Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([C:17]([OH:19])=[O:18])=[CH:5][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)C>O1CCOCC1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH:7]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[C:3](=[O:20])[C:4]([C:17]([OH:19])=[O:18])=[CH:5]2)=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Cn2cc(Br)c(=O)c(C(=O)O)c2)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: N#Cc1ccc(Cn2cc(C(=O)O)c(=O)c(-c3cccc(C(F)(F)F)c3)c2)cc1
Temperature: 60 °C

Procedure:
A mixture of 5-bromo-1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 12b, 0.56 g, 1.68 mmol), 3-(trifluoromethyl)phenylboronic acid (0.39 g, 2.05 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg, 0.10 mmol) and Cs2CO3 (0.82 g, 2.51 mmol) in dioxane (4 mL) is heated for 24 h at 60° C. The reaction mixture is acidified with acetic acid and purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 186 mg (28% of theory); ESI mass spectrum: [M+H]+=399; Retention time HPLC: 1.22 min (Z002—002).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[Cl:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:69][CH2:70][C:71]1[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77]>CN(C=O)C>[Cl:25][C:16]1[C:17]([C:22](=[O:23])[NH:69][CH2:70][C:71]2[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=2[CH3:77])=[N:18][C:19]([Cl:21])=[CH:20][C:15]=1[N:14]([CH3:26])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylic acid (75 mg, 0.19 mmol) in DMF (2 ml) cooled to 0° C. h was added DIPEA (48 μl, 0.28 mmol) followed by PyBOP (116 mg, 0.22 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89% purity, 35 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 16 h after which the reaction was poured onto water (30 ml) and extracted with EtOAc (3×50 ml) after which the combined organics were washed with brine (50 ml) and dried (Na2SO4) and evaporated. The crude product was purified using a 5 g silica Isolute column eluting with a gradient of 0% to 100% EtOAc in heptane to afford the title compound as a white solid which contained ˜45% w/w tripyrrolidinophosphene oxide by NMR—this compound was used in the next stage of the synthesis without any further purification. LC-MS 93%, 1.97 min (3.5 minute LC-MS method), m/z=538.0/539.45/542.05, 1H NMR (500 MHz, Chloroform-d) δ 10.03 (br. s, 1H), 8.13-7.97 (m, 1H), 6.79 (s, 1H), 5.87 (s, 1H), 4.50 (d, J=6.1 Hz, 2H), 4.16 (br. m, 2H), 3.78-3.62 (m, 1H), 2.72 (s, 3H), 2.65 (br. m, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 1.73-1.63 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH3:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Br)cc2F)c1=O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. m.p. 154° C.;
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([C:17](=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>O1CCCC1>[C:11]1([C:17](=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][C:27]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=3)([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CCCC(N=C(c2ccccc2)c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N=C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a flask, lithium bis(trimethylsilyl)amide (LHMDS) (1M) in THF (2.83 mL, 2.83 mmol) was added to tetrahydrofuran (10 mL). The reaction mixture was cooled to −78° C., and then a solution of methyl 3-(diphenylmethyleneamino)cyclohexanecarboxylate (700 mg, 2.18 mmol) and tetrahydrofuran (1 mL) was added drop-wise to the reaction mixture at −78° C. The reaction was stirred at −78° C. for 30 minutes. Afterwards, 4-fluorobenzylbromide (0.402 mL, 3.27 mmol) was added, and the reaction was stirred for an additional 24 hours at 0° C. Upon reaction completion, the reaction was quenched with saturated ammonium chloride solution (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried with sodium sulfate, and concentrated to yield crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C(=O)C)[CH:10]=[CH:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].C(=O)(O)[O-]>C(O)C.C(Cl)(Cl)Cl>[C:2]([O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1)(=[O:1])[CH3:3]
Reactant: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)O[C@H]1C=C[C@@H](O)C1
Yield: 74.5 %

Procedure:
Dissolve (-)-acetic acid cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enyl ester (192 mg, 0.85 mmol, prepared in example 11) in ethanol (1.5 mL) and treat with p-toluenesulfonic acid (11.7 mg). Stir the reaction at room temperature for 2 hours. Add carbonate or bicarbonate to neutralize the reaction mixture and concentrate under vacuum. Purify the residue by chromatography (silica gel, 3 g, 1.5×3 cm column, 33% ethyl acetate/hexane, 80 mL), to provide the title compound (90 mg, 75% yield, 91% ee), [α]20 D =-66.1°, (c=0.63, chloroform).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([F:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O)cc2)cc1F
Reactant: OC1CCOCC1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(OC3CCOCC3)cc2)cc1F

Procedure:
The title compound was prepared from rac-[1-(3-fluoro-4-methyl-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (ISN): 442.4 (M−H)−.
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:44])[C@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:41]4[CH2:42][CH2:43][C@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C(F)(F)F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.76 (s, 1H), 3.83 (t, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 2.12 (m, 2H), 1.85-1.72 (m, 4H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 499 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1

Procedure:
3-hydroxybenzoic acid (30.0 g, 0.22 mol), methanol (101 ml) and concentrated sulphuric acid (2.7 ml) were added together and heated under reflux for 4 h. The reaction mixture was allowed to cool and the methanol was removed. The crude product was dried in vacuo and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[C:37](=[O:42])[CH2:38]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CN1CCNCC1=O
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)c(OC)cc23)c2c1OCO2
Yield: 71.3 %

Procedure:
This was prepared by the method described in example 13 using N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-methylpiperazin-2-one (226 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (166 mg, 72%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.10 (quintet, 2H), 2.61 (t,2H), 2.72 (m, 4H), 2.95 (s, 3H), 3.15 (s, 2H), 3.31 (t, 2H), 3.40 (s, 3H), 3.61 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 6.06 (s, 2H), 6.96 (s, 1H), 7.03 (s, 1H), 7.12 (s, 1H), 7.26 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:38])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:18][CH:17]=2)[CH2:7][C:6]1=[O:39])([OH:3])=O.C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:62][N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>ClCCl>[CH3:62][N:63]1[CH2:68][CH2:67][N:66]([C:1]([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:15](=[O:38])[C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)=[CH:18][CH:17]=3)[CH2:7][C:6]2=[O:39])=[O:3])[CH2:65][CH2:64]1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)O)c4ccccc43)cc2)cc1
Reactant: CN1CCNCC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CC(=O)N(CC(=O)N4CCN(C)CC4)c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(carboxymethyl)-4-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydro -quinoxalin-2-one (100 mg) in dichloromethane (10 ml) were added triethylamine (0.030 ml) and diphenylphosphinic chloride (54.7 mg) and the solution was stirred at ambient temperature for 30 minutes. Triethylamine (0.030 ml) and 1-methylpiperazine (0.032 ml) were added to the solution and the mixture was stirred at ambient temperature for 3 hours. The solution was washed with water and brine and dried over magnesium sulfate. The organic solution was evaporated in vacuo and the residue was subjected to a silica gel column (10 g, 2% methanol in chloroform). The object fractions were evaporated in vacuo and the residue was solidified with diethyl ether to give 1-[(4-methyl-1-piperazinyl)carbonylmethyl]-4-{4-[2-(4methylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydro -quinoxalin-2-one (77.0 mg) as a white powder.
Reaction SMILES: C[C:2](O)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]=[CH2:4].[CH3:12][C:13]([OH:23])(CCC=C(C)C)CCC>>[CH2:13]([OH:23])[CH2:12][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:2][CH2:3][CH3:4]
Reactant: C=CC(C)(O)CCCCCC
Reactant: CCCC(C)(O)CCC=C(C)C
Product: CCCCCCCCCCCO

Procedure:
In "Materials Tested as Insect Attractants" compiled by M. Beroza and N. Green in Agriculture Handbook No. 239 in Table 2 it is stated that 3-methyl-1-nonen-3-ol has, on a scale of 1 to 3, an attractancy of "1" for the Oriental Fruit Fly and an attractancy of "1" for the Mediterrean Fruit Fly and 4,8-dimethyl-7-nonen-4-ol has on a scale of 1 to 3 an attractancy of 37 2" for the Oriental Fruit Fly and an attractancy of "3" for the Mediterrean Fruit Fly and an attractancy of "1" for the Mexican Fruit Fly and an attractancy of "1" for Drosophila.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[N:12]=[CH:11][C:10]=1[C:23]#[N:24])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+]>CN(C)C=O>[C:23]([C:10]1[CH:11]=[N:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:9]=1[CH:8]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:24]
Reactant: CCOC(=O)C(Cl)Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Temperature: 60 °C
Reaction time: 1.75 h
Yield: 54 %

Procedure:
To a stirred, slightly warmed solution of 1.4 grams (0.003 mole) of ethyl 2-chloro-3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]propionate in 25 mL of N,N-dimethylformamide was added in one portion 0.1 gram (0.004 mole) of sodium hydride. Upon completion of the addition the reaction mixture was warmed to about 60° C., where it was stirred for 1.75 hours. The reaction mixture was then allowed to cool to ambient temperature, where it was stirred for about 18 hours. The reaction mixture was again warmed to about 60° C., where it was stirred for two hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue remaining was stirred with water for about 40 minutes, giving a solid that was collected by filtration. The solid was recrystallized from ethanol and water, yielding 0.6 gram of ethyl 3-[4-cyano-1-(2,3,4-trichlorophenyl)-1H-pyrazol-5-yl]acrylate, m.p. 131°-134° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[N:6][C:5]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[CH:4][C:3]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnc(Nc3ccc4cccnc4c3)cc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of [6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine, Example 88, (100 mg, 0.3 mmol) in dioxane (2 mL) was added 4-methoxyphenylboronic acid (46 mg, 0.3 mmol, Aldrich), followed by the addition of 2M aq Na2CO3 (0.2 mL, 0.4 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol, Aldrich). The mixture was flushed with N2 and heated under at 100° C. under N2 atmosphere for 24 h. The reaction mixture was cooled to room temperature, additional amounts of 2M aq Na2CO3 (0.2 mL, 0.4 mmol), 4-methoxyphenyl-boronic acid (46 mg, 0.3 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol) were added and the mixture was heated at 100° C. with stirring under N2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with 5% Na2CO3. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography, eluting with MeOH:CH2Cl2 (1:19), to give the title compound as a tan crystalline solid. MS (ESI, pos. ion) m/z: 473 (M+1). MP: 215-217° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](F)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:30]#[N:31]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([S:5][CH2:3][CH3:4])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:30]#[N:31]
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of sodium hydride (82 mg, 2.04 mmol) in 6 mL of tetrahydrofuran is added ethanethiol (77 mg, 1.12 mmol) in 6 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2 hours. A solution of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.51 mmol) in 7 mL of tetrahydrofuran is added via syringe and the reaction mixture is heated at 70° C. for 5 hours, then cooled to room temperature. The reaction volume is reduced by concentration in vacuo and then partitioned between ethyl acetate and water. The aqueous layer is extracted with additional ethyl acetate and the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 10% to 30% ethyl acetate in hexane to provide 154 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-ethylsulfanyl-6-methoxy-3-quinolinecarbonitrile, mp 212-214° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3=[CH:23][N:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)CCN(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.CCCCCCC.C1COCC1>[C:36]1([CH:35]([C:19]2[N:18]([S:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:17])=[O:16])[C:22]3=[CH:23][N:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)[OH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccncc21
Reactant: O=Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)c2ccccc2)cc2ccncc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a solution of lithium diisopropylamide (1.2 mL of a 2 M solution in THF/heptane, 2.3 mmol) in THF (3 mL) was added a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.2 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.18 mL, 1.2 mmol) in THF (5 mL), dropwise at −25° C. After 0.5 h, a solution of benzaldehyde (0.24 mL, 2.3 mmol) in THF (6 mL) was added dropwise. After 1 h, the reaction mixture was warmed to 10° C. and quenched by the addition of saturated NH4Cl (5 mL). The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 9:1 hexanes/EtOAc to EtOAc) gave phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (155 mg, 37%) as a mixture of enantiomers: 1H NMR (500 MHz, DMSO-d6) δ 6.36 (1H, d, J=5.5 Hz), 6.43 (1H, d, J=5.5 Hz), 6.75 (1H, s), 7.32-7.36 (5H, m), 7.53 (2H, dd, J=8.4, 7.6 Hz), 7.59 (1H, d, J=5.2 Hz), 7.66-7.70 (1H, m), 7.82-7.85 (2H, m), 8.35 (1H, d, J=5.2 Hz), 9.22 (1H, s); ESI MS m/z 365 [C20H16N2O3S+H]+; HPLC (Method A) 91.9% (AUC), tR=16.5 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[C:55]([O:59][CH3:60])(=[O:58])[CH:56]=[CH2:57]>CN(C=O)C>[F:19][C:18]([F:20])([F:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:5]([C:4]([C:22]([F:25])([F:24])[F:23])=[N:3][C:2]=3/[CH:57]=[CH:56]/[C:55]([O:59][CH3:60])=[O:58])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1
Reactant: C=CC(=O)OC
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1nc(C(F)(F)F)n2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 80 °C

Procedure:
1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (50.0 mg, 0.118 mmol), Pd(AcO)2 (2.6 mg, 0.0118 mmol, 0.1 equiv.) and P(o-tol)3 (14.4 mg, 0.0472 mmol, 0.4 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (1 mL), a solution of Et3N (30.0 mg, 0.295 mmol, 2.5 equiv.) in DMF (1 mL) and a solution of methyl acrylate (50.8 mg, 0.59 mmol, 5.0 equiv.) were successively added. The mixture was heated at 80° C. for 19 h. And then, the solvent was removed from the reaction mixture to give a crude mixture. The crude mixture was purified by a column chromatography (SiO2=25 g, EtOAc/hexane=1:7 to 1:3, Rf=0.1 with EtOAc/hexane=1:7) to give (E)-methyl 3-(6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridin-1-yl)acrylate as light yellow crystals.