Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].[CH2:10]([Mg]Br)[CH:11]([CH3:13])[CH3:12]>C(OCC)C>[CH2:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5])[CH:11]([CH3:13])[CH3:12]
Reactant: C=Cc1ccccc1Br
Reactant: CC(C)C[Mg]Br
Solvent: CCOCC
Product: C=Cc1ccccc1CC(C)C
Temperature: 25 °C

Procedure:
In a 15-liter separable four-necked flask equipped with a stirrer and a reflux condenser were placed 3 liters of sufficiently dried diethyl ether, 915 g (5 moles) of o-bromostyrene and 31 g of bis(1,3-diphenylphosphino)propanenickel(II) chloride, and the above-mentioned diethyl ether solution of isobutylmagnesium bromide was added thereto dropwise with stirring at room temperature. After the completion of the addition, stirring was continued under the reflux of diethyl ether, until the reaction had been over. After the end of the reaction, the solution was cooled to room temperature, and was then thrown into pieces of ice in order to inactivate remaining isobutylmagnesium bromide. The resultant ether layer was separated by a separating funnel, and was washed with water until it had become a neutral state. Afterward, diethyl ether was distilled off, thereby obtaining 716 g of crude o-isobutylstyrene.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH3:28][O:29][C@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][O:29][C@@:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:34]([F:37])([F:36])[F:35])[C:31]([NH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:3][OH:4])=[O:32]
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Reactant: CCCCCCCCc1ccc(CCC(N)CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(CCC(CO)NC(=O)[C@](OC)(c2ccccc2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
2-Amino-4-(4-octylphenyl)butanol (10 mg), N,N-dimethyl-p-aminopyridine (17.5 mg), anhydrous triethylamine (11.4 μl) and anhydrous methylene chloride (1 ml) were mixed and the mixture was stirred under a nitrogen atmosphere at room temperature. Thereto was added (R)-α-methoxy-α-trifluoromethylphenylacetyl chloride (16.8 μl) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by thin layer chromatography (eluent; chloroform:methanol=9:1) to give the two diastereomer mixtures. Moreover, the mixture was purified by high performance liquid chromatography (eluent; methanol:water=88:12, flow rate; 8.0 ml /minute) to give the subject oily substance (9.8 mg) of 67.8 minutes at retention time and the subject oily substance (9.6 mg) of 71.6 minutes at retention time.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:23]>>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1cccc(F)c1F
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1cccc(F)c1F

Procedure:
Quantities: 1-bromoheptane (46.6 g, 0.26 mol), potassium carbonate (70 g, 0.5 mol) and compound from Example 37 (31.2 g, 0.24 mol). The experimental procedure was as described in Example 38.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[CH2:16][CH2:17]2)=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: N#Cc1cnc(Br)s1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-thiazole-5-carbonitrile (Tetrahedron Lett. 1977, 21, 1813).
Reaction SMILES: [Br-].[O:2]=[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:4]1.O1CCCC1.CC(C)([O-])C.[K+].[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=O>O>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:51]([O-:53])=[O:52])=[C:47]([CH:50]=1)[CH:48]=[C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3](=[O:2])[O:4]1
Reactant: O=C1OC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(=Cc2cc(Cl)ccc2[N+](=O)[O-])c2ccccc21
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a mixture of (3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl) phosphonium bromide (5.1 g) and tetrahydrofuran (50 mL) were added potassium tert-butoxide (1.3 g) and 5-chloro-2-nitro benzoaldehyde (1.0 g) at room temperature under an argon atmosphere, followed by stirring for 5 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:43])=[C:28]([NH:30][C:31]([C:33]3[CH:34]=[N:35][C:36](S(C)(=O)=O)=[N:37][CH:38]=3)=[O:32])[CH:29]=2)=[O:23])[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH3:43])=[C:28]([NH:30][C:31]([C:33]3[CH:34]=[N:35][C:36]([O:7][CH2:6][C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:37][CH:38]=3)=[O:32])[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: OCc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2cscn2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
To a solution of thiazole-4-methanol (79 mg) in THF (1 mL) at 0° C. under argon was added 1M lithium bis(trimethylsilyl)amide in THF (0.35 mL). After 30 minutes N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (127 mg, 0.34 mmol) in THF (3 mL) was added and the reaction warmed to room temperature and stiired for 5 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic phases washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a 12 g silica cartridge eluting with a gradient of 0 to 5% Methanol/DCM to give the title compound as a solid (31 mg, 23%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.29 (s, 3H), 2.85 (m, 1H), 5.63 (s, 2H), 7.36, (d, 1H) 7.67 (dd, 1H), 7.83 (dd, 2H), 8.49 (d, 1H), 9.14 (m, 2H), 10.14 (s, 1H); Mass Spectrum: M+H+ 410.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].C1N2CCN(CC2)C1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][O:5][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)CO
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CCC(CC)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-ethyl-1-butanol (1.00 g, 9.79 mmol), triethylenediamine (1.32 g, 11.7 mmol) in DCM (30 mL, 0.5 mol) cooled to 0° C. was added p-toluenesulfonyl chloride (1.96 g, 10.3 mmol) in DCM (10 mL) The reaction mixture was stirred for 30 min, and extracted with 1.0N NaOH (2×40 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and isolated by rotary evaporation to give the title compound (2.40 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:8].[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:11][CH:12]=1
Reactant: O=C(CCCCCBr)Nc1ccc(O)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: O=C(CCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 45.7 g (0.16 mol) of 6-bromo-N-(4-hydroxyphenyl)hexanamide, 26.0 g (0.16 mol) of 1-phenylpiperazine and 22.4 ml (16.3 g, 0.16 mol) of triethylaminwe in 400 ml of ethanol was heated under reflux overnight and then concentrated under vacuum. The residue was mixed with sodium bicarbonate solution and trichloromethane. The resulting suspension was filtered. The solid was recrystallized from ethanol-water and then from acetonitrile to give the end product as tan crystals, mp 157°-159°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:22]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])=[N:13][CH:14]=1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cn1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(-c2ccc(Cl)cc2Cl)cn1)N1CCCCC1
Yield: 67.3 %

Procedure:
A solution of 0.23 g (1 mmol) of 5-(2,4-dichloro-phenyl)-pyridin-2-ylamine and 0.2 g (1.1 mmol) of piperidine-1-sulfonyl chloride (preparation: Bull. Soc. Chim. Fr.; 1936, p 2143) in pyridine (10 ml) was heated to reflux until completion of reaction according to HPLC analysis (20 h). After concentration in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9/1 to 1/1) as eluent. Combination of the purified fractions and concentration in vacuo gave 0.26 g (67%) of the desired piperidine-1-sulfonic acid [5-(2,4-dichloro-phenyl)-pyridin-2-yl]-amide as a brown crystalline solid. ISN mass spectrum, m/e: 384 (M−1 calculated for C16H17Cl2N2O2S: 384).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCOCC2)c(F)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCOCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 47.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(4-morpholinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (61 mg, 0.086 mmol, 47%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 9.28 (s, 1H), 8.61 (d, J=2.20 Hz, 1H), 8.24-8.32 (m, 2H), 7.88 (dd, J=8.62, 2.38 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.32-7.39 (m, 1H), 7.16-7.23 (m, 1H), 7.14 (d, J=8.80 Hz, 1H), 6.90-7.00 (m, 3H), 6.74 (d, J=6.60 Hz, 1H), 6.69 (d, J=5.13 Hz, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 3.73-3.80 (m, 4H), 2.78-2.86 (m, 2H), 2.58-2.65 (m, 2H), 2.52-2.58 (m, 4H). MS (ESI): 710 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[OH:10]O>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:9])[C:4]([CH3:8])=[CH:5][C:6](=[O:10])[CH:7]=1
Reactant: Cc1cccc(C)c1O
Reactant: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C=C(C)C1=O
Temperature: 55 °C

Procedure:
A mixture of 2,6-dimethylphenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 50-60° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and 2,6-dimethyl-1,4-benzoquinone formed (97%) was separated by chromatographic purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c2c(-c3ccc(O)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 7 h
Yield: 95.6 %

Procedure:
In an argon atmosphere, 2.3 g (6.2 millimoles) of Compound 11 obtained in Example 11 was dissolved in 100 ml of methylene chloride. The solution was cooled to 0° C. Slowly 1.8 ml (18.7 millimoles) of boron tribromide was added to the solution, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was cooled to 0° C., and then 30 ml of methanol was added. The mixture was stirred at room temperature for 30 minutes. 3/4 volume of the solvent was evaporated under reduced pressure. 18 ml of 3N hydrochloric acid was added. The precipitate was collected by filtration, and recrystallized from DMF-water to obtain 2.1 g (yield: 96.3%) of Compound 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:11][C:12]([NH:22][CH2:20][CH3:21])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1Cl
Reactant: CCN
Product: CCNC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(2,2,2-trifluoroethyl)glycine and ethylamine: MS (ES) m/z 320 (M+1).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:21](COCC[Si](C)(C)C)[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.C1CCCCC=1>C(O)C>[CH2:31]([N:18]1[C:19](=[O:30])[C:20]2[NH:21][C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)=[N:14][C:15]=2[N:16]=[CH:17]1)[CH2:32][CH3:33]
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCn1cnc2nc(-c3cn[nH]c3)[nH]c2c1=O
Yield: 36.7 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.1 g, 0.201 mmol), Pd (OH)2 (20%) (0.2 g), in ethanol (4 ml) and cyclohexene were stirred under nitrogen balloon for 25 hrs. Reaction mixture was filtered through celite bed washed with methanol (20 ml). The filtrate was concentrated under vacuum and the crude product was purified by column chromatography using silica gel (100-200 mesh) and 5 to 6% methanol in DCM as an eluent to obtain 1-propyl-8-(1H-pyrazol-4-yl)-1,7-dihydro-purin-6-one (0.018 g, 24%) as white solid.
Reaction SMILES: [N+:1]([C:4]1[C:9](OC)=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:6][N:5]=1)([O-])=[O:2].[NH2:16][NH2:17]>>[OH:2][N:1]1[C:4]2[N:5]=[CH:6][CH:7]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=2[N:17]=[N:16]1
Reactant: COc1c(C(C)(C)C)ccnc1[N+](=O)[O-]
Reactant: NN
Product: CC(C)(C)c1ccnc2c1nnn2O

Procedure:
The above-identified compound is prepared by reacting 2-nitro-3-methoxy-4-t-butylpyridine with hydrazine in accordance with the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]([O:29]CC)=[O:28])=[CH:14]3)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]([OH:29])=[O:28])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(COC)nc3)cc(OC3CCOCC3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylate (5.8 g) in ethanol (100 mL) and tetrahydrofuran (100 mL) was added 1N aqueous sodium hydroxide solution (27 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, 1N hydrochloric acid (27 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was recrystallized from ethyl acetate-diethyl ether to give the title compound (3.2 g, yield 59%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[C:15](O)([C:17](F)(F)F)=O>O.CC#N>[NH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([C:11]1[CH:10]=[C:15]([CH3:17])[CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: COc1cccc(C(=O)c2cccc(C)c2)c1N

Procedure:
Intermediate A-19 was prepared from 3-methoxy-2-nitrobenzoic acid according to the general synthetic procedure described for Intermediate A-18. HPLC RT=2.21 min (H2O/CH3CN with TFA, Sunfire C18 3.5 μm, 2.1×30 mm, gradient=2 min, wavelength=220 nm). [M+H+]=246.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[C:26]([O:30][C:31](=[O:43])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][C:35]=1[CH:41]=[O:42])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:26]([O:30][C:31](=[O:43])[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][C:35]=1[CH:41]=[O:42])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC(=O)OC(C)(C)C)c(C=O)c1
Temperature: 55 °C

Procedure:
A flame-dried 100 mL round bottomed flask was charged with toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester (3.74 g, 10.5 mmol), 3-(2-formyl-4-hydroxyphenyl)acrylic acid tert-butyl ester (2.0 g, 8.05 mmol), and anhydrous DMF (40 mL). Cesium carbonate (3.94 g, 12.1 mmol) was added, and the reaction was heated to 55° C. under a nitrogen atmosphere for 18 h. The volatiles were removed in vacuo, and the crude residue was dissolved in EtOAc (250 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a yellow oil (1.70 g, 49%). 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H), 2.38 (s, 3H), 3.01 (t, J=6.6 Hz, 2H), 4.34 (t, J=6.6 Hz, 2H), 6.24 (d, J=15.6 Hz, 1H), 7.12 (dd, J=8.8, 2.9 Hz, 1H), 7.38 (d, J=2.9 Hz, 1H), 7.40-7.45 (m, 3H), 7.58 (d, J=8.8 Hz, 1H), 7.98 (dd, J=6.4, 2.0 Hz, 2H), 8.33 (d, J=15.6 Hz, 1H), 10.3 (s, 1H). MS (ES) m/e 434 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[C:31]1([NH:41][C:42]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([C:25]6[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=6)=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCNC1
Product: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCN(C(=O)Nc2cccc3ccccc23)C1

Procedure:
The title compound was prepared from 2-[1-(piperidin-3-yl)-ethylamino]-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine according to the procedure described in EXAMPLE 29 using 1-naphthylisocyanate. Mass spectrum (ESI) 569.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)=[O:24])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.00 (M+H+); retention time=1.09 minutes.
Reaction SMILES: [CH:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]1[CH:4]=[CH:3][CH2:2]2.N12CCCN=C1CCCCC2.[N+:27]([CH3:30])([O-:29])=[O:28]>Cl>[N+:27]([CH2:30][C:6]1([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH:1]2[CH:5]1[CH:4]=[CH:3][CH2:2]2)([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)C=C1CC2CC=CC12
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CC1(C[N+](=O)[O-])CC2CC=CC21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl bicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.73 g, 8.39 mmol) was dissolved in nitromethane (10 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour and then heated with stirring at 50 to 60° C. for 5 hours. The mixture was allowed to cool and then diluted with 1 N hydrochloric acid and saturated saline, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.98 g, 89%).