Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([O:27][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:36][N:35]=2)[CH:31]=[CH:32]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: C#CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4cnc5[nH]ccc5c4)c3cc2OC)CC1
Temperature: 85 °C
Yield: 76.2 %

Procedure:
4-Chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (300 mg, 0.8 mmol) was dissolved in dimethylacetamide (10 ml). 5-Hydroxy-7-azaindole (118 mg, 0.88 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (122 mg, 0.88 mmol) were added and the mixture heated to 85° C. for 1.5 hours. The reaction mixture was cooled, filtered and concentrated. The resulting residue was preabsorbed on silica and eluted with methylene chloride/methanol (saturated with ammonia) (90/10) to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (288 mg, 76%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1>[Si:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]4[N:33]=[CH:34][N:35]=[C:9]34)[CH2:4][CH2:3]2)=[CH:48][CH:49]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 45 h

Procedure:
4′-{[4-(cis-4-Hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.46 g), 4-{[tert-butyl(dimethyl)silyl]oxy}phenol (0.49 g) and triphenylphosphine (0.29 g) were dissolved in tetrahydrofuran (2 mL), a solution of diisopropyl azodicarboxylate (0.58 mL, 1.9 M toluene solution) in tetrahydrofuran (1 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 45 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as an oily compound (0.22 g, 33%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[O:10][CH2:11][CH3:12].O.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1cc(I)ccc1N(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOc1cc(C#N)ccc1N(C)C
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
N,N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 2.58 mmol) was dissolved in DMF (4 mL). Zinc cyanide (0.18 g, 1.54 mmol) was added. Argon was passed through the mixture for 10 min. Tetrakis(triphenylphosphine)palladium (148 mg, 0.13 mmol) was added and the mixture was heated at 110° C. for 24 h. The reaction mixture was cooled and poured into water. The mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 20% ethyl acetate in hexanes gave N,N-dimethyl-2-ethoxy-4-cyano-aniline (187 mg, 38%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1)[CH2:2][CH3:3].[NH3:19]>>[CH2:1]([N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=S)Nc1ccn(CCCCC#N)n1
Reactant: N
Product: CCCN=C(N)Nc1ccn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-[3-propylthioureido]pyrazol-1-yl)valeronitrile (1.01 g.) in saturated methanolic ammonia (30 ml.) was treated with orange mercuric oxide (0.82 g.) and the suspension stirred at room temperature for 18 hours. The black suspension was filtered through diatomaceous earth and the filtrate evaporated to give 5-(3-[2-propylguanidino]pyrazol-1-yl)valeronitrile as a brown oil which was used without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
Sodium hydride (60%, 1.2 g, 30 mmol) is added to a solution of 4-chlorothiophenol (4.3 g, 30 mmol) in THF (30 mL). The resulting solution is stirred for 10 minutes then the solvent is removed in vacuo. Acetone (60 mL) is added followed by 5-bromothiophene-2-carboxaldehyde (3.0 mL, 25 mmol). The mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the resulting slurry diluted with CH2Cl2. This solution is washed three times with 1N NaOH then dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography (gradient of 1 to 5% EtOAc in heptane) to give the desired product (6.2 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.13, 7.31-7.39, 7.63, 9.78.
Reaction SMILES: C[O:2]C(=O)C=CC1C2N(C3C=CC=CC=3)C(C(F)(F)F)=NC=2C=CC=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[N:30]1([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:53])([F:54])[F:52])[CH:37]=2)[CH2:31][CH2:32][O:2][CH2:28][CH2:29]1
Reactant: COC(=O)C=Cc1cccc2nc(C(F)(F)F)n(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CCOCC1
Yield: 60 %

Procedure:
This was prepared from 3-(3-phenyl-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one to afford the title compound as a white solid (350 mg, 60%), m/z 402.2 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]1[N:13]=[N:12][C:11]([C:14]2[CH:40]=[CH:39][C:17]([O:18][C:19]3[C:33]([CH:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[CH:32][C:22]4[NH:23][C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[N:25][C:21]=4[CH:20]=3)=[CH:16][CH:15]=2)=[N:10]1>C(Cl)(Cl)Cl>[C:1]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[C:33]1[C:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([C:11]3[N:12]=[N:13][N:9]([CH3:8])[N:10]=3)=[CH:40][CH:39]=2)=[CH:20][C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:23][C:22]=2[CH:32]=1)(=[O:3])[CH3:2]
Reactant: Cn1nnc(-c2ccc(Oc3cc4nc(-c5ccccn5)[nH]c4cc3C3CCCN3)cc2)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(-c2nnn(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.006 ml of acetic anhydride was added to a chloroform (1 ml) solution of 24.7 mg of 5-(4-(2-methyl-2H-tetrazol-5-yl)phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole enantiomer A obtained in Example 542, and the reaction liquid was stirred at room temperature for 10 minutes. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain one chiral form of the entitled compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH2:25]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:33]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CCCCCCCCNCCCCCCCC
Solvent: CC(=O)CC(C)C
Product: CCCCCCCCN(CCCCCCCC)CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 8.3 ml of dioctylamine, and 50 ml of methyl isobutylketone, a reaction similar to that conducted in Example 142 was carried out. As a result, 0.9 g of N-(trans-4-methylcyclohexyl)-4-(2-dioctylaminoethoxy )-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Product: O=C(O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1

Procedure:
This was prepared analogously from 4-fluoro-3-nitrobenzoic acid and 3-bromoaniline.
Reaction SMILES: [F:1][C:2]1[C:3]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:4]([NH:9]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+]>Cl.COCCOC.O>[NH2:9][C:4]1[C:3]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:24])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(F)c(F)c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a −78° C. solution of 2.5 g (11.724 mmol) N-(3,4-difluorophenyl)-2,2-dimethylpropanamide in 39 ml anhydrous THF was added drop wise over 15 mins 18 mL (28.136 mmol) n-BuLi (1.6M solution in cyclohexanes). After 1 hr at −78° C., 4 mL (26.966 mmol) ethyl 4-fluorobenzoate was added dropwise and the reaction mixture stirred from −78° C. to rt. After 45 mins, the reaction mixture was cooled to 0 C and quenched with saturated ammonium chloride and poured into a 1:1 mixture of ether:water and warmed to room temperature. The organic phase was isolated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide (6-3). A solution of 3.5 g (10.706 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide in 43 mL 6N HCl and 8.6 mL DME was heated to 100° C. After 24 h at 100° C., the reaction mixture was cooled to room temperature and sodium carbonate was added until reaction mixture was basic. The reactions was diluted with water, extracted three times with ether, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-20% EtOAc:hexane) afforded (6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.85-7.80 (m, 2H, ArH); 7.17-7.11 (m, 3H, ArH); 6.47 (ddd, J=2.01 Hz, 3.66 Hz, 9.16 Hz, 1H, ArH); 4.84 (br s, 2H, ArNH2). ES MS+1=252.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(N)=O)=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=[N:28]CCC2)CC1.BrN1C(=O)CCC1=O.[OH-].[K+]>CO.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:28])=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(OCc2ccccc2)ccc1CCC(N)=O
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: COCOc1cc(OCc2ccccc2)ccc1CCN
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 28.42 g of 3-(4-benzyloxy-2-methoxymethoxyphenyl)propionamide and 40.4 mL of 1,8-diazabicyclo[5.4.0]-7-undecene in 895 mL of methanol was added 16.04 g of N-bromosuccinimide at 65° C. After the mixture was stirred at 65° C. for 15 minutes, to the reaction mixture was added additional 16.04 g of N-bromosuccinimide at 65° C. After being stirred at 65° C. for 15 minutes, the resulted mixture was concentrated under reduced pressure to remove the solvent. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give oily product. To a solution of this residue in 242 mL of ethanol was added 67.6 mL of 8 mol/L aqueous potassium hydroxide solution, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue were added 500 mL of ethyl acetate, 50 mL of toluene, and 300 mL of water, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel (eluent: hexaneethyl acetate) to give 80.0 g of 2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine as a colorless oil.
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]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][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:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 120 °C
Yield: 48.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (Example 151, step B) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (64 mg, 0.093 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.35 (s, 1H), 8.34 (d, J=15.93 Hz, 2H), 8.21 (d, J=5.31 Hz, 1H), 8.03 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.69 Hz, 1H), 7.71 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.78 Hz, 1H), 7.35-7.46 (m, 3H), 7.16-7.22 (m, 2H), 6.95 (t, J=6.78 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.43-6.48 (m, 2H), 4.04 (q, J=6.96 Hz, 2H), 3.07-3.13 (m, 4H), 2.42-2.51 (m, 4H), 2.25 (t, J=7.33 Hz, 2H), 1.40-1.48 (m, 2H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([OH:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)c(Cl)c1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)O)c(Cl)c1Cl

Procedure:
To 20.7 g (0.1 mole) off 2,3-dichloro-4-hydroxybenzoic acid was added 8 g of sodium hydroxide dissolved in 150 ml water. The solution was warmed to 60° and 12.6 g (0.1 mole) of dimethyl sulfate added. The mixture was then heated at 70° for 2 hours, cooled, acidified and filtered to yield 16.7 g. (75%) of the product, m.p. 224°-226°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1>C(OCC)(=O)C.CO.C(=O)([O-])O.[Na+]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]2[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-n1cnc(CO)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
[1-(2-Methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]methanol (500 mg, 2.0 mmol) and stannous chloride dehydrate (2.35 g, 10.4 mmol) were suspended in a mixture of 40 ml of ethyl acetate and 20 ml of methanol. The reaction mixture was refluxed for 1 hour, cooled to room temperature and diluted with acquous sodium hydrogencarbonate solution. Extraction with ethyl acetate gives the title compound (311 mg, 71%) as a yellowish viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:17])=[O:15])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methyl-benzene (15.0 g, 79.8 mmol) in dichloromethane (300 mL) was added nitronium tetrafluoroborate (11.7 g, 87.8 mmol) in portions at 0° C. The mixture was heated at reflux for 5 h and was then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give crude 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g), which was used directly in the next step.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:25]([CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH3:27])[CH2:24][NH:23][CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:25]([CH:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)[CH3:27])[CH2:24][N:23]([C:7]([Cl:10])=[O:6])[CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 126.8 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (29 mg, 0.098 mmol) in CH2Cl2 (2 mL) at −78° C., was added a solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (intermediate XV-B-1) (100 mg, 0.25 mmol) and pyridine (0.043 mL, 0.54 mmol) in CH2Cl2 (2 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded 58 mg (50%) of the title compound as a light yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=CO[N:7]=1)=[O:4].[NH2:11][C:12]1[CH:17]=NC=CN=1>>[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[N:11][CH:12]=[CH:17][N:7]=1)=[O:4]
Reactant: Nc1cnccn1
Reactant: O=C(CBr)Nc1ccon1
Product: O=C(CBr)Nc1cnccn1

Procedure:
This compound is prepared by an analogous method to 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) by replacing 3-aminoisoxazole with 2-aminopyrazine
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4]1.Cl[C:13]1[N:14]=[N+:15]([O-:26])[C:16]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][CH2:23]3)=[CH:19][C:17]=2[N:18]=1.CCN(CC)CC>COCCOC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:5][CH2:4]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COC1CCN(CCN)CC1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC1CCN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Yield: 78.6 %

Procedure:
Crude 2-(4-methoxy-1-piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et3N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 42 (2.16 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 131-133° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.50-3.56 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.21-3.26 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.72-2.82 (m, 2H, CH2N), 2.60 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.20-2.26 (m, 2H, CH2N), 2.15 (br p, J=7.4 Hz, 2H, H-7), 1.84-1.92 (m, 2H, CH2), 1.57-1.65 (m, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 76.2, 56.3, 55.5, 50.7 (2), 38.2, 33.1, 32.3, 30.8 (2), 25.7. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.0; H, 7.4; N, 20.4%.