated and water (10 mL) was added. The product was extracted with ethyl acetate (30 mL×3) and the solvent was removed in vacuo. The product was crystallized in acetate and washed with ether. 128 mg (50% yield) of grew powder 15 was obtained. mp: 161° C. 1H NMR (DMSO-d6, ppm): 10.84 (s, 1 H, NH), 9.62 (s, 1 H, NH), 7.75 (d, 1 H, J=2.1 Hz, Ar--H), 7.22-7.10 (m, 2 H, Ar--H), 6.20 (s, 1 H, Ar--H), 6.43-6.40 (dd, 1 H, J=2.4, 8.5 Hz, Ar--H), 5 5.18-5.15 (t, 1 H, J=5.5 Hz, OH), 4.57-4.56 (d, 2 H, J=5.4 Hz, CH2OH), 2.01 (s, 3 H, CH3), Anal. (C11H12N2O2), C, H, N.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:6])=[O:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(O)C>[C:8]1(/[CH:7]=[CH:3]/[C:4](=[O:5])/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1

Procedure:
(3) Hill and Barbaro, Experiments in Organic Chemistry. Contemporary Publishing Co. of Raleigh, Inc., Raleigh, 1996. 5 g of sodium hydroxide, dissolved in 25 ml of water and 25 ml of 95% ethanol, was cooled to 20 to 25° C. 2.9 g (50 mmol) of acetone and 10.6 g (100 mmol) of benzaldehyde were added, and a yellow precipitate formed. After 20 minutes the solution was filtered, and the solid was recrystallized from ethyl acetate to afford 10.1 g (86.3%) of bright-yellow platelets: mp 111.9-112.5° C. (lit. mp 112° C., Hill and Barbaro, supra). 1H NMR (250 MHz) δ 7.79-7.73 (d, 1 H), 7.65-7.61 (m, 4 H), 7.44-7.41 (t, 6 H), 7.13-7.07 (d, 1 H) ppm.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)=[O:14])=[CH:11][N:10]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[N:7]=[CH:8][N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C1COCC1>[C:31]1([O:30][C:28](=[O:29])[NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:13]([C:12]3[C:5]4[C:4]([NH2:3])=[N:9][CH:8]=[N:7][C:6]=4[N:10]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:11]=3)=[O:14])[CH:16]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Oc3ccccc3)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
NaH (0.21 g, 5.1 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (1.5 g, 4.7 mmol) in THF. (35 mL). After stirring for 1 h at room temperature, phenyl chloroformate (0.82 g, 5.4 mmol) was added. The resulting reaction mixture was stirred for an additional 3.5 h, quenched with water (15 mL), and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated sodium bicarbonate (20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude reaction mixture was triturated (CH2Cl2) and filtered to afford the title compound as a white solid (1.78 g, 87%). MS: 442.3 (MH+); HPLC Rf: 2.5 min. (HPLC method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(O)CCCC.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:17][CH2:18][CH2:19][CH2:20][NH2:21])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: NCCCN
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCO
Product: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Yield: 87 %

Procedure:
To a sealed tube was charged a mixture of 6,9-dichloro-1,2,3,4-tetrahydroacridine (1.0 g, 3.97 mmoL), 1,3-diaminopropane (1.67 mL, 19.83 mmoL) and 4 mL 1-pentanol. The mixture was heated to 160 degree Celsius for 24 h. After cooled down and saturated sodium bicarbonate was added, the mixture was extracted with dichloromethane three times. The combined extract was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel with 10-20% MeOH/CH2Cl2 (1% ammonium hydroxide) to give the desired product as brown oil (1.0 g, 87%).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)C=C.Cl[C:22]1[CH:27]=CC=C[C:23]=1Cl>>[CH2:27]([C:6]1[C:5]([OH:4])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[CH:22]=[CH2:23]
Reactant: C=CCOc1ccc2c(ccn2-c2ccc(Cl)cc2)c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2c1ccn2-c1ccc(Cl)cc1

Procedure:
5-allyloxy-N-(4-chlorophenyl)indole (Step B; 1.4 g, 4.93 mmol) was refluxed in 20 mL 1,2-dichlorobenzene for 4 hours. The reaction mixture was cooled and immediately purified by flash chromatography on silica gel (gradient elution: hexane then 10% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-methoxybenzyl chloride (0.41 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[CH3:15][C:13](=[CH2:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-N-(2-methyl-4-nitrophenyl)acrylamide was prepared as described in Example 1a starting from 2-methyl-4-nitroaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.98 (3H, s), 2.34 (3H, s), 5.59 (1H, s), 5.91 (1H, s), 7.74 (1H, d, J=8.8 Hz), 8.07 (1H, dd, J=8.8 Hz, J=2.7 Hz), 8.15 (1H, d, J=2.6 Hz), 9.53 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:4][CH:3]=1.C[CH2:23][CH2:24][C:25]([CH2:27][C:28]([O-])=[O:29])=O.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([C:25]1[CH2:27][C:28](=[O:29])[C:3]2[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:10](=[O:19])[C:11]4=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]4[C:13]3=[O:14])[CH:4]=2)[N:1]=1)[CH3:23]
Reactant: CCCC(=O)CC(=O)[O-]
Reactant: Nc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC1=Nc2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)C1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of N-(2-(4-aminophenoxy)ethyl)phthalimide (4.2 g), methylpropionylacetate (1.94 g) and p-toluenesulphonic acid (100 mg) in benzene (95 ml) was stirred and heated at reflux for 3 hours with azeotropic removal of water. Volatile material was then removed by evaporation and the residue was added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (25 ml). The mixture was heated at reflux for 15 minutes and then cooled to ambient temperature. Hexane (80 ml) was added to the mixture which was triturated to give a solid. The solid was collected by filtration and washed with hexane. Ethyl acetate (70 ml) was added to the solid and the mixture was heated at reflux for 5 minutes and then cooled in an ice-bath. The undissolved solid was collected by filtration and washed with ethyl acetate to give 2-ethyl-6-(2-phthalimidoethoxy)-4-quinolone (2.5 g) as an off white solid, m.p. 168°-171° C.; NMR (d6 -DMSO): 1.24(t, 3H), 2.59(q, 2H), 4.0(t, 2H), 4.28(t, 2H), 5.87(s, 1H), 7.18(dd, 1H), 7.45(m, 2H), 7.84(m, 4H), 11.4(br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11]C(=O)C)[S:8][C:5]2=[N:6][CH:7]=1.[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1>>[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34]([C:2]5[CH:3]=[C:4]6[N:10]=[C:9]([NH2:11])[S:8][C:5]6=[N:6][CH:7]=5)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(=O)Nc1nc2cc(Br)cnc2s1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6sc(N)nc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using N-(6-bromo[1,3]thiazolo[5,4-b]pyridin-2-yl)acetamide (Journal of Heterocyclic Chemistry (2003), 40, 261-268) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.38 (m, 2H), 7.88 (brs, 2H), 7.83 (d, 1H), 7.72 (d, 1H), 7.76 (dd, 1H), 7.05 (d, 1H), 4.63 (s, 2H), 4.33 (m, 2H), 3.83 (m, 2H), 2.72 (m, 2H), 2.46 (s, 2H), 1.61 (m, 2H), 0.83 (s, 6H); MS (EI) for C25H26N6OS: 459 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:13][C:14]([Cl:20])([Cl:19])[C:15](=[NH:18])OC.[C:21]([OH:24])(=[O:23])[CH3:22]>>[C:21]([OH:24])(=[O:23])[CH3:22].[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15](=[NH:18])[C:14]([Cl:20])([Cl:19])[Cl:13]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: Nc1cnc2ccccc2c1N
Solvent: CC(=O)O
Product: N=C(Nc1cnc2ccccc2c1N)C(Cl)(Cl)Cl
Yield: 80 %

Procedure:
In the same manner as in Ref. Ex. 17, 1.59 g of 3,4 -diaminoquinoline (V-1) in 20 ml of acetic acid was treated with 1.9 g of methyl trichloroacetimidate to give 3.13 g (yield: 80%) of the titled compound (VIII-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](F)=[CH:10][C:11]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:28]CC)C>CCCCCC.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH:9]=[CH:10][CH:11]=[O:28])=[CH:4][CH:3]=1
Reactant: CC(C)(C(F)=CC#N)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C=CC=O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 97 %

Procedure:
A solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentenenitrile, (Z)- (15.6 g, 69.7 mmol) in diethyl ether is treated dropwise with diisobutylaluminum hydride (83.6 mmol, 83.6 mL of a 1M solution in hexane) over 90 minutes at -45° C. under nitrogen, stirred at -40° C. for 35 minutes, and diluted sequentially with water and 2N hydrochloric acid at -10° C. The resultant aqueous mixture is stirred at room temperature for one hour and extracted with diethyl ether. The organic extracts are combined, washed.sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown oil (15.34 g, 97% yield).