Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][Cl:14])(=O)=O)=CC=1.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Yield: 99.5 %

Procedure:
A mixture of 102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy -benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate, and 1.66 g (4.1 mmol) of methyl-tricapryl ammonium chloride in 900 ml of acetone was stirred rapidly at reflux for 18 hr. The mixture was filtered and the solvent was removed giving 106 g of the tile compound after recrystallization from a chloroform-hexane mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:19]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1nc(-c2ccc(Br)cc2)oc1C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1nc(-c2ccc(Br)cc2)oc1C
Temperature: 50 °C
Yield: 46 %

Procedure:
[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (11.6 g, 37.4 mmol) is dissolved in anhydrous tetrahydrofuran (150 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (28 mL of 2M soln., 56.1 mmol) is slowly added to the solution at room temperature. This is then heated to 50° C. for 6 hours. The solution is allowed to cool to room temperature and methyl iodide (7.0 mL, 112 mmol) is added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acid methyl ester (5.57 g, 17.19 mmol) is isolated in 46% yield after column chromatography. The racemic 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl)-propionic acid methyl ester is resolved on a Chiralcel OJ column (4.6×250 mm). Eluted with 40% isopropanol in heptane with 0.2% dimethy-ethylamine at 1 mL per minute with detection at 260 nM and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 99.4% ee).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][Si:35]([CH3:40])([CH3:39])[CH2:36][CH2:37]O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:17]([C:18]([O:20][CH2:37][CH2:36][Si:35]([CH3:40])([CH3:39])[CH3:34])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: C[Si](C)(C)CCO
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-(4,6-dimethoxypyrimidin-2-yl)oxy-2-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) were dissolved in 50 ml of tetrahydrofuran, and the mixture was refluxed under heating and stirring for one hour. After cooling the reaction solution, 2-(trimethylsilyl)ethanol (6.0 g) and potassium carbonate (1.5 g) were added thereto, and the mixture was refluxed under heating and stirring for one hour. The reaction solution was poured into ice water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was evaporated under reduced pressure. The residue thereby obtained was purified by silica gel column chromatography to obtain the above identified compound as a pale yellow oily substance (2.4 g). Refractive index nD20 : 1.5159.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=1.O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH:19]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
Sodium hydride (63%, 25 g, 656 mmol) was added to a solution of 4-methoxybenzyl alcohol (90.3 g, 654 mmol) and tert-butyl (5-chloro-2-nitrophenyl)methylcarbamate (US200216506 A1, 156 g, 544 mmol) in DMF (1.4 L) at room temperature, and the mixture was stirred at 80° C. for four hours. After leaving to cool, water (1.5 L) was added to the reaction mixture. The precipitated solid was collected by filtration to obtain the title compound (209 g, 99%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:13][C:14]1[CH:32]=[C:31]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH:30]=[C:29]([CH3:44])[C:15]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][O:27][CH3:28])=[C:21]([CH:24]=1)[CH:22]=[O:23]>C1COCC1>[CH3:44][C:29]1[CH:30]=[C:31]([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:35]([CH3:37])[CH3:36])[CH:38]([CH3:40])[CH3:39])[CH:32]=[C:14]([CH3:13])[C:15]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][O:27][CH3:28])=[C:21]([CH:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:23])[CH:24]=1
Reactant: Brc1ccccc1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirring solution of bromobenzene (0.45 g, 2.89 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.16 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 h and a solution of 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxybenzaldehyde (example 35; step e, 1.2 g, 2.63 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford [5-(2,6-dimethyl-4-triisopropylsilanyloxy-benzyl)-2-methoxymethoxy-phenyl]-phenyl-methanol as an yellow oil (1.4 g, 99.6%): 1H NMR (200 MHz, DMSO-d6): δ 7.23 (m, 6 H), 6.85 (d, J=8.8 Hz, 1 H), 6.68 (m, 1 H), 6.56 (s, 2 H), 5.92 (d, J=4.0 Hz, 1 H), 5.62 (d, J=4.0 Hz, 1 H), 5.10 (q, J=4.0 Hz, 2 H), 3.84 (s, 2 H), 3.23 (s, 3 H), 2.11 (s, 6 H), 1.23 (m, 3 H), 1.06 (d, J=6.4 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=15% ethyl acetate in hexanes; Rf=0.50.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[I-].C[N:15](C)N(C)C>CS(C)=O>[C:1]([C:3]1([NH2:15])[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:4]1[NH2:5])#[N:2]
Reactant: CN(C)N(C)C
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Agent: [I-]
Solvent: CS(C)=O
Product: N#CC1(N)C=CC([N+](=O)[O-])=CC1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67 mmol) in dimethylsulfoxide (25 ml) was added tetramethylhydrazine iodide (534 mg, 2.67 mmol) and sodium t-pentoxide (880 mg, 8.01 mmol). The mixture was stirred at room temperature for 12 hrs., the reaction was quenched with 10% HCl. Precipitated solids were filtered and the remaining solution was extracted with ethyl acetate, the solvent was evaporated and chromatography of the resulting solid on silica gel (25%EtOAc/Hexane) gave the desired product (254 mg, 53%). 1H NMR (CD3COCD3): δ7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([N+:25]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.[Fe]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:15][CH:16]=2)=[C:6]([NH2:25])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A suspension of 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-nitro-benzoic acid methyl ester (22.8 g, 56 mmol), Fe powder (16.4 g, 282 mmol) and NH4Cl (15.1 g, 282 mmol) in aqueous EtOH [prepared from EtOH (228 mL) and H2O (228 mL)] was gradually heated to reflux and gently refluxed for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite pad. The filtrate was evaporated. The aqueous residue was portioned between AcOEt and H2O, made basic to pH 9 with K2CO3, and then filtered through celite pad. The organic layer was separated, washed with H2O and brine, dried over MgSO4 and evaporated. The oily residue was crystallized in the treatment with i-Pr2O (200 mL) and stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration, washed with i-Pr2O and dried at 60° C. overnight under reduced pressure to give the title compound as colorless crystal (13.9 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([NH:45][C:46](=[O:47])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:36][CH:37]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 62.7 %

Procedure:
To a solution of (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (148 mg, 0.3 mmol) in dichloromethane (4 mL) was added benzyl isocyanate (40 μL, 0.32 mmol) and the mixture was stirred at room temperature for 90 hours. After filtration, the reaction product was rinsed with diethyl ether to provide 118 mg (yield 63%) of the title compound. m.p. 169°-171° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1OC1CCCCC1

Procedure:
Then, N-(2-fluoro-5-nitrophenyl)methanesulfonamide and cyclohexanol are subjected to etherification in the presence of a base to give N-(2-cyclohexyloxy-5-nitrophenyl)methanesulfonamide.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.Cl.O>N1C=CC=CC=1>[C:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 94 %

Procedure:
128 ml benzoyl chloride is dripped into a solution of 170 g 4-hydroxybiphenyl in 500 ml pyridine, at 20° C.; subsequently, the reaction mixture is heated under reflux for 30 min. After cooling, the reaction mixture is mixed with a solution of 500 ml concentrated hydrochloric acid and 750 ml water. The remaining precipitate is filtered off, washed neutral with water, dried and recrystallized from n-butanol (melting point: 150° C.); yield: 94%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[S:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1>>[S:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:10]1
Reactant: OC1CCCSC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCCSC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahyrothiopyran-3-ol by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C@H:10]([NH:16][C:17](=O)[O:18]C(C)(C)C)[CH2:11][O:12][CH:13]([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:26](F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:10]([CH2:11][O:12][CH:13]([F:15])[F:14])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])(=[O:18])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Tert-Butyl {(1R)-2-(benzylamino)-1-[(difluoromethoxy)methyl]-2-oxoethyl}carbamate (340 mg, 0.987 mmol) was stirred with trifluoroacetic acid (2.25 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, stirred with acetic anhydride-pyridine (1:1, 5.8 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (230.5 mg, 77.2%) as a white solid. Mp: 186.9° C. 1H NMR (300 MHz, DMSO-d6): (ppm) 8.60 (t, 1H), 8.30 (d, 1H), 7.28-7.45 (m, 5H), 6.67 (wt, 1H), 4.58 (m, 1H), 4.40 (d, 2H), 3.98 (d, 2H) and 1.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[CH:30]=[CH:29][S:28][C:27]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:25])=[O:24])=[C:6]1[CH3:15]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-benzenesulfonylthiophene-2-carbaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][N:25]=[C:24]3[N:37]([S:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)(=[O:42])=[O:41])[CH:38]=[CH:39][C:23]=23)[CH2:17][CH2:16]1)=O)(C)(C)C.[C:49](#[N:52])[CH:50]=[CH2:51]>C(Cl)Cl>[C:43]1([S:40]([N:37]2[C:24]3=[N:25][CH:26]=[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)[C:22]([NH:21][CH:18]4[CH2:19][CH2:20][N:15]([CH2:51][CH2:50][C:49]#[N:52])[CH2:16][CH2:17]4)=[C:23]3[CH:39]=[CH:38]2)(=[O:41])=[O:42])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCN1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.421 g, 0.724 mmol) in CH2Cl2 (10 ml) at 25° C. The reaction mixture was stirred at 25° C. for 30 min, then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×100 ml) and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in DMF (8 ml) at 25° C. Acrylonitrile (1.0 ml, 0.200 mmol) was added and the reaction mixture was stirred at 25° C. for 18 h, then was concentrated under reduced pressure. The residue was partitioned between water (100 ml) and EtOAc (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded N-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyclopentyl-acetamide (0.169 g, 63%) as a white foam. LCMS (Method G, ESI): RT=0.70 min, m+H=535.4. This material was used in the next step below without additional characterization.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH:20]([CH3:22])[CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH:20]([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: CC(C)c1n(N)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC(C)c1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 48 h

Procedure:
1.49 g of 4-dimethylamino-benzaldehyde are added to a solution of 0.88 g of 1,3-diamino-2-isopropyl-imidazolium chloride in 15 ml of glacial acetic acid. After allowing the reaction mixture to stand at room temperature for 2 days, the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropyl-imidazolium chloride of melting point 241°.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[C:7]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)cc1CN1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(OCC(=O)O)c(CN2CCCCC2)c1
Reaction time: 15 h
Yield: 173.1 %

Procedure:
To a methylene dichloride (2.0 ml) solution of tert-butyl [4-tert-butyl-2-(piperidin-1-ylmethyl)phenoxy]acetate (75 mg, 0.21 mmol), trifluoroacetic acid (0.2 ml, 2.7 mmol) was added at ambient temperature under nitrogen atmosphere. After being stirred for 15 hours, additional trifluoroacetic acid (1.0 ml, 13.5 mmol) was added. After being stirred additionally for 10 hours, the resulting mixture was concentrated under reduced pressure and azeotrope with toluene to furnish 111 mg of the title compound as slightly yellow oil, which was used for the next reaction without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][C@@:16]([S:39]([CH3:42])(=[O:41])=[O:40])([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Pd+2].O1CCOCC1.O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C@@:16]([CH3:15])([S:39]([CH3:42])(=[O:41])=[O:40])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)[C@@](C)(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Reactant: Oc1ccc(I)cc1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCc1ccc(-c2ccc(O)cc2)cc1)S(C)(=O)=O
Yield: 54 %

Procedure:
A mixture of palladium (II) EnCat (0.1 equiv), potassium carbonate (3.0 equiv), 4-iodophenol and ethyl(2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate, which may be prepared as in Preparation 8A, was heated to 80° C. in 10:1 1,4-dioxane-water to provide the title compound (54%) after purification by flash chromatography on silica gel. MS (LCMS) m/z 399.5 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H) 1.72 (s, 3H) 2.18-2.28 (m, 1H) 2.47-2.58 (m, 2H) 2.72-2.84 (m, 1H) 3.04 (s, 3H) 4.22-4.31 (m, 2H) 4.91 (s, 1H) 6.85-6.92 (m, 2H) 7.17-7.24 (m, 2H) 7.40-7.51 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH3:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: Cc1ccc(CO)cc1
Reactant: CCOC(=O)N=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)OCc1ccc(C)cc1
Yield: 106.7 %

Procedure:
66.5 g of ethoxycarbonyl isothiocyanate were added dropwise to a solution of 61 g of p-methylbenzyl alcohol in 500 ml of tetrahydrofuran and 2 ml of triethylamine and the mixture was refluxed for 24 hours. The mixture was concentrated to dryness to obtain 135 g of raw p-methylbenzyl N-carbethoxy -thiocarbamate.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CS(C)=O>[F:12][C:13]([F:17])([F:16])[CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: FC(F)(F)CI
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To sodium hydride (60% in oil, 240 mg, 6.0 mmol) 0° C. was added 2 mL anhydrous dimethylsulfoxide. The resulting suspension was stirred for 15 minutes at 0° C. 4-Hydroxybenzaldehyde (610 mg, 5.0 mmol) was added dropwise as a solution in 2 mL dimethylsulfoxide and the resulting mixture stirred for 30 minutes at 0° C. Trifluoroethyl iodide (1.5 mL, 15.24 mmol) was added and the reaction mixture was heated to 55° C. for 24 h. The reaction mixture was cooled to room temperature and poured into water. Organics were extracted with ether (3×50 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (20% ethyl acetate in hexanes) to give 4-(2,2,2-trifluoroethoxyl)benzaldehyde (250 mg, 24%) as an oil. Used without further characterization.