Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH:4]1([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22]4)=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To an ethanol (8 mL) solution of methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylate (1.4 g) synthesized in Example 1, 6 N aqueous sodium hydroxide solution (1.32 mL) was added and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was left to cool to room temperature and, after adding water, extracted with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with chloroform. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the titled compound as a colorless amorphous substance (1.22 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine) palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235-237° C.; 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+@ m/z 306.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33]([C:37](O)=[O:38])[S:34][C:35]=1[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[S:34][C:35]([CH3:36])=[C:31]([CH3:30])[CH:32]=4)=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)sc1C
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)c(C)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4,5-dimethylthiophene-2-carboxylic acid (23 mg, 0.15 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:23])[CH2:11]1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CNC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
To a solution of 3-{6-fluoro-2-[(S)-1-(9H-purin-6-ylamino)ethyl]benzoimidazol-1-yl}azetidine-1-carboxylic acid tert-butyl ester (214 mg, 0.47 mmol) in DCM (5 mL) at 0° C. was added TFA (1.7 mL) dropwise. The mixture was stirred at 0° C. for 20 min then slowly warmed to RT. Stirring was continued at RT for 1.5 h. The volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford 378 as a white solid (160 mg, 96%). LCMS (Method K): RT 1.73 min [M+H]+ 353.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br s), 8.17-8.07 (2H, m), 7.95 (1H, br s), 7.64 (1H, dd, J=8.82, 5.08 Hz), 7.08 (1H, td, J=9.27, 2.42 Hz), 5.80 (1H, br s), 5.63-5.53 (1H, m), 4.14-4.06 (1H, m), 4.01 (2H, d, J=7.20 Hz), 3.93-3.74 (2H, m), 1.63 (3H, d, J=6.71 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2C3=NC=CC=C3C(C3C=CC=CC=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=C[CH:24]=1>>[CH3:24][O:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Reactant: c1ccncc1
Product: COc1cccc(NN)c1

Procedure:
Therein, among the starting compounds, for example, 1-(3-hydroxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine can be obtained by heating under reflux 2-chloro-3-benzoylpyridine and 3-methoxyphenylhydrazine in pyridine to obtain the corresponding hydrazone, and subjecting to ring-closure reaction the obtained hydrazone by heating under reflux in isopentyl alcohol with the use of potassium carbonate as a deacidifying agent to obtain 1-(3-methoxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine, followed by the elimination of the methoxy group thereof with the use of a butylmercaptanaluminium chloride system.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1.[BH4-].[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:10][CH2:9][CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[C:4]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: Cc1cn(CCCN)c(-c2ccccc2)n1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cn(CCCNC(C)c2ccc(Cl)cc2)c(-c2ccccc2)n1

Procedure:
A mixture of 3-(4-methyl-2-phenylimidazol-1-yl)propyl-amine (5.3 g) and 4'-chloroacetophenone (3.8 g) was heated at 120°-125° C. for 7 hours. On cooling, the oil was dissolved in absolute alcohol (70 ml) and, after the addition of sodium borohydride (7.0 g), the mixture was boiled under reflux for 16 hours. Work-up as described in Example 3 gave an oil which was distilled at 185°-205° C. (0.06 mmHg). The main fraction was redistilled to give N-[1-(4-chlorophenyl)ethyl]-3-(4-methyl-2-phenyl-imidazol-1-yl)propylamine, b.p. 205° C. (0.04 mmHg). Glc indicated the presence of 14% of N-[1-(4-chlorophenyl)-ethyl]-3(5-methyl-2-phenylimidazol-1-yl)propylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=O)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:21]([CH2:20][C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:10]=[CH:11][CH:12]=[CH:13]4)=[N:9][N:8]=2)[N:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a suspension of (6-chloro-pyridazin-3-yl)-hydrazine (1.62 g, 11.2 mmol) and 6-quinoline acetic acid (2.1 g, 11.2 mmol) in dichloromethane (150 mL) at ambient temperature was added dicyclohexylcarbodiimide (2.3 g, 11.2 mmol). After stirring at room temperature for 4.5 hours the formed precipitate was filtered off, washed with dichloromethane and dried in vacuo to return quinolin-6-yl-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide which also contained dicyclohexylurea. This mixture was then taken up in acetic acid (250 mL) and heated for 4 hours at 50° C. After such time the mixture was concentrated onto silica gel in vacuo and purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-97:3) to return the title compound as a white solid (3.35 g, 11.1 mmol, 99% yield). Analytical data presented in Table 1.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:19][CH:20]([OH:22])[CH3:21]>>[OH:13][CH2:12][CH2:11][CH2:10][C:9]([O:22][CH:20]([CH3:21])[CH3:19])=[O:8]
Reactant: O=C(O)CCCOCc1ccccc1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxybutyric acid (20.59 mmol) in propan-2-ol (30 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (22.65 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature during 20 hours. The mixture was concentrated under reduced pressure and co-evaporated with CH2Cl2. The crude was dried under vacuum pump to give the expected compound as yellow oil in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.22 (d, J=6.26 Hz, 6H), 1.94 (quintuplet, J=6.70 Hz, 2H), 2.40 (t, J=7.47 Hz, 2H), 3.50-3.53 (m, 2H), 4.51 (s, 2H), 5 (heptuplet, J=6.22 Hz, 1H), 7.28-7.38 (m, 5H); MS (ESI) m/z=259.6 (MNa+).
Reaction SMILES: [CH:1]([C:4]([CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].[OH-].[K+].C(C(CC=C(Cl)Cl)(C(O)=O)C(O)=O)(C)C.C(C(CC=C(Cl)Cl)(C([O-])=O)C([O-])=O)(C)C.ClC(Cl)=CCC(C(C)C)C(O)=O>C(O)C.O>[Cl:18][C:17]([Cl:19])=[CH:16][CH2:15][CH:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC=C(Cl)Cl)(C(=O)OCC)C(C)C
Agent: CC(C)C(CC=C(Cl)Cl)(C(=O)O)C(=O)O
Agent: CC(C)C(CC=C(Cl)Cl)(C(=O)[O-])C(=O)[O-]
Agent: CC(C)C(CC=C(Cl)Cl)C(=O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC=C(Cl)Cl)C(C)C

Procedure:
In 20 g of ethanol were dissolved 8.8 g of the above diethyl isopropyl-(3,3-dichloroallyl)malonate and a solution of 6.4 g of potassium hydroxide in 10 g of water was added to the above ethanol solution. The mixture was refluxed overnight. Then, the reaction mixture was distilled to remove the ethanol and a sufficient amount of dilute hydrochloric acid was added to make the residue acidic. The residue was extracted with diethyl ether and the ethereal layer was dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. By this procedure there was obtained a mixture of isopropyl-(3,3-dichloroallyl)malonic acid and morbethyl isopropyl-(3,3-dichloroallyl)malonate. This mixture was subjected to decarboxylation reaction at 180° to 230° C. under a reduced pressure of 35 to 60 mmHg, whereupon 6.0 g of a mixture of α-(3,3-dichloroallyl) isovaleric acid and ethyl α-(3,3-dichloroallyl)isovalerate was obtained. In 20 g of ethanol were dissolved 6.0 g of the above decarboxylated mixture and a solution of 1.2 g of sodium hydroxide in 10 g of water was added to the above solution. The mixture was refluxed for 4 hours, after which the ethanol was distilled off. The residue was made acidic with dilute hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate and distilled to remove the low-boiling fraction. By the above procedure there were obtained 4.2 g of α-(3,3-dichloroallyl)isovaleric acid, the NMR spectrum of which appears below [yield: 70% based on diethyl isopropyl-(3,3-dichloroallyl)malonate].
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.Cl.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22]C(O)=O.C([O-])(=O)C.[Na+]>O.CC(C)=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6](/[CH:22]=[CH:21]/[C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)C=Cc1cccs1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(/C=C/c2cccs2)cc1
Yield: 54.9 %

Procedure:
9.3 g of sodium nitrite dissolved in the minimum amount of water was added to a mixture of 18.18 g of p-amino-acetophenone, 36 ml of concentrated hydrochloric acid and 36 g of water, and the resulting mixture was ice-cooled and diazotized while stirring. To the diazotized solution was added 127 cc of a solution of 16.9 g of β-2-thienylacrylic acid in acetone. An aqueous solution of 25.4 g of sodium acetate dissolved in 10 ml of water and 5.6 g of cupric chloride were then added to the mixture whereby a gas evolved and the reaction proceeded. After the reaction mixture was stirred for 24 hours while cooling, the acetone was distilled off and the residue was extracted with benzene. The benzene layer was shaken with a 5% aqueous sodium hydroxide solution, washed with water and dried over Na2SO4. The drying agent used was filtered out and the solvent was distilled off. The resulting residue was purified by column chromatography on alumina using benzene as a developing solvent to obtain 13.73 g of (E)-2-(4-acetylstyryl)thiophene in a 50% yield. The melting point of the product after recrystallization from benzene was 130° to 131° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].I[CH3:28]>CN(C)C=O.O.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][N:11]([CH3:28])[CH:12]=1
Reactant: CI
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2c[nH]nn2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 7, 1.7 g, 5.2 mmol) was stirred in N,N-dimethylformamide at 0° C. Sodium hydride (0.40 g, 10 mol) was added and the mixture was stirred for 30 minutes. Iodomethane (0.88 g, 6.2 mmol) was added and the reaction was stirred for three days, slowly warming to room temperature. The mixture was diluted with water and extracted using ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under vacuum. The residue was recrystallized using ethyl acetate to give a mixture of products (0.42 g) as beige solid. The solid was dissolved in dimethylsulfoxide (5 ml), acetonitrile (12 ml) and water (1 ml) and the isomers were separated using Gilson HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][C:8]3[CH:13]=[N:14][C:15]([CH3:17])=[N:16][C:7]=3[C:6]=2[CH:18]=1.CN(C)[CH:21]=[N:22][CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:10]([CH2:9][C:8]4[CH:13]=[N:14][C:15]([CH3:17])=[N:16][C:7]=4[C:6]=2[CH:18]=1)=[C:23]([C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)[N:22]=[CH:21]3
Reactant: Cc1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Reactant: Cc1cc(CN=CN(C)C)no1
Product: Cc1ncc2c(n1)-c1cc(Br)ccc1-n1cnc(-c3cc(C)on3)c1C2

Procedure:
From 10-bromo-5,7-dihydro-2-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-one according to scheme 1, step 7 using N,N-dimethyl-N′-(5-methyl-isoxazol-3-ylmethyl)-formamidine instead of (E)-(dimethylaminomethyleneamino)-acetic acid ethyl ester. Clear gum, m/z (ISP) 407/409 (MH)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([N:23]1[C:27]([NH2:28])=[CH:26][C:25]([CH3:29])=[N:24]1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:28][C:27]2[N:23]([CH2:21][CH3:22])[N:24]=[C:25]([CH3:29])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CCn1nc(C)cc1N
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)NOC)c(Cl)cn1
Temperature: 160 °C
Yield: 12.5 %

Procedure:
A 20-mL microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (100 mg, 0.320 mmol), 1-ethyl-3-methyl-1H-pyrazol-5-amine (60.1 mg, 0.481 mmol), cesium carbonate (313 mg, 0.961 mmol), 1,4-dioxane (5.0 mL) and THF (1.0 mL). The reaction mixture was degassed by nitrogen for 10 min. (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (19.95 mg, 0.032 mmol) and Palladium(II) acetate (3.60 mg, 0.016 mmol) in minimum amount of 1,4-dioxane were then added. The tube was sealed and reaction mixture was heated in microwave oven 160° C. for 40 min. The resulting suspension was cooled to room temperature and filtered through celite. The filtrate was evaporated to dryness and the crude reaction mixture was purified by reverse-phase HPLC to give the title compound as a solid (16 mg, 24% yield) MS: M(C19H21ClN6O2)=400.86, (M+H)+=401; 1H NMR (400 MHz, MeOD) δ ppm 7.92 (s, 1 H) 7.44-7.66 (m, 3 H) 7.11-7.25 (m, 1 H) 6.61 (s, 1 H) 5.99 (s, 1 H) 3.98 (q, J=7.3 Hz, 2 H) 3.80 (s, 3 H) 2.21 (s, 3 H) 1.32 (t, J=7.2 Hz, 3 H).
Reaction SMILES: C([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Rh].C1(C)C=CC=CC=1>[CH:12]([O:11][C:9]([C:8]1[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH2:4][CH:3]=1)=[O:10])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl[Rh]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12

Procedure:
A mixture of the benzhydryl ester from Example 28 (2.5 g, 4.79 mmol), tris-(triphenylphosphine(chlororhodium (3.5 g, 4.79 mmol) and dry toluene (75 ml) was refluxed under nitrogen for 5.5. hours. The reaction mixture was cooled. the rhodium complex was removed by filtration and the filtrate was poured slowly into petroleum ether (250 ml) with stirring. The precipitated solid, which was a mixture of rhodium complex and product, was collected. The product was purified by chromatography on a silica gel column (250 g) using 99:0.5 chloroform:ethyl acetate as eluent. Fractions of 4.5 ml were collected; fractions 1-47 discarded, 48-66 contained bis-(triphenylphosphine)carbonylchlororhodium, and 67-198 contained the product. NMR data indicated the product after chromatography to be the Δ3 isomer instead of the Δ2 isomer. A decoupling experiment showed the 2-methylene group at 3.3 ppm. to be coupled with the 3-proton at 6.6 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][CH:26]([CH3:41])[CH2:27][CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)[CH2:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=2)[CH2:27][CH:26]([CH3:41])[CH3:25])=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Reactant: CC(C)CC(CN)c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(CNC(=O)c1cn(-c2ncccn2)nc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 4-methyl-2-[4-(trifluoro-methyl)phenyl]pentan-1-amine (54 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with CH2Cl2 (5 mL). The CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient from 20% EtOAc/Hex to 60% EtOAc/Hex) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, s), 8.89 (2H, d, J 4.8), 8.33 (1H, bs), 7.64 (2H, d, J 8), 7.55 (1H, t, J 4.8), 7.46 (2H, d, J 7.6), 3.44 (1H, m), 3.33 (1H, m), 3.07 (1H, m), 1.57 (1H, m), 1.51 (1H, m), 1.26 (1H, m), 0.81 (6H, d, J 6.4). MS (M+1)=452.14; RT=1.36 min. *IC50.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of 1A (95 mg, 0.36 mmol) in DMF (2 mL) was added Cs2CO3 (260 mg, 0.8 mmol), followed by benzyl bromide (74 mg, 0.43 mmol). After stirring at RT under argon for 4 h, the mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated under vacuum. The resulting residue was chromatographed on silica gel (10 g) eluted with 20-30% EtOAc in hexane (step-wise gradient) to obtain the title compound (112 mg, 88%).