Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[I-].[Na+].C(=O)(O)[O-].[Na+].[CH3:29][S:30]([CH2:33][CH2:34][CH2:35]Br)(=[O:32])=[O:31].CS(CCC[Cl:44])(=O)=O>CN(C=O)C.CO>[ClH:44].[ClH:44].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:35][CH2:34][CH2:33][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)CCCCl
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: CS(=O)(=O)CCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1cc(OC2CCN(CCCS(C)(=O)=O)CC2)c2ncccc2c1
Product: Cl
Temperature: 150 °C
Yield: 18 %

Procedure:
A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (30 mg, 0.2 mmol) and sodium bicarbonate (110 mg, 1.3 mmol) in DMF (2 ml) was treated with a solution of mixture of 3-bromopropyl methyl sulfone and 3-chloropropyl methyl sulfone (for example, as prepared for Intermediate 19) (124 mg) in DMF (0.5 ml) and the mixture was heated at 150° C. for 15 min in a Smith Creator™ microwave oven. The reaction mixture was applied to an SCX-2 cartridge (10 g), preconditioned with methanol, and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo and the residue (126 mg) was purified by MDAP. Appropriate fractions were combined and concentrated in vacuo and the residue (30 mg) was applied to an SCX-2 cartridge (5 g), pre-conditioned with methanol and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were combined and concentrated in vacuo to give the free base of the title compound (21 mg, 18%): This was treated with 1.25 M hydrogen chloride solution in methanol (0.15 ml) and the solution was evaporated in vacuo to give the title compound (22 mg, 89%): LCMS RT=2.49 min, ES+ve m/z 405 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1)[CH:2]=C.[N:14]1(C(OC(C)(C)C)=O)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:42]>>[ClH:42].[N:14]1([CH2:2][CH2:1][C:4]2[CH:13]=[CH:12][C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[CH:5]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCCl
Reactant: C=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cl
Product: O=C1OCc2cc(CCN3CCNCC3)ccc21
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5-(prop-2-en-1-yl)-2-benzofuran-1(3H)-one (2.30 g, 13.2 mmol) was dissolved in DCM (30 mL) and cooled to −78° C. Ozone was bubbled through the solution until the color changed (to orange). Nitrogen was bubbled through the solution for about one minute to remove any residual ozone. tert-Butyl piperazine-1-carboxylate (1.64 g, 8.80 mmol) in DCM was added followed by sodium triacetoxyborohydride (11.2 g, 52.8 mmol). The reaction mixture was permitted to warm to room temperature and was stirred overnight. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, then dried over MgSO4. The crude product was purified by preparative TLC eluting with 5% methanol in DCM. The resulting 1,1-dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate was deprotected (of Boc) as described in Method 1 of the synthesis of 5.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][OH:17])[CH3:14].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]3=[N:35][CH:36]=[N:37][C:38]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[C:33]3[CH:32]=[N:31]2)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>CS(C)=O>[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16][O:17][C:6]([N:43]1[CH2:44][CH2:45][CH:40]([O:39][C:38]2[N:37]=[CH:36][N:35]=[C:34]3[N:30]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25][CH:26]=4)[N:31]=[CH:32][C:33]=23)[CH2:41][CH2:42]1)=[O:7])[CH3:14]
Reactant: CCC(CC)CO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)COC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
Di-imidazol-1-yl-methanone (0.51 mmol, 83 mg), and 2-ethyl-butan-1-ol (0.51 mmol, 52 mg) were dissolved in DMSO (1 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.17 mmol, 70 mg) and triethylamine (0.51 mmol, 72 μL) were added and heated in a microwave at 120° C. for 6 minutes. The progress of the reaction was monitored by LCMS. The reaction mixture was quenched with water and the product was extracted with ethylacetate. Removal of organic solvents in vacuo and purification by HPLC provided Compound A119 as a white solid (38 mg, 36%). Exact mass calculated for C24H31N5O5S 501.60, found 502.3 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH2:7][CH2:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[Cl:28])[CH:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30].C(N(CC)CC)C>CCOCC.O>[Cl:1][CH2:2][C:3]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:19]=2[Cl:28])[CH:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 33.2 %

Procedure:
Chloroacetyl chloride (3 g, 0.027 mole) was added dropwise to a stirred solution of [2-hydroxyethyl]5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (8.1 g, 0.02 mole), triethylamine (2.5 g), and ether (150 ml). The heat given off during the reaction raised the temperature of the ether solution to reflux. After completion of addition, the mixture was kept at reflux for 10 min. The mixture then was allowed to cool to room temperature, poured into 200 ml of water, and 400 ml of ether was added. The ether extract was washed three times with water, dried CaSO4 and condentrated to 8.6 g of yellowish oil. The oil was column chromatographed through silica gel with 20% ethyl acetate-80% hexane as eluent to afford 3.2 g of pure [2-chloroacetoxyethyl]5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate, as a pale yellow gummy material; nmr (CDCl3) δ 4.16 (S, 2H), 4.50 (S, 4H), 6.98-8.18 (m, 6H); ir (CHCl3) 1752, 1765.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13]
Reactant: COCOCc1cc(O)ccc1Br
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1cc(OCc2ccc(C#N)cc2)ccc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-3-(methoxymethoxymethyl)phenol (2.47 g, 10.0 mmol), 4-cyanobenzyl bromide (1.88 g, 9.50 mmol), and potassium carbonate (1.66 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. for overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[4-bromo-3-(methoxymethoxymethyl)phenoxymethyl]benzonitrile (1.88 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To a 50° C. solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1995:3482) in 10 mL of tetrahydrofuran was added 0.059 g of maleic anhydride. The cold solution stirred for 15 minutes, and then the ice bath was removed. The reaction warmed to room temperature where it continued stirring for 15 hours. The suspension was heated under reflux for 30 minutes and then stirred at room temperature another 15 hours. Another 0.059 g of maleic anhydride and 20 mL of tetrahydrofuran were added, and the reaction was refluxed for an additional 2 hours. After another 15 hours at room temperature, the reaction was refluxed for 15 hours. The reaction was filtered, and the light tan solid was recrystallized first from dimethyl-formamide and then a second time from methanol to afford 0.036 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reaction time: 19 h
Yield: 90.8 %

Procedure:
Combine a slurry of 0.176 kg of 10% Pd—C (50% water wet) and 1.7 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide in 17.5 L of DMF with hydrogen (50 psi, 345 kPa). After 19 h, filter the reaction mixture, add a portion of the DMF solution (5 L) to water (10 L), and stir the slurry for 2 h—repeat twice to work up the entire reaction volume. Filter the slurries together, and wash the resulting filter cake with water (3×7 L). Dry the filter cake to afford 1.42 kg of biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:34])(=[O:36])=[O:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 0.84 mmol) in methanol (46 mL) at 0° C. was added a solution of potassium permanganate (133 mg, 0.84 mmol) in water (23 mL) dropwise. After stirring for 2 h at 0° C., the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered through a short silical gel pad (QingDao silica gel, 200-300 mesh), and concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (370 mg, 87%): LC/MS m/e calcd for C26H25N3O4S2 [M+H]+ 508.63, observed 508.2.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:14][CH2:15][CH3:16]
Reactant: N#CCC#N
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
26.4 g of malononitrile was dissolved in 60 ml of N,N-dimethylformamide and 56 g of potassium carbonate was added thereto, followed by stirring for 1 hour at room temperature. To the solution was added 40 g of iodobutane at about 0° C. and stirred for 30 minutes at the same temperature and for additional 4 hours at room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 17 g of 2-butylmalononitrile.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:23]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15](=[O:18])[CH2:16][CH3:17])[C:19](=[O:22])[CH2:20][CH3:21])=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCC(=O)C(CCCCCCc1ccc(O)cc1)C(=O)CC
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccc(CCCCCCC(C(=O)CC)C(=O)CC)cc1
Reaction time: 72 h

Procedure:
A mixture of 3.9 g. of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione (Example 28), 12 g. of 2-bromoethyl ethyl ether, 4 g. of potassium carbonate and 1 g. of potassium iodide in 40 ml. of acetone was heated at reflux for 48 hours and then allowed to stand at room temperature for three days. The reaction mixture was then filtered and concentrated to remove the solvent. The residue was distilled at 200°-205° C. (0.001 mm.) to give 4-{6-[4-(2-ethoxyethoxy)phenyl]hexyl}-3,5-heptanedione as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH2:15](N(CC)CC)C.Cl[C:23]([O:25][C:26]1(C)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1([CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1)[NH:6][C:23]([O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]
Reactant: CC1(OC(=O)Cl)CCCCC1
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CC1(C)C=CC=CC1)NC(=O)OC1CCCCC1
Reaction time: 8 h

Procedure:
A suspension of 0.59 g. (2.1 mM) of phenylalanine methylester hydrochloride in 10 ml. of chloroform is cooled to 0°C. After the pH of the mixture is adjusted to 8 by addition of triethylamine, 4.5 mM of 1-methylcyclohexyl chloroformate is added portion-wise at 0°C. while maintaining the pH of the reaction at 8 by addition of triethylamine. The reaction is stirred overnight at 20°-25°C. After adding chloroform, the reaction mixture is washed with 5% sodium bicarbonate solution, 50% saturated sodium chloride solution, 0.2 N sulfuric acid saturated with sodium sulfate, twice with 50% saturated sodium chloride solution, and then the reaction solution is dried over sodium sulfate. The solvent is removed to afford an oil of 1-methylcyclohexyloxycarbonyl phenylalanine methyl ester.
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(O)C>[C:1]([C:3](=[CH:12][NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:17]([F:25])([F:26])[F:16])=[CH:19][CH:20]=1)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(C(F)(F)F)cc1
Yield: 90.8 %

Procedure:
A mixture of α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (10 g) and 45 ml of ethanol is heated to effect dissolution. Then 8.12 g of p-trifluoromethylaniline in 10 ml of ethanol is added and the mixture heated at reflux for 45 minutes. The mixture is cooled and filtered to give 14.01 g of α-cyano-β-(4-trifluoromethylanilino)-N-ethoxycarbonylacrylamide, which is added to about 60 ml of tetralin and heated at reflux for several hours. On formation of precipitate, the mixture is allowed to cool and then filtered, washed with ether, to yield 5-cyano-1-(4-trifluoromethylphenyl)uracil, m.p. 230.5°-231.5°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O>[CH2:30]([O:32][CH2:33][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2])[CH3:31]
Reactant: CCOCCl
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCn1c(-c2ccccc2SCC)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (270 mg) and DMF (10 ml), 60% of sodium hydride (in oil) (80 mg) and chloromethyl ethyl ether (188 μl) were sequentially added under ice-cooling. The mixture was heated to room temperature, and stirred for 5 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 180 mg of 3-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 33) and 70 mg of 1-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 34)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH3:6])=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(F)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-fluoro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-fluoro-2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [NH2:1][C:2]1C=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O.[N:14]#N>COCCOC>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[N:14]=[CH:6][CH:5]=[CH:4][N:3]2[CH:12]=1
Reactant: N#N
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: ClCc1cn2cccnc2n1
Temperature: 65 °C
Yield: 14 %

Procedure:
A solution of 2-Aminopyridine (19.02 g, 0.2 mol) in anhydrous DME (70 mL) was added to 1,3-dichloroacetone (25.39 g, 0.2 mol) to form a slurry in a 250-mL 3-necked round bottomed flask outfitted with a reflux condenser and a N2 line. The mixture heated at 65° C. for 18 h, warmed to 80° C. for 3 h and allowed to cool back to room temperature over 2 h. The DME was removed in vacuo and H2O was added to dissolve the resulting solid. Saturated NaHCO3 was added to basify the solution to a pH to 8 and ethyl acetate was used to extract the product (3×300 mL). Both phases were stored in the freezer overnight. The organic phase was dried over Na2SO4, filtered and concentrated to give an orange solid. The aqueous layer was extracted again with ethyl acetate (2×200 mL), then CH2Cl2 (2×200 mL) and these organic layers were dried over Na2SO4, filtered and concentrated to an orange solid. The two solids were combined and dissolved in hot 5–10% MeOH in CH2Cl2, and allowed to cool. The resulting orange crystals were filtered and washed with cold CH2Cl2. A small amount of ether was added to the mother liquor and scratched and put in the freezer. The resulting solid was filtered cold and washed with cold ether. The two batches of solid were combined and dried in the vacuum oven to yield 4.93 g (14%) of the desired product.
Reaction SMILES: Br[C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)=[O:28]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (5 g, 14.9 mmol) in THF (20 ml), 2 M solution of i-PrMgCl in THF (22.4 ml, 44.9 mmol) was added at −40° C. under nitrogen atmosphere. The resulting mixture was allowed to stir for 10 min at −40° C. and cooled to −78° C. The reaction mixture was treated with DMF (7.29 ml, 89.8 mmol) and slowly warmed to RT. The mixture was stirred for 1 h at RT and quenched with saturated aqueous solution of NaHCO3. The crude was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Yield 3 g. LC-MS: [M+1]=285.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:18][C:15]2=[CH:16][N:17]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([C:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:3]5[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=5[F:1])[CH:13]=[C:14]4[CH:20]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1cnc(N2CCC(c3cc4cc(-c5ccc(S(C)(=O)=O)cc5F)ncc4o3)CC2)nc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (70 mg), 2-chloro-5-ethyl-pyrimidine (25 mg), N,N-diisopropyl-ethylamine (67 μL), and N,N-dimethylformamide (1 mL) is stirred at 120° C. for 4 h and then at 100° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=481 [M+H]+.