Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:12][C:13]1([CH3:27])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH:18]=[C:17]([CH:25]=[O:26])[CH:16]=[CH:15][C:14]1=2.[Cl-].[NH4+]>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:18]1[C:19]2[C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22][C:13]([CH3:27])([CH3:12])[C:14]=2[CH:15]=[CH:16][C:17]=1[CH2:25][OH:26]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2c1ccc(CO)c2C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
17.13 ml (0.121 mol) of trimethylsilylacetylene and 100 ml of THF were introduced into a three-necked flask. A solution of 48.5 ml (0.121 mol) of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under a stream of nitrogen and the mixture was permitted to heat to room temperature. This solution was introduced dropwise into a solution of 23.8 g (0.11 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in 100 ml of THF at -78° C. The reaction mixture was permitted to heat to room temperature, was poured into an aqueous ammonium chloride solution and was extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). After evaporating the solvents, 29.9 g (86%) of the expected alcohol were recovered in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH:11][CH:12]=[N:13][C:14]#[N:15].CN(C)C=O.[K].[CH3:23][C:24]([OH:27])(C)[CH3:25].BrCC(=O)C>O>[NH2:15][C:14]1[N:13]=[CH:12][N:11]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C:2]2([CH3:16])[CH3:1])[C:23]=1[C:24](=[O:27])[CH3:25]
Reactant: CC(C)(C)O
Reactant: CC1(C)Cc2ccccc2C1NC=NC#N
Agent: CC(=O)CBr
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(N)ncn1C1c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
316 Parts of N-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-N'-cyanoformamidine were suspended in 282 parts of N,N-dimethylformamide. To this suspension were added slowly 163 parts of 2-methyl-2-propanol potassium salt and after stirring at room temperature for 4 hours there were added dropwise 194 parts of bromopropanone. After 48 hours, the reaction mixture was poured into water and extracted with 1,1'-oxybisethane. The separated organic layers were evaporated and the residue was crystallized first from a mixture of 1,1'-oxybisethane and petroleum ether. The precipitate was filtered off and dried and then recrystallized from methylbenzene. The product was filtered off and dried, yielding 93 parts (23%) of [4-amino-1-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-1H-imidazol-5-yl]ethanone; mp. 174°-175° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:8][C:7]=1[F:18])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([F:18])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH:11]=1)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,2,2-trifluoro-N-{2-fluoro-5-[(trimethylsilyl)ethynyl]phenyl}acetamide (5.3 g, 17 mmol) in THF (400 mL) was cooled to 0° C., and a 1.0 M solution of TBAF in THF (17 mL, 17 mmol) was added dropwise. The resulting mixture was stirred for 10 min. at 0° C. The reaction was quenched with water (150 mL), concentrated under reduced pressure, and extracted with DCM. The combined organic layers were concentrated under reduced pressure, and the crude solid was used in the next reaction without further purification. ES-LC/MS m/z=230 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]2.[ClH:18]>O1CCOCC1>[ClH:18].[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ccc2c(c1)CNC2
Reaction time: 1 h

Procedure:
2 g (235.3 mmol) of tert-butyl 5-hydroxy-1,3-dihydroisoindole-2-carboxylate are dissolved in 20 ml of a 4 M hydrogen chloride solution in dioxane. After 1 h at 22° C., the mixture is evaporated to dryness in vacuo. The resultant white crystals (1.4 g (96%) MW 171.6) are employed in the following reactions without further purification.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:26])=[C:11]([CH3:25])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[C:23]=1[CH3:24])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH3:24][C:23]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:16][C:12]=2[C:11]([CH3:25])=[C:10]([CH3:26])[C:9]=1[NH2:8]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccccc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)CO2
Yield: 72 %

Procedure:
Using N-benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 276, the title compound was synthesized in the same manner as in Reference Example 30. Yield 72%. Melting point: 94-95° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])[CH3:8].O=[C:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[NH2:23][C:22]1[C:3]2[C:2](=[CH:21][CH:20]=[CH:19][C:4]=2[O:5][CH2:6][C:7]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])([CH3:8])[CH3:9])[N:1]=[C:25]([CH3:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)C1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37b) and ethyl 3-oxobutanoate as a bright yellow solid (55%). MS 428 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[C:15](=[N:25][OH:26])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3ccc(F)cc3)cc(Cl)c2O1
Yield: 99 %

Procedure:
A mixture of 4,7-dichloro-2,3-dihydro-5-(4-fluorobenzoyl)benzo[b]furan-2-carboxylic acid (12.4 g), hydroxylamine hydrochloride (20.6 g) and pyridine (120 ml) was refluxed for 5.5 hours. Aftre distilling off the solvent, water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. By distilling off the solvent, 12.8 g of 4,7-dichloro-2,3-dihydro-5-(4-fluoro-α-hydroxyiminobenzyl)benzo[b]furan-2-carboxylic acid was obtained. This compound (12.8 g) was dissolved in 150 ml of anhydrous dimethylformamide, and to the ice-cooled solution, 4.8 g of 60% sodium hydride was added in small portions under agitation. After continuing the agitation for 5 hours at room temperature, the mixture was left to stand overnight. Water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 4.4 g of 5-chloro-7,8-dihydro-3-(4-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 215°-218° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 333.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>C1COCC1.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[C:19]=[S:20]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N=C=S)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-methyl-3-nitroaniline (1.00 g, 6.57 mmol) and triethylamine (2.75 ml, 19.7 mmol) in THF (150 ml) was added dropwise thiophosgene (0.55 ml) at 0° C. After addition, the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was diluted with water and extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under vacuum to afford 1.04 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:31]=[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:31]=[C:32](/[C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)\[CH3:33])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(C)=CBr)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (43 mg, 0.184 mmol) was dissolved in DMF (4 mL) Copper (I) iodide (4 mg, 0.0184 mmol) L-proline (4.2 mg, 0.037 mmol) and K3PO4 (78 mg, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (50 mg, 0.22 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, Oxalate salt) δ (ppm): 7.60 (m, 3H), 7.10 (m, 2H), 6.98 (m, 3H), 3.80 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H), 2.82 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[F:14][CH:13]([F:15])[C:11]1[CH:10]=[C:9]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.8) (0.47 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.264 g, 1.2 mmol) according to the general procedure III. Obtained as a yellow solid (0.066 g, 15%). MS (ISP) 434.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1.[Cl-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.7 %

Procedure:
Under an argon atmosphere, 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methylphenyl}-1-pentanol (compound 10) (45.7 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. 1,8-Diazabicyclo[5.4.0]-7-undecene (37 mg) was then added to the solution, and the mixture was cooled to 0° C. N-Tert-butylbenzenesulfineimidoyl chloride (43 mg) was dissolved in methylene chloride to prepare a solution, the solution was added thereto, and the mixture was stirred at 0° C. for 40 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (27.6 mg, yield 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23>>[Cl:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][C:12]=3[CH:17]([C:22]([O:24][CH3:25])=[O:23])[O:18][C:19](=[O:21])[CH3:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Product: COC(=O)C(OC(C)=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Yield: 43.7 %

Procedure:
A procedure similar to that described in Example 9-7) was performed with 4-tert-butoxycarbonylaminomethyl-2-(1-methoxycarbonyl-1-acetoxymethyl) aniline (500 mg, 1 mmol) and (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (413 mg, 1.4 mmol) to give 275 mg of the title compound (43.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[CH3:16][NH:17][OH:18].[OH-].[Na+]>C(O)C.O>[CH3:16][N+:17]([O-:18])=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=[N+](C)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.7 %

Procedure:
To a stirred suspension of 9.97 g (50.9 mmol) of 2,3,4-trimethoxybenzaldehyde and 4.43 g (53.1 mmol) of N-methylhydroxylamine hydrochloride in 100 mL of ethanol was added a solution of 2.05 g (51.3 mmol) of sodium hydroxide in 15 mL of water. The mixture was stirred at room temperature for 22 h and evaporated in vacuo to remove the bulk of the solvent. The residual solid was taken up in 150 mL of dichloromethane, washed with 50 mL of water and dried over MgSO4. Removal of the solvent afforded 11.31 g of N-methyl-C-(2,3,4-trimethoxyphenyl)nitrone as a white solid. 1H-NMR (CDCl3) d 3.85-3.95 (9H), 6.75 (d, 1H), 7.65 (s, 1H), 9.1 (d, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:27]=2)OC1>>[F:36][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(C#N)cc3)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)cc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-4-carbonitrile as described in Example 65 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-4-carbonitrile as a yellow solid: δH (360 MHz, CDCl3) 7.26 (1H, d, J 7), 7.44 (1H, dd, J 8 and 8), 7.55-7.63 (2H, m), 7.70 (2H, dd, J 7 and 1), 7.79 (2H, dd, J 7 and 1), 8.11 (1H, s), 8.74 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8](O)=[O:9])([CH3:4])[CH3:3].N1C=CC=CC=1.C(Cl)(=O)C([Cl:25])=O>C(#N)C>[CH3:1][C:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([Cl:25])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)Oc1cccc(Cl)c1C(=O)O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)Oc1cccc(Cl)c1C(=O)Cl
Reaction time: 0.5 h

Procedure:
2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoic acid (68.6 mg, 0.3 mmol) was weighed into a 1 dram septum-capped vial containing a micro stir bar under nitrogen. Dry acetonitrile (300 microliter), dry pyridine (24 microliter, 0.3 mmol) and oxalyl chloride (26 microliter, 0.3 mmol) were added in order to the vial using microliter syringes. The yellow homogeneous solution was stirred for 30 minutes to afford a solution of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzoyl chloride.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[CH:48]1([NH:51][C:52](=[O:69])[NH:53][C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)[CH2:50][CH2:49]1>>[CH:48]1([NH:51][C:52]([NH:53][C:54]2[CH:59]=[CH:58][C:57]([C:24]3[CH:29]=[C:28]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]4[CH3:47])[N:25]=3)=[CH:56][CH:55]=2)=[O:69])[CH2:50][CH2:49]1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a brown solid, (43 mg, 17%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[S:13][C:14]([CH2:17]Cl)=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:19]([C:21]1[NH:22][C:23]2[C:24]([N:31]=1)=[N:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[S:13][C:14]([CH2:17][N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CCOCC1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Product: CCOC(=O)C1(c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)s2)CCOCC1

Procedure:
The product of Step 4, above (40), was alkylated as described in Example 1, Step 5, using 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (7) to obtain the title compound (41).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[CH:21][CH:20]=1.N1CCCCC1>CCO>[CH3:17][N:18]([CH3:31])[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(CNc2[nH]nc(Nc3cccnc3)c2C(N)=O)c2ccccc12

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide 8 (100 mg) was suspended in EtOH (3 mL) and 4-Dimethylamino-1-naphthaldehyde (1 eq.) and piperidine (I drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-(((4-(dimethylamino)naphthalen-1-yl)methyl)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.C([Sn]([CH2:45][OH:46])(CCCC)CCCC)CCC>>[OH:46][CH2:45][C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(CO)n3)cccc2s1

Procedure:
The reaction of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (233 mg, 0.5 mmol, Example 7(d)) and tributylstannyl-methanol (322 mg, 1.0 mmol, prepared according to the procedure described in Synthetic Communication, 1994, 24, 1117-1120) under the conditions of Example 7(e) gave the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:15]I>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1
Reactant: CI
Reactant: CCOC(=O)Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccncc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A solution of ethyl 2-(pyridin-4-yl)acetate (1.00 g, 6.06 mmol) in THF (10 ml) was added dropwise to a suspension of sodium hydride (0.24 g, 6.06 mmol, 60%) in THF (10 ml) at −50° C. under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h. Methyl iodide (2.10 ml, 33.6 mmol) in THF (10 ml) was added slowly at −50° C. over a period of 15 min, then the reaction mixture was warmed up to −10° C. and continued to stir for another 4 h. The reaction mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The crude was washed with diethyl ether (10 ml) to get 550 mg (50.7%) of ethyl 2-(pyridin-4-yl)propanoate as a colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[NH2:28])C.[OH-].[K+].Cl>C(O)C.O>[NH2:28][C:6]1[CH:7]=[C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:9]=[CH:10][C:5]=1[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
In a solution of 0.6 g of crude 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid ethyl ester in 7 ml of ethanol, a solution of 0.5 g of potassium hydroxide in 2.0 ml of water was added, and stirred at room temperature for 18 hours. After the completion of the reaction, 20 ml of ice water was added in the reaction mixture, adjusted to pH 2 to 3 with concentrated hydrochloric acid, and then extracted with ethyl acetate (20 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.6 g of crude aimed product as yellow oily substance. The resulting product was used as such without purification for the next step.