Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
Sodium hydroxide (25 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (875 mg) in THF (4 mL) and water (4 mL). The reaction mixture was stirred at 90° C. for 1 hour, and then at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was removed, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoic acid (E105) (101.6 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.63 (2H, t), 2.99 (2H, t), 4.98-5.04 (1H, m), 7.10 (1H, dd), 7.30 (1H, s), 7.56 (1H, d), 7.81 (1H, dd), 8.56 (1H, dd), 8.90 (1H, d), 11.11 (1H, s), 12.14 (1H, br s); δF (DMSO-d6, 376 MHz): −115.5; MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([NH:38][S:39]([C:42]1[S:46][C:45](Cl)=[N:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F-].[K+].O>C1(C)C=CC=CC=1>[C:34]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[N:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 47.2 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.55 g, 0.93 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.26 g, 1.0 mmol), tetrakis(triphenyl-phosphine)palladium (0.064 g, 0.055 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.23 g) as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[CH3:32][S:29]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)(=[O:31])=[O:30]
Reactant: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H](C[C@H]1CCCOC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 138.5 %

Procedure:
To a solution of benzyl (5)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (26 g, 69.99 mmol) and triethylamine (21.21 g, 210 mmol) in CH2Cl2 at 0° C. was added mesyl chloride (16.1 g, 140 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The reaction was quenched with ice-cold water, extracted with CH2Cl2 (3×100 ml), washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the product (36 g), which was used for the next step without purification.
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]=1[C:13]#[N:14].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:14][C:13]1[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][C:15]=2[O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[N:10]=[C:2]([CH3:9])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N#Cc1c(N)cccc1OC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydrous toluene (200 mL) was added to a solution of 2-amino-6-(cyclohexyloxy)benzonitrile (Example Hb, 49.8 g, 0.230 mol) in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottom flask sitting in an oil bath at room temperature. SnCl4 (53.9 mL, 0.461 mol) was added slowly over a period of approximately 1 h. The oil bath temperature was then raised to 110° C. and the reaction mixture was stirred at that temperature for 2.5 h. It was then cooled down to 5° C., still under nitrogen, and the toluene was decanted away from the immiscible viscous oil at the bottom of the flask. The viscous oil was further concentrated under vacuum at 60° C., re-dissolved in boiling ethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. The solution was diluted with more EtOAc (1.5 L), cooled down to −15° C., and neutralized with NaOH (3 N, 500 mL). The organic layer was separated, and the aqueous emulsion was extracted once more with ethyl acetate. The insoluble tin salts were filtered out from the aqueous layer, then both the salts and aqueous filtrate were washed once more with ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and passed through a silica column using 0% to 60% ethyl acetate in hexanes. The product was purified by recrystallization from EtOAc to give the title compound as an off-white solid (64.3 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m, 2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s, 3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz, 1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs, 2H). MS 329 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:24]([NH:26][CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)=[O:25].CO.[ClH:40]>O1CCOCC1>[ClH:1].[ClH:40].[NH2:16][CH:13]1[CH2:12][CH2:11][CH:10]([NH:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:24]([NH:26][CH2:27][C:28]23[CH2:29][CH:30]4[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]4)[CH2:37]2)[CH2:35]3)=[O:25])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared from [4-[[[4-chloro-3-[[(tricyclo[3.3.1.1 3,7]dec-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]-carbamic acid, 1,1-dimethylethyl ester (0.26 g, Example 33a), methanol (5 ml) and 4N hydrochloric acid solution in dioxane (1 ml). Solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give the title compound as a white powder (0.190 g).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:18][CH3:19])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:3]1.[CH2:20]([O:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(OC(=O)C)(=O)C>>[CH2:12]([C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH:4]=[CH:3][C:2](=[C:30]([C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:33])[C:31]#[N:32])[CH:7]=[CH:6]2)=[CH:18][CH:19]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCOC(=O)CC#N
Reactant: CCC(CCCc1ccccc1)n1ccc(=O)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCOC(=O)C(C#N)=C1C=CN(c2ccc(CCCCCC)cc2)C=C1
Temperature: 140 °C

Procedure:
In a 50 ml round bottom flask with stirbar, reflux condenser and nitrogen bubbler was placed the 4-(4-oxo-4Hpyridin-1-yl)hexylbenzene (0.638 g, 2.5 mmol), octylcyanoacetate (1.97 g, 10 mmol) and acetic anhydride (5.0 g). This mixture was heated in a 140° C. oil bath for 4.0 hours. After this period the mixture was cooled and crystalline product was isolated by suction filtration and washed well with acetic anhydride. The crude product was crystallized once from 1-propanol as yellow crystals (0.90 g, 83%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].O>CCOCC>[C:5]1([O:4][C:2](=[O:3])[NH:12][OH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C(NO)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Phenyl chloroformate (10 g, 63.8 mmol) in ether (10 mL) was added dropwise to a stirred mixture of finely ground hydroxylamine hydrochloride (63.8 mmol, 4.43 g) and potassium carbonate (58.4 mmol, 8.07 g) in ether (10 mL) containing water (1 mL) at 0° C. The mixture was stirred at room temperature for three days, filtered, and the solvent evaporated to give the Phenyl-N-hydroxycarbamate as crystals, m.p. 99.5°-100.7° C. (9.20 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[CH:23](OCC)=O.[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][S:9]([NH:8][C:6]1[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]2[C:20](=[O:21])[CH:22]=[CH:23][O:1][C:2]=2[CH:7]=1)(=[O:11])=[O:10]
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
In 70 ml of toluene was suspended 3.4 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. 17 ml of ethyl formate was added thereto. Further, 3.4 g of sodium hydride (purity: 60%) was added thereto in portions in 20 minutes. The mixture was refluxed for 5 hours. The reaction mixture was introduced into 300 ml of ice water. The aqueous layer was separated and adjusted to pH 4 with 4N hydrochloric acid. The mixture was then extracted with two 100-ml portions of ethyl acetate. The extracts were combined and subjected to distillation under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of acetic acid. 1 ml of concentrated hydrochloric acid was added. The mixture was heated for 30 minutes at 50°-60° C. 200 ml of water was added thereto. The resulting mixture was extracted with 200 ml of ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 2.28 g (yield: 65%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 216.7°-217 6° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C(N(CC)[C:9](=[O:12])[CH2:10][CH3:11])C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=O)=[C:18]([OH:31])[CH:17]=1.C([O-])(O)=O.[Na+].Cl>ClC1C=CC=CC=1Cl>[Br:15][C:16]1[CH:17]=[C:18]2[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[C:10]([CH3:11])[C:9](=[O:12])[O:31]2)=[CH:20][CH:21]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1O
Reactant: CCC(=O)N(CC)CC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1c(-c2ccc(F)cc2)c2ccc(Br)cc2oc1=O
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Phosphorous oxychloride (95.0 μL, 1.02 mmol) was added dropwise, at rt to a solution of N,N-diethylpropionamide (146 μL, 1.02 mmol) in 1,2-dichlorobenzene (1 mL). After 30 min. at rt, (4-bromo-2-hydroxyphenyl)(4-fluorophenyl)methanone (300 mg, 1.02 mmol) was added all at once. After 10 min. the reaction mixture was heated at 140° C. for 16 h and allowed to cool to rt. It was poured into 5% NaHCO3 (20 mL) and the resulting mixture stirred at 60° C. for 20 min., cooled to rt, acidified (pH=1) with 6N HCl and extracted with CHCl3. The combined organics were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was subjected to chromatography on silica gel (EtOAc/toluene 1:100) affording the title compound as a white solid, contaminated with ˜10% of an impurity. It was used as such in the following step.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14](O)([CH3:17])([CH3:16])[CH3:15].CCCCCC>S(=O)(=O)(O)O>[CH2:8]([O:7][C:5]([NH:4][C:3]1[CH:10]=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:2]=1[F:1])=[O:6])[CH3:9]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
2-Fluoro-N-ethoxycarbonylaniline (1.00 g, 5.46 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (5.00 g) to prepare a solution. t-Butyl alcohol (0.440 g, 6.01 mmol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. Thereafter, t-butyl alcohol (0.440 g, 6.01 mmol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. t-Butyl alcohol (0.440 g, 6.01 mmol) was again added dropwise thereto over a period of 30 min. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for one hr. The reaction solution was cooled to room temperature. n-Hexane (10 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (10 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 1.45 g of N-ethoxycarbonyl-4-t-butyl-2-fluoroaniline as an oily crude product (yield on weight basis 111%). The crude product was further subjected to separation and purification by column chromatography on silica gel to give 1.17 g of a mixture of 4-t-butyl-2-fluoro-N-ethoxycarbonylaniline with 5-t-butyl-2-fluoro-N-ethoxycarbonylaniline (yield 90%, 4-t-Bu: 5-t-Bu=82:18).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([O:27][C:2]2[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)([F:19])[F:20]
Reactant: Oc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reactant: N#Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cnc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred mixture of 2-chlorothiazole-5-carbonitrile (14.68 mg, 0.102 mmol) and 6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-ol (V) (25 mg, 0.068 mmol) in dry DMSO (1 mL) was added potassium carbonate (18.71 mg, 0.135 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at RT for 4 hours, then diluted with DCM and washed with 2N HCl/water. The organic extract was evaporated and purified on silica (ISCO, 12 gram column, gradient to 50% EtOAc/Hexanes over 15 minutes) to afford the title compound. Yield=18 mg (52.9%) of a yellow white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 6.90 (s, 1H), 6.82-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.59 (d, J=14.3 Hz, 1H), 5.16 (d, J=15.3 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.63 (d, J=16.3 Hz), −104.07 (dd, J=56.5, 10.2 Hz), −104.33 (d, J=16.3 Hz), −107.58 (t, J=6.8 Hz), −110.27 (d, J=39.5 Hz), −110.97 (d, J=40.9 Hz). MS(ESI): m/z 478.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:23]=[CH:24][C:3]([CH2:2][P:26]([CH3:25])(=[O:30])[O:27][CH2:28][CH3:29])=[CH:4][CH:5]=2)=[O:8])=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: CCOP(C)OCC
Product: CCOP(C)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
90 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 45 μL of diethyl methylphosphonite in the microwave at 120° C. for 5 minutes. The reaction was evaporated to dryness and purified by reverse phase HPLC to give pure ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl(methyl)phosphinate. MS (Q1) 429 (M)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[O:2].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14]>C1COCC1>[F:14][C:13]([F:16])([F:15])[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)[OH:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cn1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
To a −78° C. solution of 5-formylpicolinonitrile (1.0 g, 7.58 mmol) and tetrabutylammonium triphenyldifluorosilicate (4.9 g, 9.10 mmol) in 60 mL of THF was added a solution of trimethyl(trifluoromethyl)silane (1.62 g, 114 mmol). The mixture was stirred for 20 min at −78° C. Then the cooling bath was changed to an ice bath. After stirring for another 30 min, the reaction was quenched with sat. NH4Cl(aq.). The mixture was extracted with EtOAc (3×). The organic layer was washed with sat. NaHCO3(aq.), brine, then dried (MgSO4) and concentrated. The product 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (600 mg) was obtained by silica gel chromatography (elution with 0-40% EtOAc/Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: CCCCCCC
Product: O=C(Cl)c1cc(Cl)ccc1O
Temperature: 60 °C
Yield: 99.3 %

Procedure:
A solution of 5-chloro-2-hydroxy-benzoic acid (20.0 g, 116 mmol) in heptane (232 mL, 0.5 M) was treated with thionyl chloride (25.4 mL, 348 mmol) and heated to 60° C. for 6 h. After cooling to room temperature, the solution was concentrated under reduced pressure to give 5-chloro-2-hydroxy-benzoyl chloride as a thick yellow oil (22 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:7](=O)[C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:37]([F:38])=[C:36]([F:39])[CH:35]=[C:34]([F:40])[C:33]=3[F:41])=[N:22][C:3]=12>[Zn].C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[CH2:7][C:6]=2[CH:5]=[C:4]2[NH:20][C:21]([C:23]3[C:24](=[O:43])[NH:25][CH:26]=[CH:27][C:28]=3[NH:29][CH:30]([CH3:42])[CH2:31][C:32]3[C:33]([F:41])=[C:34]([F:40])[CH:35]=[C:36]([F:39])[C:37]=3[F:38])=[N:22][C:3]=12
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)CN(C1CCN(C)CC1)C2=O
Yield: 34.3 %

Procedure:
A mixture of 4-methyl-6-(1-methylpiperidin-4-yl)-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.93 g, 1.65 mmol), zinc dust (1.02 g, 15.6 mmol), and 30 mL of acetic acid was heated at reflux for 14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 0.33 g (36.3%) of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 12.95 (s, 1H, NH), 11.32 (d, J=8.5 Hz, 1H, NH), 11.25 (d, J=4.1 Hz, 1H, NH), 7.80 (s, 1H, ArH), 7.77-7.75 (m, 1H, ArH), 7.63 (t, J=7.0 Hz, 1H, ArH), 6.19 (d, J=7.5 Hz, 1H, ArH), 4.41 (d, J=3.5 Hz, 2H, CH2), 4.29-4.21 (m, 1H, CH), 4.06-4.01 (m, 1H, CH), 3.07-3.06 (m, 2H, CH2), 2.92-2.90 (m, 2H, CH2), 2.43 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.09 (m, 2H, CH2), 1.91-1.83 (m, 2H, CH2), 1.72-1.69 (m, 2H, CH2), 1.36 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, positive) m/z 583.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH3:34])[CH:17]([C:19]4[CH:33]=[CH:32][C:22]5[N:23](C6CCCCO6)[CH:24]=[N:25][C:21]=5[CH:20]=4)[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:23]1[C:22]2[CH:32]=[CH:33][C:19]([CH:17]([N:16]([CH3:34])[C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH3:18])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: CC(c1ccc2c(c1)ncn2C1CCCCO1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(c1ccc2[nH]cnc2c1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 50 °C
Yield: 45.1 %

Procedure:
To a solution of 86 (68 mg, 0.148 mmol) in MeOH (50 mL) and water (10 mL) was added TsOH.H2O (44 mg, 0.148 mmol). The reaction mixture was heated at 50° C. for 18 h. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC to afford 25 mg (45%) of (±)-N2-(1-(1H-benzo[d]imidazol-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine (88) as white solid: MS (ESI) m/z=375.3 (M+1).