Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]3C(C)(C)[O:18][CH2:19][CH:13]3[CH2:12]2)[CH:7]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([NH:8][C:9](=[O:22])[CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH:13]([CH2:19][OH:18])[CH2:12]2)[CH:7]=1
Reactant: Cc1ccc(F)cc1NC(=O)CN1CCN2C(COC2(C)C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(F)cc1NC(=O)CN1CCNC(CO)C1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 8.5 parts of N-(5-fluoro-2-methylphenyl)tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide and 105.6 parts of hydrochloric acid solution 0.5N was stirred and refluxed for 2 hours. The reaction mixture was cooled to room temperature. The whole was alkalized with sodium carbonate and salted out. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.4 parts (59.4%) of N-(5-fluoro-2-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide; mp. 127.7° C. (intermediate 145).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1=[O:24].BrCC(OC[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>>[CH2:1]([O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:6]1=[O:24])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: O=C(CBr)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O

Procedure:
Prepared by a similar method described for the preparation of 600a/103 (Step D), except benzyl bromoacetate was used instead of methyl bromoacetate to give 600b in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][O:7]CC1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl.B(Br)(Br)Br>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)[C@H](CCO)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 0.5 h
Yield: 119.9 %

Procedure:
A solution of 2.05 g (4.40 mmol) of (S)-4-benzyloxy-2-[4-(3,4-dichloro-phenyl)-7-oxo-[1,4]diazepan-1-yl]-butyric acid methyl ester (evaporated with toluene) in 20 ml CH2Cl2 was cooled (−20° C.) and treated with 4.62 ml (4.62 mmol, 1M in CH2Cl2) of boron tribromide. The solution was warmed in 1 h to 0° C. and kept for 1.5 h at this temperature, additional 0.22 ml (0.22 mmol, 1M in CH2Cl2) of boron tribromide was added and stirring was continued for 30 min. The mixture was extracted with cold sat. aq. NaHCO3 solution and EtOAc (3×). The organic phases were washed with sat. aq. NaHCO3 solution, aq. 10% NaCl solution, dried over Na2SO4 evaporated to give 1.98 g (76%) of the title compound as light yellow foam. MS: 375.2 (MH+, 2Cl).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[S:13][C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)=[CH:15][N:16]=2)=[N:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ncc(Br)n3ccnc23)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cnc(Nc2ncc(Br)n3ccnc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The product of Step 1 (0.125 g, 0.28 mmol) is dissolved in THF (2 mL). To this solution is added TBAF solution (1M in THF, 0.31 mL, 0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction is condensed and the residue purified by gradient column chromatography eluting with dichloromethane—5% methanolic ammonia (7 N) in dichloromethane to give the alcohol (64 mg, 69%). LCMS: Rt 2.54 min (97.7%). MS (MH+, m/z) 326.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].N1(C(N2C=CN=C2)=O)C=CN=C1>ClCCl>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:35](=[O:36])[CH2:34][C:32]#[N:33])[CH2:23]3)[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2[C@@H]1CCCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (210 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (50 mL), 2-cyanoacetic acid (63 mg, 0.74 mmol, 1.50 equiv), and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (120 mg, 0.74 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature and then diluted with dichloromethane. The resulting mixture was washed with NH4Cl and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 150 mg (62%) of 3-[(3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:34][CH2:35]1
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-1-methylpiperidine (236 mg, 0.93 mmol). The reaction was then allowed to cool to rt and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give a viscous brown solid (236 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.70 (d, J=7.5 Hz, 2H), 7.25 (d, J=7.5 Jz, 2H), 3.26-3.23 (m, 2H), 2.69-2.64 (m, 1H), 2.60-2.54 (m, 5H), 1.92-1.91 (m, 4H), 1.33 (s, 12H); MS ESI 302.2 [M+Na]+, calcd for [C18H28BNO2+Na]+ 302.22.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[O:8])=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
The product from step (b) (0.7 g) and 1,1′-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C.
Reaction SMILES: C1(C[O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2C(OCC2C=CC=CC=2)=O)C=CC=CC=1.C(N1CCCC1C(O)=O)(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:43]([O:23][C:21]([CH:20]1[CH2:19][CH2:18][NH:17][CH:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:8])=[O:34])=[O:22])[CH2:44][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(CCCCCCC1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Product: CCCCCCOC(=O)C1CCNC1CCCCCCC(=O)O

Procedure:
By substituting 3-carboxy-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester (Example 18) for the N-carbobenzoxy-DL-proline in the procedure of Example 1, 3-[(hexyloxy)carbonyl]-2-pyrrolidineheptanoic acid is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][C@@H:5]2[C@H:8]([CH:9]=1)[C@@:7]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])([CH2:10][N+:11]([O-])=O)[CH2:6]2)[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:11][CH2:10][C@@:7]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:6][C@H:5]2[C@@H:8]1[CH:9]=[C:3]([CH2:1][CH3:2])[CH2:4]2
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 43.1 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.09 g, 4.71 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (1.32 g, 23.5 mmol) and ammonium chloride (249.6 mg, 4.71 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (425.1 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:5][C:6](O)=[O:7].B>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
In a flask under argon was placed (S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (7.00 g, 24.89 mmol) in tetrahydrofuran (15 mL) and cooled to −5° C. To this mixture was added a 1.0M solution of borane in tetrahydrofuran (50.6 mL, 50.6 mmol), slowly over a 15 min period. After the addition was complete, the mixture was stirred at 0° C. for 5 h and then quenched by slow addition of a 10% aqueous citric acid solution (100 mL) and then diethyl ether (100 mL). The mixture was then extracted with diethyl ether (3×50 mL) and the organic layers were combined and washed with a 1:1 solution of water:saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel 60, 230-400 mesh; 40% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded (S)-2-benzyloxycarbonylamino-4-hydroxy-butyric acid methyl ester (4.50 g, 68%) as a colorless viscous oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH2:10]1)[CH3:8])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH:9]1[CH2:14][CH2:13][C:12]2([O:24][CH:11]2[CH2:10]1)[CH3:15])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(C)C1CC=C(C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OCCC(C)C1CCC2(C)OC2C1

Procedure:
The procedure of Example 1 was followed for the epoxidation of 4.2g (0.02 mole) of acetic acid, 3-(4-methyl-3-cyclohexenyl)butyl ester using 4.1g (0.02 mole) of 85% m-chloroperbenzoic acid in 150 ml of methylene chloride. Obtained was 4.1g of pure acetic acid, 3-(3,4-epoxy-4-methylcyclohexyl) butyl ester as a clear, colorless liquid. (See Table I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:12]=3)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
112 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.261 mmol), 1-(4-chlorophenyl)piperazine (70 mg, 0.261 mmol), DIPEA (0.068 mL, 0.392 mmol) and NaBH(OAc)3 (166 mg, 0.783 mmol).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[C:5](=O)[NH:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:14])([CH3:13])[CH2:5][NH:6]2
Reactant: CC1(C)C(=O)Nc2ccc(F)c(F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNc2ccc(F)c(F)c21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
0.15 mg (0.76 mmol) 4,5-difluoro-3,3-dimethyl-1,3-dihydro-indol-2-one were placed in 20 mL THF under argon. 0.91 mL (0.91 mmol) of a 1M lithium aluminium hydride solution in 10 mL THF were added dropwise. The reaction mixture was stirred for 1 h at 70° C., cooled and mixed with water. The reaction mixture was dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23]C=C[N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:25]1C(CN)=CC=N1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[NH:20][N:25]=[CH:23][CH:24]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1ccn[nH]1
Agent: Cl
Product: Cc1nc(NCc2ccn[nH]2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (1H-pyrazol-5-ylmethyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28-1.37 (m, 5H), 1.60-1.69 (m, 5H), 1.86 (s, 3H), 2.25 (s, 3H), 3.98 (d, J=10.74 Hz, 1H), 4.52 (d, J=4.82 Hz, 2H), 6.12 (s, 1H), 7.59 (s, 1H), 7.98 (s, 1H), 12.15 (bs, 1H); MS (ESI) m/z 301.5 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)#[N:26]>O1CCCC1>[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])=[CH:31][CH:32]=1)#[N:26]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (6 ml) was added 4-cyanophenyl isocyanate (176 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 160 mg (50.6%) of the desired product as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:41]#[N:42])[CH:44]=3)(=[O:51])=[O:50])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 490 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13]C)[N:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.FC(S(O[Si](C)(C)C)(=O)=O)(F)F.C([SiH](CC)CC)C.[C:46]1([S:52]([C:55]2[CH:62]=[CH:61][CH:60]=[CH:59][C:56]=2[CH:57]=O)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:57][C:56]3[CH:59]=[CH:60][CH:61]=[CH:62][C:55]=3[S:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(=[O:54])=[O:53])=[C:11]([CH3:13])[N:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(CC)cc(-c2ccc(F)cc2)c1-c1ccccc1
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccc(F)cc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Ethyl 2-(3-(4-fluorophenyl)-5-ethyl-2-phenyl-1H-pyrrol-1-yl)acetate (0.8 g, 2.371 mmol) was dissolved in 10 mL DCM and cooled to −78° C. Trimethylsilyl trifluoromethylsulfonate (0.964 ml, 5.34 mmol) was then added, followed by triethylsilane (1.136 ml, 7.11 mmol). The reaction mixture was stirred at −78° C. for 30 minutes. At this time, 2-(phenylsulfonyl)benzaldehyde (0.876 g, 3.56 mmol) was added portion-wise as a solution in 2.0 mL DCM. The reaction was monitored by LC/MS. Following addition of the aldehyde, the cold bath was removed and the mixture was stirred overnight (gradually warming to room temp). The reaction was quenched with sodium bircarbonate and moved to a separatory funnel. Layers were separated and the aqueous portion was extracted two additional times with DCM. The organics were combined, dried, filtered, and concentrated. The resulting crude oil was purified via column chromatography (SiO2) using a 0-40% EtOAc/hexane gradient to give ethyl 2-(3-(4-fluorophenyl)-5-methyl-2-phenyl-4-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (1.0 g, 1.762 mmol, 74.3% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 8.31-8.29 (m, 1H), 7.80-7.78 (m, 2H), 7.53-7.49 (m, 2H), 7.43-7.36 (m, 3H), 7.25-7.21 (m, 4H), 7.10-7.07 (m, 2H), 6.60-6.56 (m, 2H), 6.52-6.48 (m, 2H), 4.49 (s, 2H), 4.21 (q, 2H), 3.97 (s, 2H), 1.86 (s, 3H), 1.26 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[S:9](Cl)([Cl:12])(=[O:11])=[O:10]>CC#N>[Cl:12][S:9]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CNS(=O)(=O)Cl

Procedure:
To glycine ethylester hydrochloride (5.00 g, 35.8 mmol) in CH3CN (200 mL), was added sulfuryl chloride (29.00 g, 214.8 mmol), refluxed for 12 hr, and concentrated under reduced pressure. To the reaction mixture, was diethyl ether (100 mL), concentrated under reduced pressure (2×), and dried under vacuum. The resultant was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:40])[C@H:26]([CH2:38][SH:39])[NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([S:39][CH2:38][C@H:26]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:40])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Reactant: CC(C)(C)OC(=O)[C@H](CS)NS(=O)(=O)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1ccc2c(SC[C@H](NS(=O)(=O)c3ccc(Br)cc3)C(=O)OC(C)(C)C)nc(C)nc21
Temperature: 100 °C

Procedure:
279 mg of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) and 655 mg of N-(4-bromobenzenesulfonyl)-(R)-cysteine-tert-butyl ester (example 6b) were dissolved in 2 ml of NMP and 0.68 ml of DIPEA were added. The reaction mixture was heated to 100° C. for 4 h. The mixture was diluted with 60 ml of EE and extracted with 10% citric acid, saturated NaCl solution and with water. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude product was chromatographed on silica gel eluting with EE/toluene (1:6). Yield: 108 mg.