Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[C:32]([F:33])=[CH:31][C:15]2[N:16]3[C:20]([CH2:21][C:22](=[O:24])[NH:23][C:14]=2[CH:13]=1)=[N:19][N:18]=[C:17]3[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43]Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([N:41]([CH:46]([CH3:48])[CH3:47])[C:42](=[O:45])[CH2:43][N:23]1[C:22](=[O:24])[CH2:21][C:20]2[N:16]([C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]=2)[C:15]2[CH:31]=[C:32]([F:33])[C:12]([F:11])=[CH:13][C:14]1=2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CBr
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of KHMDS (0.5 M in THF, 16.6 mL, 8.33 mmol) at 0° C. was added 8,9-difluoro-1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(C) (2.0 g, 6.4 mmol) in DMF (20 mL). The reaction was stirred at 0° C. for 35 minutes, was cooled to −10° C., and a solution of N-benzyl-2-bromo-N-isopropyl-acetamide (Preparation 1(C) (1.9 g, 7.0 mmol) in DMF (20 mL) was added. The reaction was stirred at −10° C. for 2 hours and at room temperature for 24 hours. The reaction was quenched with a pH 6.8 buffer and the aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (4×), dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2 to 3% MeOH in CH2Cl2) provided 2.01 g of N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide. 1H NMR (CD2Cl2) δ 7.60-7.17 (m, 11H), 6.75 (q, 1H), 4.85-4.38 (m, 4H), 4.10 (q, 1H), 3.60 (q, 1H), 3.41 (s, 1H), 1.21 (q, 3H), 1.13 (q, 3H); MS 502.4 (M+1), 500.3 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:7]=1[C:8]([O:10]CC1C=CC(F)=CC=1F)=[O:9].C(OC1C=CC(C=O)=CC=1C(O)=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)OCc2ccc(F)cc2F)c1
Agent: O=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Product: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)O)c1

Procedure:
2-(2,4-Difluorobenzyloxy)-5-formylbenzoic acid was prepared from 2,4-difluorobenzyl 2-(2,4-difluorobenzyloxy)-5-formylbenzoate (1.2 g, 1 eq) using the same procedure as for 2-benzyloxy-5-formylbenzoic acid. The product was obtained as a white powder (746 mg, 89%). 1H NMR (CDCl3) δ9.97 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ar).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:23]([O:13][C:12]([C:4]1[CH:3]=[C:2]([NH2:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14])[CH:22]=[CH2:21]
Reactant: Nc1cc(C(=O)O)nc2ccccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(N)c2ccccc2n1

Procedure:
4-Amino-2-quinoline carboxylic acid (800 mg, 4.2 mmol) in DMF (10 ml) and K2CO3 (1.17 g, 8.5 mmol) was stirred at ambient temperature in the presence of allyl bromide (1.47 ml, 17 mmol) for 24 hours. The solvent was evaporated and the crude residue purified by subjecting to silico-gel chromatography, eluting with petroleum ether ethyl acetate 1/1) to give 2-allyloxycarbonyl-4-amino-quinoline (170 mg, NMR (CDCls): δ4.75-5 (m, 4H); 5.2-5.0 (m, 2H); 5.9-6.35 (m, 1H); 7.35-8.3 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:3]#[N:4].[C-]#N.[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([C:24](=[O:25])[CH:7]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH2:6][C:5](=[O:14])[C:2]([CH3:15])([CH3:1])[C:3]#[N:4])=[CH:22][C:21]=1[O:28][CH3:29]
Reactant: CC(C)(C#N)C(=O)C=Cc1ccncc1
Reactant: COc1cc(C=O)ccc1Cl
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C(CC(=O)C(C)(C)C#N)c2ccncc2)ccc1Cl
Reaction time: 0.25 h
Yield: 222.9 %

Procedure:
A solution of the product of Example 1 Step 1 (4.0 g, 20.0 mmol) in DMF (7 ml) was added to a solution of sodium cyanide (300 mg, 6.12 mmol) in DMF (7 ml) over 15 minutes at room temperature. After stirring for a further 15 minutes, a solution of 4-chloro-3-methoxy-benzaldehyde (F. Claudi et al., J. Med. Chem., 1992, 35, 4408) (640 mg, 3.75 mmol) in DMF (6 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours and then diluted with water and the pH of the solution adjusted to 9 with aqueous sodium hydrogen carbonate solution. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/ethanol/0.880 ammonia solution (90:9:1) to give the title compound (3.1 g, 42%); MS (ES+) m/e 371, 373 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Br[C:18]1[S:22][C:21]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[CH:20][CH:19]=1.[Cl-].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O.C(OCC)(=O)C>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:18]2[S:22][C:21]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:20][CH:19]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH:11]([CH3:13])[CH3:12]
Reactant: Brc1ccc(-c2nnn[nH]2)s1
Reactant: CC(C)COc1ccc(B(O)O)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(-c2ccc(-c3nnn[nH]3)s2)cc1C#N
Reaction time: 0.17 h
Yield: 13.8 %

Procedure:
In a mixed solution of 10 ml of 1,4-dioxane and 5 ml of a 1 M aqueous sodium carbonate solution were dissolved 0.31 g of (3-cyano-4-isobutoxyphenyl)boronic acid, 267 mg of 5-(5-bromo-2-thienyl)-1H-tetrazole, and 0.56 g of triphenylmethane chloride, and the solution was heated at 100° C. for 1.5 hours in the presence of 0.11 g of tetrakis-(triphenylphosphine)palladium. The reaction solution was diluted with water and ethyl acetate and then filtrated through celite. Conc. hydrochloric acid was added to the filtrate to make the solution pH=1, and the solution was stirred for 10 minutes. The solution was neutralized and extracted with a 1 M aqueous sodium hydroxide solution and the resulting aqueous layer was acidified with 1 M hydrochloric acid. Extraction with ethyl acetate was conducted and the resulting organic layer was washed with brine, followed by drying and concentration under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:THF:methanol:acetic acid=88.9:10:1:0.1) and then recrystallized from a mixed solvent (chloroform:THF:methanol:acetic acid=88.9:10:1:0.1) to obtain 52 mg of 2-isobutoxy-5-[5-(lH-tetrazol-5-yl)-2-thienyl]benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH2:28][C@H:29]([C:31](OC)=[O:32])[N:30]=1)=[CH:9]2.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].CO>O1CCCC1.O>[OH:32][CH2:31][C@H:29]1[CH2:28][S:27][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[N:30]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@@H](C(=O)OC)CS3)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@@H](CO)CS3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of triphenylphosphine oxide (1.3 g) in dichloromethane (3 mL) was added dropwise trifluoromethanesulfonic anhydride (0.59 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The obtained suspension was diluted with dichloromethane (5 mL), and a solution of N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-S-trityl-D-cysteine methyl ester (0.60 g) and thioanisole (0.74 mL) in dichloromethane (8 mL) was added. The reaction mixture was stirred at 0° C. for 2 hr, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1; volume ratio) to give a mixture(0.39 g) of methyl (4S)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. The obtained mixture of the ester and triphenylphosphine oxide was dissolved in tetrahydrofuran (3 mL), sodium borohydride (0.010 mg) was added at 0° C., and methanol (1.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2 hr. Water was added, the mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (4:1:0-0:10:1, volume ratio) to give the title compound (0.076 g, yield 20%) as colorless crystals. melting point 146.6-146.7° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([NH:10][NH2:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1)[CH3:2].[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH2:1]([S:3][C:4]1[N:9]2[C:18]([CH3:19])=[N:11][N:10]=[C:8]2[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCSc1nc(NN)cc(-c2ccccc2)n1
Product: CCSc1nc(-c2ccccc2)cc2nnc(C)n12

Procedure:
Using the method of Example 19, 2-ethylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethyl orthoacetate to provide 5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine which was recrystallized from a 50/50 mixture of ethyl acetate/cyclohexanes to provide white crystals of 5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 219.5°-220° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (15%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[NH:5][C:6]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[N:7]2.[CH3:20][O-:21].[Na+].CO.O>CN(C=O)C.C(O)(=O)C>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:19])[NH:5][C:6]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:7]2)=[C:2]([O:21][CH3:20])[CH:11]=1
Reactant: O=c1[nH]c(-c2ccncc2)nc2cc(F)cc(F)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)cc2nc(-c3ccncc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 5,7-difluoro-2-pyridin-4-yl-3H-quinazolin-4-one (0.20 g, 0.80 mmol) in DMF (3 mL) was added sodium methoxide in methanol (0.43 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water was added, the mixture was acidified with acetic acid to pH approximately 4-5, and the precipitated solid was filtered off to obtain 7-fluoro-5-methoxy-2-pyridin-4-yl-3H-quinazolin-4-one as a yellowish solid. Yield: 0.20 g (83%).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[N:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][C:21]=5[C:11]=3[CH:10]=[C:9]([C:23](OCC)=[O:24])[N:8]=2)[CH2:16][CH2:15][CH2:14]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[OH-].[Na+]>O1CCCC1.O>[C:1]1([C:7]2[C:12]3[N:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][C:21]=5[C:11]=3[CH:10]=[C:9]([CH2:23][OH:24])[N:8]=2)[CH2:16][CH2:15][CH2:14]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cc2c3cccc4c3n(c2c(-c2ccccc2)n1)CCC4
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cc2c3cccc4c3n(c2c(-c2ccccc2)n1)CCC4
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
1.4 g (4 mmol) of 8-phenyl-10-ethoxycarbonyl-5,6-dihydro-4H-pyrido[4',3':4,5]pyrrolo[3,2,1-ij]quinoline were dissolved in 25 ml of tetrahydrofuran and added dropwise to a mixture of 0.5 g (13 mmol) of lithium aluminium hydride and 10 ml of ether at a temperature of 30° C. After cooling, 1 ml of water and 1 ml of 2N sodium hydroxide solution were added dropwise successively. After boiling for 15 minutes the solid was filtered off. The filtrate was evaporated in vacuum. The residue was boiled with 20 ml of ethanol and kept at 0° C. for 24 hours. The solid was sucked off and dried. Obtained were 0.95 g of the desired product having a melting-point of 209°-211° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])[CH:13]=1>>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])[CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCCc1cccnc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCc5cccnc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.34 min.; HPLC purity 99%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O.Cl.Cl.[NH2:21][O:22][CH2:23][CH2:24][NH2:25].N1C=CC=CC=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[NH2:25][CH2:24][CH2:23][O:22][N:21]=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCCCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: COCCCCC(=NOCCN)c1ccc(C(F)(F)F)cc1

Procedure:
20.4 Mmol (5.3 g) of 5-methoxy-4'-trifluoromethylvalerophenone (melting point 43°-44° C), 20.5 mmol (3.1 g) of 2-aminooxyethylaminedihydrochloride and 10 ml of pyridine were refluxed for 15 hours in 20 ml of absolute ethanol. After evaporating the pyridine and the ethanol in vacuo, the residue was dissolved in water. This solution was washed with petroleum ether and 10 ml of 50% sodium hydroxide solution were then added. Then three extractions with 40 ml of ether were carried out. The ether extract was washed successively with 20 ml of 5% sodium bicarbonate solution and 20 ml of water. After drying on sodium sulphate, the ether layer was evaporated in vacuo. Toluene was then evaporated another three times (to remove the pyridine) and the oil thus obtained was dissolved in 15 ml of absolute ethanol. An equimolar quantity of maleic acid was added to said solution and the solution was then heated until a clear solution was obtained. The ethanol was then removed in vacuo and the residue was crystallized from 10 ml of acetonitrile at +5° C. After sucking off and washing with cold acetonitrile, it was dried in air. The melting point of the resulting title compound was 120°-121.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:22]([O:24][C:25](=[O:39])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=2)[N:29]=[N:28]1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[N:34][C:35]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])=[CH:36][CH:37]=2)[N:29]=[N:28]1)[CH3:23]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Product: CCOC(=O)Cn1cc(-c2ccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)nc2)nn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and ethyl[4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl]acetate (128 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl.[C:2]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]([F:36])([F:35])[C@@H:21]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:2]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C@H:21]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([F:35])([F:36])[F:19])=[CH:27][CH:26]=2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C1CCNCC1
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CCN(Cc2ccc([C@H](NS(C)(=O)=O)C(F)(F)F)cc2)CC1
Yield: 62 %

Procedure:
Charge a five liter round-bottom flask with DCM (1.5 L) and 4-tert-butylpiperidine hydrochloride (89 g, 0.5 mol). Add triethylamine (101.4 g, 1.0 mol) to the mixture at 21° C. followed by N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)ethyl]methanesulfonamide (155 g, 0.55 mol), and acetic acid (36 g, 0.6 mol). Add sodium triacetoxyborohydride (318.6 g, 1.5 mol) portion-wise and stir the suspension at 22° C. for 15 hours. Add saturated aqueous solution of sodium bicarbonate (1800 mL) slowly with stirring until pH of the mixture is 8. Separate the organic layer and extract the aqueous layer with DCM (3×2000 mL). Dry the combined organic layers over MgSO4; filter; collect the filtrate; and concentrate the filtrate under vacuum. Purify the residue on silica gel column chromatography eluting with DCM:MeOH (100 to 95%) to provide the title compound as an off-white solid (126 g, 61.9%). MS (m/z): 407 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([NH:21][C:27]([CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:28])[CH:18]=[CH:17][N:16]2[CH:22]=1
Reactant: O=C(O)C1CCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(N)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(NC(=O)C3CCC3)cc2n1
Yield: 15 %

Procedure:
As described for Example 47, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-7-ylamine (92 mg, 0.32 mmol) was converted, using cyclobutanecarboxylic acid instead of 3-pyridylacetic acid, to the title compound (16.4 mg, 15%) which was obtained as an off-white solid. MS: m/e=373.3 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F-].[Na+].O>O1CCCC1>[CH2:7]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:22][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(CO)cc1
Yield: 99.5 %

Procedure:
To a suspension of lithium aluminum hydride (4.05 g) in tetrahydrofuran (475 ml) was added dropwise a solution of 4-octyloxybenzaldehyde (25 g) in tetrahydrofuran (25 ml) at 55°~60° C. The reaction mixture was stirred under reflux for 1 hour, and thereto was added sodium fluoride (35.84 g) and water (11.52 ml) under ice-cooling. The mixture was stirred for 30 minutes, and filtrated. The filtrate was evaporated in vacuo to give 4-octyloxybenzyl alcohol (25.1 g) as crystals.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=O.C[N:23](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:14][C:9]1[CH:8]=[C:7]([C:5]2[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:3][NH:2][N:23]=2)[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: CN(C)C=C(C(=O)c1ccc(F)c(F)c1)c1ccncc1
Product: Fc1ccc(-c2n[nH]cc2-c2ccncc2)cc1F
Yield: 90 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 2.54 g (8.81 mmol) of 3-dimethylamino-1-(3,4-difluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one obtained in Example 6-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 2.05 g of the title compound as a white powder. (Yield: 90%)