Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[CH3:2].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:28]O>>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:28]=[C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=3)[NH:23][C:22]2=[O:27])=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3ccc(F)cc32)cc1
Yield: 41 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-phenylamine (161 mg, 1.3 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100 mg, 0.56 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (88 mg, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16]CC)=[O:15])[C:5]2=[O:19].[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:19]
Reactant: CCOC(=O)c1cn(CC)c2ncc(Br)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(Br)cnc21
Temperature: 175 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 15, 470 mg, 1.44 mmol) dissolved in ethanol (30 mL) was added 10% potassium hydroxide (2.9 mL, 2.89 mmol) and the mixture was heated to 175° C. for 1 h. The solvent was evaporated under reduced pressure to a residue. Water (20 mL) was added to the residue and the pH was adjusted to 3 with dilute hydrochloric acid (2N) to give solid precipitate which was filtered and dried to afford 340 mg (80%) of 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])/[C:3](/[CH2:17][S:18][C:19](=[O:21])[CH3:20])=[CH:4]/[C:5]1C=C[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.NCCC(OCC1C=CC=CC=1)=O>>[O:1]=[C:2]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])/[C:3](/[CH2:17][S:18][C:19](=[O:21])[CH3:20])=[CH:4]/[C:5]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)SC/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1cccc2ccccc12)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
The above (Z) acid is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>[Ni].C(O)(C)C>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:25]
Reactant: [H][H]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: CCOCC(O)(COCC)C(N)Cc1cccc2ccccc12
Yield: 90 %

Procedure:
A mixture of α,α-diethoxymethyl-β-nitro-1-naphthalenepropanol (7.75 g) and Raney nickel (0.8 g) in isopropanol (100 ml) was stirred under hydrogen at atmospheric pressure until hydrogen absorption stopped. The mixture was then degased for 15 minutes in vacuo and filtered through celite. The filtrate was evaporated in vacuo to yield α,α-diethoxymethyl-β-amino-1-naphthalenepropanol (6.37 g) as an oil.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C([N:21]([CH2:32][CH3:33])[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[CH3:30])C.[CH2:34]([N:41]1[CH2:45]C[CH:43](C#N)[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH2:34]([N:41]1[CH2:42][CH2:43][CH:33]([C:32]2[NH:21][C:22](=[O:31])[C:23]3[C:24]([CH:30]=2)=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=3)[CH2:45]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CC1CCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc2c(=O)[nH]c(C3CCN(Cc4ccccc4)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
A solution (400 mL) of diisopropylamine (26.9 g) in tetrahydrofuran was cooled to −5° C. and 1.57 M n-butyllithium hexane solution (154 ml) was added dropwise to the solution. After stirring at 0° C. for 30 min, the mixture was cooled to −78° C. and a solution (50 mL) of N,N-diethyl-2,3-dimethylbenzamide (45.1 g) in tetrahydrofuran was added dropwise. After stirring at −78° C. for 1 hr, a solution (50 mL) of 1-benzyl-3-cyanopyrrolidine (37.18 g) in tetrahydrofuran was added dropwise. After completion of the dropwise addition, the reaction mixture was heated to room temperature and the mixture was stirred overnight at room temperature. The mixture was further stirred under reflux for 1 hr and the reaction mixture was concentrated to about half. Water and methylene chloride were added and the organic layer was partitioned, washed with water, dried over magnesium sulfate and concentrated, The obtained residue was purified by column chromatography (ethyl acetate) to give (±)-3-(1-benzylpyrrolidin-3-yl)-5-methyl-2H-isoquinolin-1-one (66.38 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=O.[CH:11]([NH2:13])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1N
Product: O=c1[nH]cnc2ccsc12
Temperature: 170 °C
Yield: 32 %

Procedure:
Methyl-3-amino-2-thiophene carboxylate (510 mg, 3.24 mmol) was dissolved in formamide (20 ml) and heated at 170° C. 16 h. The solvent was evaporated. The crude residue was then purified by flash chromatography on silica gel (2-4% MeOH/CH2Cl2) to afford the title compound 256 (157 mg, 32% yield). LRMS: 152.0 (Calc.); 152.9 (found).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.CO>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7]2/[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]/2=[O:9])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(/C=C2/Oc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 41.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4dimethoxybenzaldehyde 1.23 g were dissolved in acetic acid 20 ml, concentrated hydrochloric acid 1.1 ml was added, and the mixture was stirred for 18 hours, and methanol 15 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.82 g.
Reaction SMILES: [CH2:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[N:3]2[CH2:19][CH2:20][CH2:21][CH:2]12>C1(C)C=CC=CC=1>[CH:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[N:3]2[CH2:19][CH2:20][CH2:21][C:2]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(C2=NCC3CCCN23)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(c2ncc3n2CCC3)C1
Temperature: 115 °C
Yield: 14.3 %

Procedure:
To a solution of tert-butyl 3-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate (175 mg, 0.6 mmol) in toluene (5 mL) was added BaMnO4 (2.1 g, 18 mmol) and the reaction was heated at 115° C. for 42 h. The reaction was cooled to room temperature and BaMnO4 (2 g) was added followed by toluene (2 mL). The reaction mixture was heated to 115° C. for 3 days. The mixture was cooled to room temperature and filtered through Celite followed by rinsing with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified via HPLC to afford tert-butyl 3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate as an oil (25 mg, 14%). MS (ES+) (M+H) 292.2; LCMS retention time: 1.69 minutes (Method M).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Product: Cc1ccc2nc(N3CCNCC3)ccc2c1NC(=O)CC1CCCCC1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Prepared according to the method of example 2, using N-(2-Chloro-6-methyl-5-quinolinyl)-cyclohexaneacetamide (Example 15(a)) (0.2 g) and piperazine (0.163 g). The reaction was cooled to room temperature, the resulting solid collected by filtration and recrystallised from methanol to afford the title compound (0.102 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[OH:38])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](Cl)=[O:45].Cl>ClCCl>[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[O:38][C:44]([C:40]3[O:39][CH:43]=[CH:42][CH:41]=3)=[O:45])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)/C(=N\OC(=O)c1ccco1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
Triethylamine (8.7 ml) was added to an ice-cooled suspension of 2-(2-triphenylmethylamino-4-thiazolyl)- 2-(Z-hydroxyimino)acetic acid (13 g) in 250 ml of anhydrous dichloromethane with stirring. The suspension turned to a clear, faint yellow solution. A solution of 2-furoyl chloride (3.3 g) in 20 ml of anhydrous dichloromethane was dropwise added under ice cooling, the resulting light brown solution was stirred at room temperature for one hour, the mixture was poured into 130 ml of ice-cooled 0.5N hydrochloric acid, and the formed crystals were collected by filtration and washed thrice with 30 ml dichloromethane, affording 5.2 g of the objective compound as colorless crystals.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:4][CH2:5][CH2:6][OH:8])[C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([OH:13])=[O:12])=[CH:11][CH:10]=1
Reactant: NCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Product: O=C(O)c1ccc(C(=O)N(CCCO)CCCO)cc1
Yield: 171.6 %

Procedure:
Into a 500 mL separable flask, 48.1 g of dimethyl terephthalate (manufactured by Wako Pure Chemical Industries, Ltd.) and 112 g of 3-amino-1-propanol (manufactured by Wako Pure Chemical Industries, Ltd.) were placed and subjected to heat drying at 135° C. for 6.5 hours under nitrogen gas stream. To the reaction mixture, isopropyl alcohol was slowly added to thereby provide 59.8 g of N,N-bis(3-hydroxypropyl)terephthalic acid amide, which is an amide group-containing diol. Under a nitrogen gas atmosphere, into a reactor equipped with a mixer, 8.72 g of N,N-bis(3-hydroxypropyl)terephthalic acid amide, 29.8 g of polyethylene glycol (trade name: PEG2000U, manufactured by NOF CORPORATION), and 50 g of dehydrated dimethylacetamide (organic solvent, manufactured by Wako Pure Chemical Industries, Ltd.) were placed and heated at 100° C. under stirring to thereby provide a uniform solution. To this solution, a solution prepared by dissolving 11.5 g of 4,4-diphenylmethane diisocyanate (manufactured by Wako Pure Chemical Industries, Ltd.) in 10 g of dehydrated dimethylacetamide was gradually dropped. After the dropping was completed, the solution was heated for an hour under stirring. The reaction solution was cooled to 80° C. and subsequently reprecipitation was caused with 620 g of acetonitrile. The solid precipitate was isolated by filtration and then washed twice with 160 g of acetonitrile. Thus, a polymer was obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]=[C:24]=[O:25]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=2)[C:8]([NH:10][C:24]([NH:23][CH3:22])=[O:25])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Yield: 99.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide (303 mg, 1.0 mmol) in toluene (5 mL) was treated with methyl isocyanate (0.59 mL, 10 5 mmol). The resulting solution was heated to reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl afforded 1-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionyl]-3-methyl-urea (360 mg, 49.2%) as a pale yellow oil: FAB-HRMS m/e calcd for C17H20F4N2O2 (M+H)+361.1539, found 361.1534.
Reaction SMILES: [N:1]1([OH:6])[CH:5]=[CH:4][CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:22]([O:6][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: On1cccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(COn2cccn2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.4 %

Procedure:
To a mixture of pyrazol-1-ol (1 g, 11.9 mmol) and i-Pr2NEt (2.02 mL, 11.9 mL) in DCM (15 mL) at 0° C. was added BnBr (4.09 mL, 23.8 mmol). The mixture was allowed to warm up to r.t. and stirred at this temperature for 22 h. The mixture was concentrated in vacuo to afford a yellow paste. The crude product was purified by flash chromatography (silica gel, hexanes/DCM/Et2O (100:0:0 to 80:10:10), Rf 0.23 in hexanes/DCM/Et2O (34:3:3)) to provide the title product as a yellow oil (1.17 g, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1cc(C#N)nc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cc(C#N)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 36.5 %

Procedure:
tert-Butyl 3-(2,6-dicyano-4-pyridyl)propanoate (1.4 g, 5.5 mmol) and methyl thiosalicylate (1.7 g, 10.1 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.79 g, 36%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:16][NH2:17]>>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:17]
Reactant: NN
Reactant: COc1ccc(-c2ccc(Cl)nc2)cc1
Product: COc1ccc(-c2ccc(NN)nc2)cc1

Procedure:
Compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Coupling of a 2,5-dihalopyridine, such as 5-bromo-2-chloropyridine, with a substituted phenylboronic acid, such as 4-methoxyphenylboronic acid, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, produced 2-chloro-5-(4-methoxyphenyl)pyridine. Reaction of 2-chloro-5-(4-methoxyphenyl)pyridine with hydrazine produced 2-hydrazinyl-5-(4-methoxyphenyl)pyridine. Reaction of 2-hydrazinyl-5-(4-methoxyphenyl)pyridine with a substituted benzoic acid, such as 4-chloro-2-methoxybenzoic acid, in the presence of coupling agents, such as BOP (benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate) and NMM (N-methylmorpholine), produced 4-chloro-2-methoxy-N-(5-(4-methoxyphenyl)pyridin-2-yl)-benzohydrazide. Treatment of 4-chloro-2-methoxy-N-(5-(4-methoxyphenyl)pyridin-2-yl)-benzohydrazide with phosphorus oxychloride produced the cyclized product 3-(4-chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine, which can be converted into a salt by treatment with HCl in ethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1>C(O)C.[C].[Pd]>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCCCC2)cc1
Yield: 37.8 %

Procedure:
0.85 g of piperidine, 1.68 g of 1,4-cyclohexanedione and 40 mg of 10% palladium-carbon were heated with stirring in 40 ml of ethanol at 50° C. to 60° C. and reacted for 8 hours under air bubbling. During the reaction, ethanol was added as needed. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) and purified by silica gel column chromatography again, and 0.668 g of 1-(4-hydroxyphenyl)piperidine was obtained (yield 43.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:27]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1

Procedure:
91 mg of solid yellow 3-{4-[3-(4-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-trifluoromethylphenyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][C:11](=O)[N:10]=[C-:9]1>[O-2].[O-2].[Ti+4]>[C:2]1([N:1]2[CH2:12][CH2:11][NH:10][C:9]2=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CO[C-]=N1
Agent: [Ti+4]
Agent: [O-2]
Product: O=C1NCCN1c1ccccc1
Temperature: 0 °C
Yield: 47 %

Procedure:
Aniline (15.40 g; 0.165 mole) and 2-oxazolidone (9.60 g; 0.110 mole) were refluxed for 6.5 hours with 1.00 g (0.0125 mole) of titanium dioxide (Harshaw Ti 0720 which had been calcined at 300° C. for 4 hours). The reaction mass was cooled to 0° C. and the crystals which had formed were filtered off. The crystals were recrystallized from ethanol to give N-phenylimidazolidone in 47% yield. The conversion based on 2-oxazolidone was 99%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCC3CC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and (aminomethyl)cyclopropane (52 μl; 0.73 mmol; 5.0 eq.) as a white solid (43 mg, 78%). HPLC, Rt: 3.19 min. (purity 78.6%). LC/MS, M+(ESI): 420.0, M−(ESI): 418.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=2[N:20]=[CH:21][N:22]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:17]2[C:18]3[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH:6]=1)=[O:4]
Reactant: Cn1ccc2c(Cl)ncnc21
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.40 g (8 mmol) of 3-methoxycarbonyl-1H-indole are added to 30 cm3 of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere, and 0.32 g (10 mmol) of sodium hydride are then added. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.35 g (8.05 mmol) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 10 cm3 of dimethylformamide are then added, and the mixture is heated at a temperature in the region of 100° C. for 16 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then poured into a mixture of 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated out after the phases have settled, washed with twice 200 cm3 of water and then with 200 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.35 g of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole are obtained in the form of an off-white solid. Mass spectrum (EI): m/e 306 (M+) (base peak).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([OH:23])[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2].N1C=CN=C1.[Si:29](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([O:23][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O)C4)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.9 %

Procedure:
To a solution of the alcohols 10 (1.08 g, 3.42 mmol) in dichloromethane (20 mL) was added imidazole (1.6 eq, 0.37 g, 5.43 mmol) followed by tert-butyldiphenylsilylchloride (1.6 eq, 1.42 mL, 3.64 mmol). The mixture was stirred 16 h at room temperature under nitrogen then poured into 1N HCl (100 mL). The layers were separated and the aqueous layer was extracted with ether (3×50 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give an oil (2.2 g), Rf 0.55 (10% EtOAc/hexane), which was used without further purification.