Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH:14]([OH:26])[CH:15]=[CH:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[Cl:25])CCCCCCCCCCC.S(=O)(=O)(O)[OH:28].O1CCOCC1>CO.O>[OH:26][CH2:14][C:15](=[O:28])[CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=1[Cl:25]
Reactant: CCCCCCCCCCCCSC(O)C=Cc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 28 °C
Reaction time: 18 h
Yield: 16.6 %

Procedure:
To an emulsion of dodecylsulfanyl-3-(2,4,6-trichloro-phenyl)-prop-2-en-1-ol (0.82 g; 1.9 mmol), prepared as described in example P61 in methanol (3 ml) was added dropwise 30% sulfuric acid (1.5 ml; 5.6 mmol). The temperature increased from 23° C. until 28° C. The mixture was heated at 60° C. for 5 h. Dioxane (2 ml) was added and reaction was stirred at 60° C. for 18 h. The biphasic mixture was transferred in a sealed microwave vial and heated at 80° C. for 10 min and at 100° C. for 10 min. The mixture obtained was poured in water and was extracted once with ethyl acetate. Organic layer was washed three times with water, dried over sodium sulfate and evaporated. The crude oil obtained was subject to flash chromatography (eluant: c-hexane/ethyl acetate 4:1). 80 mg (18% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one was obtained as a light yellow solid.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[N:15]=1>COCCOCCOC>[CH3:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:17]=[C:18]([NH:22][C:3]3[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=3)[CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: Cc1nc(-c2cccc(N)c2)cs1
Reactant: CSc1nccc(=O)[nH]1
Solvent: COCCOCCOC
Product: Cc1nc(-c2cccc(Nc3nccc(=O)[nH]3)c2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To 2-(methyl-thio)pyrimidine-4(3H)-one, 1, (1 g, 14.08 mmol) in diglyme (9 mL) is added 3-(2-methylthiazol-4-yl)benzenamine (3.20 g, 16.90 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 1.0 g (25% yield) of the desired compound. MS (ESI, pos. ion) m/z: 285 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](N(CC)CC)C.IC>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.18 mmol) and triethylamine (49 μL, 0.35 mmol) in DMF (1 mL) at −78° C., iodomethane (177 μL, 0.17 mmol, 1.0M in DMF) was added. The reaction was allowed to stir for 1 h while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 30 mg (34%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (dd, 1 H), 3.75 (dd, 1 H), 3.37-3.26 (m, 1H), 2.98 (dd, 1H), 2.70-2.65 (m, 2H), 2.56-2.50 (m, 1H), 2.47-2.30 (m, 1H), 2.26-2.18 (m, 2H), 2.14 (s, 3H), 2.11-2.01 (m, 1H), 1.61 (t, J=10.5 Hz, 1H); LC-MS [M+H]+=495, RT=2.10 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[O:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:12]([O:11][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: CCON
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Product: CCON=Cc1ccc(F)cc1
Yield: 58 %

Procedure:
Reaction of 4-fluorobenzaldehyde with ethoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5) and distillation (58% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.35 (3H, t, J=7.07 Hz, CH3), 4.24 (2H, q, J=7.07 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.07 (1H, s, CH).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[C:15]([C:24]([F:27])([F:26])[F:25])[C:14]=1[CH2:28][S:29][C:30]1[CH2:34][C:33]([CH3:36])([CH3:35])[O:32][N:31]=1.[OH2:37]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:16]=[C:15]([C:24]([F:25])([F:27])[F:26])[C:14]=1[CH2:28][S:29]([C:30]1[CH2:34][C:33]([CH3:36])([CH3:35])[O:32][N:31]=1)(=[O:9])=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2Cl)=NO1
Reactant: O
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(S(=O)(=O)Cc2c(C(F)(F)F)nn(-c3ccccc3)c2Cl)=NO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.2 %

Procedure:
0.63 g of m-chloroperbenzoic acid (purity: 70%, 2.6 mmoles) was added, with ice-cooling, to a solution of 0.4 g (1.0 mmoles) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1-H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 15 ml of chloroform. The mixture was stirred at room temperature for 22 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The resulting crystals were washed with hexane to obtain 0.4 g (yield: 83.2%) of 3-(5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylsulfonyl)-5,5-dimethyl-2-isoxazoline as white crystals (melting point: 132 to 133° C.).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][CH2:13][CH2:14][SH:15].C(Cl)(Cl)Cl>C(O)C.O>[S:15]1[CH2:14][CH2:13][NH:12][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NCCS
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2NCCS2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of 4-cyanobenzaldehyde (0.86 g, 6.6 mmol) in ethanol (15 ml) was added a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 18 h. The bulk of the ethanol was removed by rotary evaporator and the residue was treated with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified with solid sodium carbonate (0.3 g) resulting in the formation of an oil. The mixture was extracted with ether (2×25 ml), washed with brine (1×50 ml), dried (MgSO4) and evaporated to give a clear oil that solidified on standing (0.62 g). Column chromatography (silica gel, 100% chloroform) afforded pure 4-(1,3-thiazolidin-2-yl)benzonitrile (6) (0.56 g, 67%) as clear oil that solidified on standing, mp 57-58°. 1H nmr (CDCl3, 300 MHz) 3.05-3.15, m, H4,4; 3.2-3.35, m, H5; 3.4-3.5, m, H5; 5.64, s, H2; 7.63, app. s, H2′,3′,5′,6′. ESI (+ve) MS m/z 191 (M+H, 100%).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O>[ClH:1].[CH:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Solvent: O
Product: N[C@@H]1CCC[C@@H]1C1CCCCC1
Yield: 33.9 %

Procedure:
Using rhodium-on-charcoal catalyst in a Paar shaker, 12.6 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 204°-206° C. in 100 ml of water was hydrogenated. In 20 hours when the theoretical amount of hydrogen had been taken up the catalyst was removed by filtration, the filtrate made basic with sodium hydroxide solution, and the resulting precipitate was extracted into ether. After evaporation of the ether the residue was distilled, B.P. 100°-102° C. (6.0 mm). The hydrochloride salt was prepared and recrystallized from isopropanolether to give 4.4 g of cis-2-(cyclohexyl)cyclopentylamine hydrochloride, M.P. 174°-176° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@H:14]1[CH2:19][NH:18][C@H:17]([CH3:20])[CH2:16][NH:15]1>ClCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:15]2[CH2:16][C@@H:17]([CH3:20])[NH:18][CH2:19][C@@H:14]2[CH3:13])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: ClCCl
Product: C[C@@H]1CN(c2nnc(Cl)c3ccccc23)[C@@H](C)CN1
Temperature: 130 °C

Procedure:
1,4-dichlorophthalazine (1.0 g, 5 mmole) and trans-2,5-dimethyl piperazine were combined in a reaction vial and heated to 130° C. for 3 h with stirring. After cooling to room temperature, the solid residue was dissolved in 150 mL of dichloromethane and washed with 1×20 mL of 1:1 saturated NaHCO3 solution:H2O and 1×20 mL of saturated NaCl solution. The organic phase was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (100:5:1 dichloromethane:methanol:triethylamine) afforded 1-chloro-4-(trans-2,5-dimethylpiperazin-1-yl)phthalazine. MS (M+H)+=277.1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[I:16][C:17]1[C:18]([CH3:30])=[C:19]([CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27])[C:20]([OH:22])=O.[CH3:31][C:32]([N:35]1[C:39]([OH:40])=[CH:38][CH:37]=[N:36]1)([CH3:34])[CH3:33].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C.ClCCl>[CH3:31][C:32]([N:35]1[C:39]([OH:40])=[C:38]([C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:17]([I:16])[C:18]=2[CH3:30])[CH:37]=[N:36]1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)n1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(C(=O)c2cnn(C(C)(C)C)c2O)ccc(S(C)(=O)=O)c1I
Reaction time: 1.5 h

Procedure:
A solution of 8.4 g (40 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL of acetonitrile was added to a mixture of 13.6 g (40 mmol) of 3-iodo-2-methyl-4-methylsulfonylbenzoic acid and 5.6 g (40 mmol) of 1-(1,1-dimethylethyl)-5-hydroxypyrazole in 80 mL of acetonitrile with stirring. The mixture was allowed to stir for 1 hour and was then filtered, washing the filter cake with a little acetonitrile. Triethylamine (16.8 mL, 120 mmol) and acetone cyanohydrin (1 mL, 10 mmol) were added with stirring to the filtrate. After about 1.5 hour, dichloromethane was added and the resulting mixture was washed with a mixture of 2N aqueous hydrochloric acid and saturated aqueous sodium chloride. It was then concentrated by evaporation under reduced pressure. The residue obtained was dissolved in dichloromethane and the resulting solution was extracted with dilute aqueous sodium hydroxide. The aqueous extract was acidified with concentrated aqueous hydrochloric acid and the resulting mixture was extracted with dichloromethane. Fifty mL of triethylamine was added to the dichloromethane extract and the resulting solution was washed with saturated aqueous sodium chloride solution and then several times with 2N aqueous hydrochloric acid. It was then concentrated by evaporation under reduced pressure. The residue was triturated with hexane to obtain 16.8 g (72.7 percent of theory of the title compound as a light yellow powder melting at 171-172° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH2:18])=[N:13][NH:14]2)=[C:10]([F:19])[C:9]=1[F:20]>N1C=CC=CC=1>[Br:7][C:8]1[C:16]([F:17])=[C:15]2[C:11]([C:12]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:13][NH:14]2)=[C:10]([F:19])[C:9]=1[F:20]
Reactant: Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12
Temperature: 3 °C
Reaction time: 76 h

Procedure:
0.82 cm3 of butyryl chloride is added to 2.1 g of 6-bromo-4,5,7-trifluoro-1H-indazole-3-amine, prepared previously, in 20 cm3 of pyridine, after cooling to about 3° C., and the mixture is then left at room temperature for 76 hours. The reaction medium is concentrated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 100 cm3 of ethyl acetate, 100 cm3 of tetrahydrofuran and 40 cm3 of water. The organic phase is washed with 2×40 cm3 of distilled water and then with 40 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtration and concentration under reduced pressure (2 kPa; 40° C.), the residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa; 40° C.), 0.53 g of N-(6-bromo-4,5,7-trifluoro-1H-indazol-3-yl)butanamide is obtained in the form of a pink solid melting at 255°-257° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=O>>[Br:20][C:17]1[CH:16]=[C:13]2[C:12](=[CH:19][CH:18]=1)[N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[N:10]=[CH:14]2
Reactant: COc1ccc(NN)cc1
Reactant: O=Cc1cc(Br)ccc1Br
Product: COc1ccc(-n2ncc3cc(Br)ccc32)cc1

Procedure:
In analogy to Example 187, step 1, 4-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a light brown solid. MS (m/e)=303.0 [M+H+].
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:9]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:22][C:8]=2[C:7]=1[OH:29])=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33]>C[O-].[Na+].CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:22][C:8]=3[C:7]([OH:29])=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[N:11]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)c1nc(-c2ccc(C#N)cc2)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2nc(C(=O)NCC(=O)O)c(O)c3sc(-c4ccccc4)nc23)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 4-(4-cyano-phenyl)-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (132 mg, 0.33 mmole) and glycine (2.46 g, 32.8 mmole) in 0.5 M sodium methoxide/methanol (49 ml) was refluxed for 16 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (100 ml) and extracted with dichloromethane (2×50 ml). The remaining aqueous solution was acidified to pH=2 with 0.1 N HCl (28 ml). The resulting precipitate was filtered, washed with water and dried to give the title compound as a white solid (76 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.56 (t, 1H), 8.91 (d, J=8.2 Hz, 2H), 8.19 (m, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.64 (m, 3H), 4.07 (d, J=6.2 Hz, 2H); MS: (+) m/z 429.23 (M−1).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C1CCCCC1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=2.O[Li].O.Cl.C1COCC1>CO.C1COCC1.O.O>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2)[CH:10]=[CH:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 2 °C

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (117 g, 349 mmol) and LiOH.H2O (26.4 g, 629 mmol) in MeOH/THF/H2O (1:1:1, 1.8 L) was heated at reflux for 3 h. The reaction mixture was cooled in an ice/H2O bath to ˜2° C., neutralized with 1M HCl (˜650 mL) (added at such a rate that temperature did not exceed 5° C.), diluted with H2O (1 L) and stirred while warming to ambient temperature. The precipitates were collected by filtration rinsed with H2O and dried to yield the mono THF solvate of 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-(135.5 g, 345 mmol, 99%) as a yellow solid, which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 11.01 (br s, 1H), 8.77 (s, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.82 (dd, J=1.5, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 3.84 -3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 172.7, 135.5, 130.7, 122.3, 120.9(2), 118.8, 113.3, 111.1, 67.9(2), 37.0, 32.2(2), 27.0(2), 26.1, 25.5(2). LCMS: m/e 320 (M−H)−, ret time 2.21 min, column A, 4 minute gradient.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Br[CH2:24][CH:25]1[O:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:27]1[CH2:26][CH:25]1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC4CO4)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 4-[3'-hydroxyanilino]6-(3'-methylanilino)pyrimidine (1 g), 1-bromo-2,3-epoxypropane (0.44 ml) and potassium carbonate (0.95 g) in DMSO (12 ml) was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4) and evaporated to give 4-[3'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino)pyrimidine in 38% yield, m.p. 143°-145° C.;
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirred suspension of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH) afforded the title compound (226 mg, 69% yield). MS m/z=247.1 [M+H]+. Calc'd for C10H10N6S: 246.30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1.C(OC(N(C)CCCC(OC(OCC(C)C)=O)=O)=O)(C)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:62])([F:63])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1)[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: CC(C)COC(=O)OC(=O)CCCN(C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C(=O)OC(C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: -22 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (109 mg, 0.50 mmol) in THF (5 mL) was treated with 4-methyl-morpholine (101 mg, 1.0 mmol) followed by isobutyl chloroformate (68 mg, 0.5 mmol) and cooled to −22° C. under argon. The reaction mixture was stirred for 20 mins while warming to −15° C. After re-cooling to −24° C., 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) was added and the resulting suspension was slowly warmed to RT and stirred for 16 hrs. The reaction mixture was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)-amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (218 mg, 1.0 mmol) in THF (5 mL), 4-methyl-morpholine (101 mg, 1.0 mmol) and isobutyl chloroformate (137 mg, 1.0 mmol) at RT. The reaction mixture was stirred at RT for 24 hrs and then heated at 60° C. for 7 hrs. After standing at RT for 18 hrs, the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM. The product containing fractions were concentrated in vacuo and the resulting residue (456 mg, 0.5 mmol) in THF (5 mL) was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (1.09 g, 5.0 mmol) in THF (20 mL), 4-methyl-morpholine (760 mg, 7.55 mmol) and isobutyl chloroformate (680 mg, 5.01 mmol) at RT. The resulting mixture was heated at 50° C. for 65 hrs and then purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM followed by 10% MeOH in DCM affording the title compound (241 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:24])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N+:19]([O-:40])([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CC[N+]1([O-])CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (22.2 mg, 0.05 mmol) in DCM (10 mL) and MeOH (1 mL) was added MCPBA (11.2 mg, 0.07 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3, the combined organic extracts were dried (Na2SO4), and concentrated in vacuo. The crude product was purified by RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-1-ethylpiperidine-1-oxide; 1HNMR (MeOD-d4) δ7.91 (s, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 3.28 (m, 4H), 2.91 (m, 1H), 2.32 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 1.83 (s, 2H), 1.64 (d, 2H), 1.31 (t, 3H); ESMS m/z 460.2 (M+H+).