Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[NH:21][N:22]=[C:23]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:21]([CH3:32])[N:22]=[C:23]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OCc1ccccc1
Reaction time: 18 h
Yield: 69.4 %

Procedure:
4-(8-Benzyloxy-7-methoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.50 g, 6.15 mmol) is dissolved in N,N-dimethylformamide (72 ml). K2CO3 (1.70 g, 12.3 mmol) and iodomethane (421 μl, 6.76 mmol) are subsequently added at room temperature, and the reaction mixture is stirred for 18 h (TLC (HPTLC) monitoring). The mixture is then added to water (500 ml) and stirred for 30 min. The precipitate obtained is filtered off with suction and chromatographed over flash silica gel (120 g, solvent gradient cyclohexane/0-100% by vol. of ethyl acetate/0-40% by vol. of ethanol). The residue from the product fractions is suspended in 2-propanol, filtered off with suction and dried in a high vacuum, giving 4-(8-benzyloxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (1.79 g, 4.27 mmol) as a solid having a melting point of 230.4° C. MS: 421.1 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[C:32]([C:35]#[N:36])([CH3:34])[CH3:33].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([Cl:22])=[C:24]([C:32]([C:35]#[N:36])([CH3:33])[CH3:34])[CH:25]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ccc(Cl)c(C(C)(C)C#N)c4)c3)cc2s1
Yield: 41.5 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 4-chloro-3-(1-cyano-1-methylethyl)benzoic acid (240 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (112 mg, 42%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])#[N:6].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1.O>[C:5]([C:7](=[C:2]([CH3:4])[CH3:1])[C:8]([O:10][CH3:11])=[O:9])#[N:6]
Reactant: COC(=O)CC#N
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C(C)C
Yield: 58.4 %

Procedure:
87 g (1.5 mol) of acetone were initially charged in 100 ml of benzene. After addition of 131 g (1.33 mol) of methyl cyanoacetate, 16 g (0.28 mol) of acetic acid and 9.7 g (0.13 mol) of ammonium acetate, the mixture was heated at reflux on a water separator for 10 hours. For work-up, the mixture was washed twice with ¼-concentrated hydrochloric acid and water. The solution was dried with magnesium sulfate and the solvent was removed, and the resulting crude product was distilled. 108 g (55% yield) of methyl 2-cyano-3-methyl-but-2-enoate were isolated (B.p. 95° C./5.2 mbar).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH2:63][CH2:64][OH:65])[O:55][C:54]=4[N:66]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:52][C:53]4[N:58]([CH2:59][C:60]#[N:61])[C:57](=[O:62])[CH:56]([CH2:63][CH2:64][OH:65])[O:55][C:54]=4[N:66]=3)=[CH:46][CH:45]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)C(=O)C(CCO)O4)cc2)CCC1
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: N#CCN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 61.1 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(cyanomethyl)-3-(2-hydroxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.027 mmol) was reacted to afford the title compound (7.5 mg). 1H NMR (500 MHz, CH3OD) 7.67 (s, 1H), 7.41 (d, 2H), 7.38 (d, 2H), 7.30 (m, 3H), 7.24 (m, 2H), 5.18 (dd, 1H), 5.11 (s, 2H), 3.81-3.89 (m, 2H), 2.71-2.77 (m, 2H), 2.52-2.58 (m, 2H), 2.27-2.30 (m, 1H), 2.16-2.23 (m, 2H), 1.93-2.10 (m, 1H). LCMS (Method A): RT=3.78 min, M+H+=456.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[C:11](=S)=[S:12].C(N(CC)CC)C.IC.[CH3:23][S:24]([CH3:26])=O>>[CH3:23][S:24][C:26]([S:12][CH3:11])=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: S=C=S
Reactant: CS(C)=O
Solvent: CI
Solvent: CCN(CC)CC
Product: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (60.0 g, 416 mmol) in DMSO (150 mL) was added carbon disulfide (25 mL, 420 mmol) and triethylamine (116 mL, 832 mmol). The mixture was stirred at room temperature for 1 h then cooled to 0° C. and 52 mL (830 mmol) of iodomethane was added. The reaction mixture was allowed to slowly warm to room temperature and stirred for 15h. The mixture was decanted into an ice—H2O mixture and a solid was precipitated by agitation of the solution. The solid was collected by filtration, washed with a 1:1 mixture of petroleum ether: Et2O, and dried under vacuum to provide 29.7 g (28.8%) of 5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione as an orange solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CO.Cl[C:9]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1.Cl>CC(N(C)C)=O>[CH3:1][O:2][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1
Reactant: COC(=O)c1cc(Cl)nc(-c2ccccc2)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25% NaOMe/methanol solution (92 μL) was added to an MeOH (2 mL) solution of methyl 2-chloro-6-phenylpyridine-4-carboxylate (1100 mg), and stirred at room temperature for 2 hours. Further, 25% NaOMe/methanol solution (92 μL) was added to it, and stirred under heat with refluxing for 2 hours and 30 minutes. DMA (3 mL) was added to it, and stirred overnight at 130° C., then 25% NaOMe/methanol solution (92 μL) was added to it, and stirred at 130° C. for 7 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, dried, and purified through reversed-phase high-performance liquid chromatography [acetonitrile/water+0.11% trifluoroacetic acid] to obtain the title compound as a white powder.
Reaction SMILES: Cl.COC(OC)CNC.[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>[Pd].C(O)C>[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH2:14][OH:15].[CH3:10][O:11][C:12]1[C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=[CH:16][C:13]=1[CH3:14]
Reactant: COc1c(C=O)ccc2c1OCO2
Agent: [Pd]
Agent: CNCC(OC)OC
Agent: Cl
Solvent: CCO
Product: COc1c(C)ccc2c1OCO2
Product: COc1c(CO)ccc2c1OCO2
Yield: 1 %
Yield: 0.8 %

Procedure:
To 100 ml of ethanol, were charged 1.83 ml of ethanol containing 22.2 g of hydrochloric acid dissolved therein, 3.96 g of N-methylaminoacetaldehyde dimethylacetal, 1.0 g of 2-methoxy-3,4-methylenedioxybenzaldehyde, 10 ml of ethanol and 0.12 g of 5% palladium on carbon catalyst, and hydrogenation was carried out at room temperature for 3.5 hours. The amount of hydrogen absorption was 120% of the theoretical amount. After the reaction was over, the catalyst was filtered out and 2N NaOH aqueous solution was added to the reaction mixture to make the filtrate alkaline (pH 11). The resulting mixture was then extracted with ethyl acetate. The liquid extract was analyzed by GC and LC to show 1.47 g of 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal (yield 93%), 0.012 g of 2-methoxy-3,4-methylenedioxybenzylalcohol (yield 1%) and 7.4 mg of 2-methoxy-3,4-methylenedioxy toluene (yield 0.8%), while 2-methoxy-3,4-methylenedioxybenzaldehyde of the starting material not being recognized. The selectivity to the desired 2-methoxy-3,4-methylenedioxy-N-methylbenzylamino dimethylacetal was 99%.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23]Br)[CH:19]=[CH:20][CH:21]=1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3cccc(OC)c3)cs2)c(C)s1
Yield: 64.5 %

Procedure:
32 mg (0.133 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 2 mL of reagent grade acetone. 3′-Methoxy-2-bromo acetophenone (0.155 mmol; 36 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 2.5 h The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo. The solid was purified on 1 mm silica plate eluting with 25% ethyl acetate/hexane to afford 31 mg (63% yield) of methyl 4-[4-(3-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[C:4]([C:12]([NH:14][CH:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])[CH:3]=1.CC1(C)COB([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]1[CH:10]=[CH:11][C:7]([C:5]2[S:6][C:2]([C:39]3[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=3)=[CH:3][C:4]=2[C:12]([NH:14][CH:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:13])=[CH:8]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccccc1)NC(=O)c1cc(Br)sc1-c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)Cc2ccccc2)c(-c2ccoc2)s1
Reaction time: 4 h

Procedure:
1,1-dimethylethyl [2-({[5-bromo-2-(3-furanyl)-3-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (140 mg, 0.277 mmol), 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (54 mg, 0.277 mmol), Pd(PPh3)4 (16 mg, 13.8 μmol) and K2CO3 (153 mg, 1.11 mmol) in dioxane (2.3 mL) and H2O (462 uL) were combined in a sealed tube. After 4 h at 80° C., additional 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (54 mg, 0.277 mmol) and Pd(PPh3)4 (16 mg, 13.8 μmol) were added. After an additional 12 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly: LCMS (ES) m/z=507 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1.C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH:35]=O)[CH3:30].C([BH3-])#N.[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35][N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)[CH3:30]
Reactant: c1cncc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3cccnc3)CC2)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a solution of piperidin-4-yl-pyridin-3-yl-amine dihydrochloride (37.5 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in ethanol (1 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate B21, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 11.3 mg (23%) of the title compound. MS (ISP): 326.3 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5]1=[O:20]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: Cn1ccc2cc(-c3ccccn3)ccc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(Br)c2cc(-c3ccccn3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
At 0° C., bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was added dropwise to 2-methyl-6-pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 20 min. Extractive work up with CH2Cl2 and purification by silica gel chromatography (PE:EA=5:1-1:1) gave the title compound (73.0 mg, 47.7%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.79 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 1H), 3.64 (s, 3H). LCMS: 314.9 (M+H)+
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1OC)([O:3][CH2:4][CH3:5])=[O:2].C([Al](CC)CC)C.[CH:28]#[N:29].C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1[C:28]#[N:29])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C#N
Reactant: CCOC(=O)CCCCCCC1=C(OC)C(O)CC1=O
Agent: CC[Al](CC)CC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCC1=C(C#N)C(O)CC1=O
Yield: 44.4 %

Procedure:
The procedure similar to that of Step 3 (a) of Example 1 was repeated using 9.4 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-hydroxy- 2-cyclopenten-1-one, 8.2 g of triethyl aluminum, 2.0 g of hydrocyanic acid, and a mixed solvent of benzene and toluene to provide 4.1 g of oily 2-(6'-carbethoxyhexyl)-3-cyano-4-hydroxy-2-cyclopenten-1-one.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: NC1C=CCCCC1
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Yield: 61 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), succinic anhydride (1.0 g) and acetic acid (10 ml) was heated under reflux for 24 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The oily product thus obtained was purified by column chromatography on silica gel to obtain 1.07 g of N-(2-cycloheptenyl)succinimide [Compound (214)].
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29]C(C(F)(F)F)=CN=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C#C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[F:59][C:60]1C=CC(I)=[CH:62][C:61]=1[CH3:67]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][C:60]([F:59])=[C:61]([CH3:67])[CH:62]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(I)ccc1F
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Agent: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Cc1cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1F
Yield: 67 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-fluoro-4-iodo-2-methylbenzene in 67% yield.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14]>>[CH2:1]([NH:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC/C=C/c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using trans-cinnamic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 440 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C1N2CN3CN(C2)CN1C3.O.[C:34](=O)(O)[O-:35].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH:34]([C:20]1[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH:19]=1)[CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=1)=[O:35]
Reactant: O=C([O-])O
Reactant: COc1ccccc1CNC(=O)c1ccc(C(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
8.7 g of N1-(2-methoxybenzyl)-4-(trifluoromethyl)benzamide was dissolved in 20 ml trifluoroacetic acid, and 3.9 g of hexamethylene tetramine was added, and the mixture was reacted at 85° C. for 3 hours. The reaction solution was returned to room temperature, and water and ethyl acetate were added, and further sodium bicarbonate was added until the pH reached 8. After extracting with ethyl acetate, the extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (2:1), 4.2 g of N1-(5-formyl-2-methoxybenzyl)-4-(trifluoromethyl)benzamide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([C:50]([F:60])([F:61])[F:49])[CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 63.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (74 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethyl-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (81 mg, yield 59%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([OH:18])[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(=O)([O-])[O-].[K+].[K+].Cl[N:28]1[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[NH:29]1.C(Cl)Cl>CN(C)C=O.CO>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][N:28]3[N:29]=[C:30]([O:36][CH3:37])[CH:31]=[C:32]([O:34][CH3:35])[NH:33]3)[C:15]([Cl:19])=[CH:14][C:13]=2[F:20])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC1=CC(OC)=NN(Oc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc2Cl)N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
4-Chloro-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (prepared according to the procedure as described in U.S. Pat. No. 5,281,571) (0.25 g, 0.76 mMol) was dissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (0.13 g, 0.91 mMol) and 2-chloro-4,6-dimethoxytriazine (0.16 g, 0.91 mMol) were added. The suspension was stirred at 90° C. for 2 hours under a nitrogen atmosphere and processed. The residue was subjected to column chromatography on silica gel eluting with methylene chloride:methanol, 99:1, to give the title compound (0.29 g, 81.6%). 1H NMR (CDCl3, TMS): 4.01 (6H, s), 4.07 (3H, m), 7.35 (1H, d, J=9.1 Hz), 7.45 (1H, d, J=6.6 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]([F:25])([F:26])[F:27])=[C:17]([CH3:16])[CH:18]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ccc1OC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OC(F)(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (562 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (550 mg, 2.15 mmol, Step-1 of Intermediate-1) and 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (550 mg, 2.15 mmol, Amine-80, single enantiomer) in a similar manner to Intermediate-2.