Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:20]([CH3:22])=[CH2:21])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12

Procedure:
The mixture of 1-cyclohexyl-3-[7-isopropenyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (70 mg, 0.163 mmol) and Pd/C (17 mg, 0.016 mmol) in MeOH (1.6 mL) was shaked under 50 psi of H2 atmosphere overnight, filtered through a pad of celite, and washed with MeOH. The filtrate was concentrated to give crude 1-Cyclohexyl-3-[7-isopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea, which was dissolved in a solution of HCl in AcOH (1M, 1.6 mL). The reaction mixture was heated at 50° C. in the sealed tube for 2 hr, concentrated to dryness, dissolved in 2 mL of MeOH:H2O:Et3N 8:1:1 and ethylenediamine (0.11 mL, 1.63 mmol) was added. The reaction mixture was stirred overnight, concentrated and purified by SiO2 chromatography (8 g SiO2, DCM/MeOH 0 to 10% MeOH) to give 9 mg of 1-cyclohexyl-3-(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as a pale yellow solid (18% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.125 g, 0.449 mmol) was reacted with N-(2-azidoethyl)-4-heptylbenzamide (0.129 g, 0.449 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-heptylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), δ 7.65 (d, 2H), δ 7.27 (s, 1H), δ 7.09 (d, 2H), δ 6.39 (s, 1H), δ 6.22 (s, 2H), δ 4.47 (s, 2H), δ 3.81 (s, 2H), δ 3.96 (s, 4H), δ 2.20 (s, 2H), δ 2.05 (s, 2H), 1.48 (m, 12H), δ 1.17 (m, 8H), δ 0.77 (t, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 149.6, 148.2, 147.1, 138.6, 131.5, 128.6, 127.4, 122.1, 106.4, 84.8, 67.1, 49.4, 40.2, 37.9, 36.9, 31.9, 31.3, 31.1, 29.8, 28.4, 29.3, 28.9, 28.3, 28.1, 28.0, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for C31H47N7O3 (M+) 565.3704. found 656.3737, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-heptylbenzamide hydrochloride (0.194 g, 86% yield). 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), δ 7.71 (d, 2H), δ 7.24 (d, 2H), δ 6.45 (s, 1H), δ 4.74 (s, 2H), 3.90 (s, 2H), δ 2.63 (s, 2H), δ 2.61 (t, 2H), δ 2.41 (S, 2H), δ 1.58 (m, 6H), δ 1.26 (m, 10H), δ 0.85 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 150.2, 147.4, 131.2, 128.5, 127.6, 127.3, 108.4, 51.4, 39.6, 36.5, 35.6, 31.8, 331.3, 29.1, 29.1, 28.3, 28.0, 27.7, 24.1, 22.6, 13.4, 13.3 ppm; HRMS (ESI) calcd for C26H39N7O (M+) 465.3216. found 465.3207.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCOCC3)ccc2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.1 g) was reacted with morpholine via General Procedure B to afford quantitative yield of 4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)morpholine.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C(O)C.C(O)(=O)/C=C/C(O)=O>CS(C)=O>[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)CO3
Temperature: 80 °C
Yield: 60.9 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.45 g, 1.2 mmole) and 4-(4-fluorobenzoyl)piperidine (0.73 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.28 g of the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.30 g of pale yellow solid, m.p. 229-230° C.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([CH:20]1[C:24]([CH3:25])=[CH:23][C:22](=O)[N:21]1C(OC(C)(C)C)=O)=[O:19].N1C(C)=CC=CC=1C>ClCCl>[CH3:16][O:17][C:18]([C:20]1[NH:21][C:22]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:23][C:24]=1[CH3:25])=[O:19]
Reactant: COC(=O)C1C(C)=CC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1[nH]c(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 23 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
tert-Butyldimethylsilyltrifluoromethanesulfonate (9.99 ml, 11.49 g, 43.5 mmol, 3.0 equiv) was added to a stirring solution of 3-methyl-5-oxo-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.7 g, 14.5 mmol, 1.0 equiv) and 2,6-lutidine (5.07 ml, 4.66 g, 43.5 mmol, 3.0 equiv) in dichloromethane (100 ml) at 23° C. The mixture was stirred at 23° C. for 15 h, then washed with pH=7 buffer solution (30 ml). The aqueous layer was extracted with two 40 ml portions of dichloromethane. The combined organic layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (3% ethyl acetate-hexanes initially, grading to 6% ethyl acetate-hexanes) to afford 5-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (3.46 g, 89%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13]>C(OCC)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: N#Cc1ccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 4-amino-benzonitrile and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 204-206° C. (diethylether)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15].S([O-])(O)(=O)=O.[K+].O>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:8][C:6]2([O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:7]2)[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Reactant: OCC(O)CO
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)CC12OCC(CO)O2
Reaction time: 7 h

Procedure:
In a 2 l three-necked flask there are introduced 308 g of 1-menthone (2 mol), 276 g of glycerol (3 mol) and 5 g of potassium hydrogen sulphate in toluene. This mixture is refluxed in a water separator. After 7 hours, 42 g of water have separated. The mixture is neutralised and distilled.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43](Cl)=[O:44]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43]([NH:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:44]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC(C)CC1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl α-(2-aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (549 mg, 1.36 mmol), CH2Cl2 (8.4 mL), and diisopropylethylamine (0.29 ml, 1.6 mmol) at 0° C. is added 3,4-difluorobenzoyl chloride (0.21 mL, 1.6 mmol). The solution is stirred at 0° C. for 1 hour and 16 hours at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) gives 477 mg (64%) of the title compound as a white solid (mp 147°-148° C.):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Sn](C)(C)C)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Product: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
Prepared from 4-methylphenyltrimethylstannane (Example 69, Step A) and 2-bromonitrobenzene by the procedure described in Example 69, Step B. 1H NMR (200 MHz,CDCl3): 2.39 (s,3H), 7.23 (m,3H), 7.45 (m,3H), 7.58 (t,7 Hz,1H), 7.80 (d,7 Hz,1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27]Br)[CH3:24]>CN(C)C=O>[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)[CH3:24]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Oc2ccccc2)cc1)OCC
Temperature: 150 °C

Procedure:
150 g of potassium carbonate and 4 g of finely powdered potassium iodide are added to a solution of 112 g (0.6 mole) of 4-phenoxyphenol and 157.6 g (0.8 mole) of bromoacetaldehyde diethyl acetal in 480 ml of dimethylformamide, and the batch is heated, under nitrogen, for 14 hours at 150° C. The salts are then removed by filtration from the reaction solution, and most of the dimethylformamide is distilled off in a water jet vacuum. The residue is dissolved in ether and the resultant solution is washed twice with water, three times with 20% potassium hydroxide solution and again with water. The ethereal solution is then dried over sodium sulfate and the ether is distilled off entirely. The resultant 4-phenoxyphenoxyacetaldehyde diethyl acetal is used without further purification for the preparation of the free aldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9]2)[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.6 mmol) in dry DMF (100 ml) under nitrogen at 0° C. was added NaH (0.264 g, 60% dispersion, 6.6 mmol) and the reaction mixture warmed to room temperature and stirred for 1 hr. Tert-butyl 4-[(4-methylphenyl)sulfonyl]oxy-1-piperidinecarboxylate (2.34 g, 6.6 mmol) was added and the resulting solution heated at 95° C. for 72 hr. The reaction was quenched by careful addition of water (150 ml). Extract with EtOAc (3×100 ml) and wash with water (4×100 ml) and brine (2×100 ml). The organic solution was dried (Na2SO4), filtered and evaporated to leave a solid which was adsorbed onto silica and purified by flash silica gel column chromatography using EtOAc then 5% MeOH/EtOAc as eluent to give in F 13-22 tert-butyl4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-piperidinecarboxylate (1.0 g, 31%) as a white solid, m.pt. 168.5-169.5° C. Rf in 10% EtOAc/MeOH=0.4. 1H NMR (d6 DMSO, 250 MHz): δ 8.14 (1H, s), 7.38-7.49 (5H, m), 7.07-7.23 (5H, m), 6.14 (2H, bs), 4.76 (1H, m), 4.11 (2H, m), 2.93 (2H, m), 1.92-2.02 (4H, m), 1.43 (9H, s). Mass spec. C28H31O3N5 (485.2430). IR (KBr disc): 3059, 1695, 1588, 1235 cm−1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (300.0 mg, 0.8 mmol, 1.0 equiv) and 1-methylpiperazine (1.12 mL, 10.1 mmol, 12 equiv) in methylpyrrolidone (9.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (15.0 mL) and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide (95.6 mg, 0.20 mmol) as yellow solids in 27% yield: 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=5.1 Hz, 1 H), 7.12 (s, 1 H), 6.83-6.86 (m, 3 H), 6.78 (s, 1 H), 3.63-3.65 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 3 H), 2.04 (s, 6 H); ESI-MS: m/z 422.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:34]=[CH:33][C:11]3[N:12]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:13]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH:27]=[N:26][C:25]([CH3:28])=[N:24]4)(O)[NH:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1>CO>[C:29]([N:12]1[C:11]2[CH:33]=[CH:34][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:14]=[C:13]1[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ncn(-c2ccc(Cl)cc2C2(O)Nc3cc(-c4cnc(N)nc4)ccc3N2C(C)(C)C)n1
Solvent: CO
Product: Cc1ncn(-c2ccc(Cl)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 70 °C
Yield: 37 %

Procedure:
A mixture of 5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-2-[5-chloro-2-(3-methyl-1,2,4-triazol-1-yl)-phenyl]-2,3-dihydro-1H-benzimidazol-2-ol plus regiosiomer (25 mg) in MeOH (25 mL) is heated at 70° C. for 16 hours. The reaction mixture is allowed to cool to room temperature and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent followed by further purification using a HPLC C-18 column with CH3CN (0.1% TFA) in H2O (0.1% TFA) as the eluent to afford 5-{1-tert-butyl-2-[5-chloro-2-(3-methyl-1,2,4-triazol-1-yl)-phenyl]-1H-benzimidazol-5-yl}-pyrimidin-2-ylamine (Example 37) (9 mg, 37%) as a white solid LCMS (ESMS): m/z 459.20 (M++1) and 5-{1-tert-butyl-2-[5-chloro-2-(5-methyl-1,2,4-triazol-1-yl)-phenyl]-1H-benzimidazol-5-yl}-pyrimidin-2-ylamine (Example 38) (6 mg, 25%) as a white solid. LCMS (ESMS): m/z 459.20 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].NN.O>CO>[NH2:17][CH2:16][C@@H:10]1[C@H:11]([CH3:15])[CH2:12][CH2:13][CH2:14][N:9]1[C:7]([C:6]1[CH:28]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)=[O:8]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A stirred solution of the product of Step 228b (274 mg, 0.590 mmol) and NH2NH2.H2O (114 mg, 2.27 mmol) in MeOH (10 mL) was heated to reflux for 2.5 h. After this time, the reaction mixture was cooled to rt then concentrated under reduced pressure. The resulting residue was triturated with a mixture of CH2Cl2/hexanes (1:1) and the solid was filtered off. The filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound as a white foam (182 mg, 93%). ESI MS (M+H) 329.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:28])=[C:4]([NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([O:28][S:30]([CH3:29])(=[O:32])=[O:31])=[C:4]([NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-[(3-fluoro-2-hydroxy-4-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)hydrazono]propanoate (4.95 g) in pyridine (50 mL) was added methanesulfonyl chloride (1.1 mL), and the mixture was stirred at 4° C. to room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous citric acid solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual light brown solid was washed with ethyl acetate-hexane to give the title compound (5.4 g, 92%) as a pale brown solid. MS 490 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.[NH2:24][C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:10]2[CH:9]=[C:4]3[C:3]([CH2:1][N:24]([C@@H:25]4[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]4)[C:5]3=[O:6])=[C:12]([CH3:13])[C:11]=2[CH3:14])=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To a solution of methyl 2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (13.5 g) in THF (270 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (5.06 g) and anhydrous magnesium sulfate (9.99 g), and the mixture was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was diluted with methanol (220 mL)-THF (250 mL), sodium triacetoxyborohydride (18.3 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to give the crude title compound (6.4 g). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.85 g). The crude title compound and the title compound purified by column were combined, and recrystallized from ethanol to give the title compound (6.48 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[O:30]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:40]2[CH:41]=[CH:42][C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Oc4ccccc4)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-phenoxyphenol: ESMS m/e: 626.6 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([CH:42]3CCCC3)=[N:38]OC=2C)=NC=1>>[CH:37]([NH:38][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:42])[CH3:36]
Reactant: COC(=O)c1ccc(OCc2c(C3CCCC3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 4 %

Procedure:
As described for example 30d, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol), instead of 6-(3-cyclopentyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted to the title compound (19 mg, 4%) which was obtained as a white solid after purification by chromatography (silica, 0 to 5% methanol in dichloromethane) and trituration with diisopropyl ether. MS: m/e=358.5 [M+H]+.