Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([OH:14])[C:10](=[CH:12][CH:13]=1)[OH:11].[CH2:15]([O:22][C:23]([NH:25][CH:26](O)[C:27]([OH:29])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:15]([O:22][C:23]([N:25]([C:13]1[CH:12]=[C:10]([OH:11])[C:9]([OH:14])=[CH:8][C:7]=1[Cl:6])[CH2:26][C:27]([OH:29])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1cc(O)c(O)cc1Cl
Reaction time: 1 h

Procedure:
Acetic acid (27 ml), concentrated sulphuric acid (3 ml) then 4-chlorocatechol (5.06 g. 35 mmole) were added to N-benzyloxycarbonyl 2-hydroxyglycine (6.75 g, 30 mmole) cooled in an ice bath. The mixture was stirred for one hour then poured onto ice and ethyl acetate and adjusted to pH7 with saturated sodium carbonate solution. The aqueous layer was collected, washed with ethyl acetate (100 ml), acidified to pH2 and extracted with ethyl acetate (3×75 ml). The extracts were washed with water (2×75 ml) and brine (50 ml) dried and evaporated to a gum which was crystallised from chloroform-cyclohexane, 5.90 g, 56%, mp 144°-145°, δ[(CD3)2CO] 5.06 (2H, s, OCH2), 5.64(1H, d, J8 Hz, CHNH), 6.6-7.0(1H, m, NH), 6.87 and 6.93(2H, 2×s, Ar), 7.30(5H, s, Ph) 8.0-9.4(3H, broad, 2×OH, CO2H). Found: C. 54.29; H, 4.04; Cl, 9.71; N, 4.07%. C16H14ClNO6 requires C, 54.63; H, 4.01; Cl, 10.08; N, 3.98%.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:2].[N+:19]([O-])(O)=O.O.N>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[NH:10][N:9]=1)[CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.5 g of 3-(3-diethylaminopropylamino)indazole. To the solution were added dropwise 0.41 ml of nitric acid (d=1.42) and 0.41 ml of sulfuric acid (sp.gr. 1.84) under cooling with ice, and the solution was stirred for 2 hours at 5°-10° C. To 12.1 ml of ice and water was added the solution, and the pH of the solution was adjusted to at least 11 with an aqueous ammonia solution. Then the solution was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue was dissolved in 50 ml of anhydrous benzene. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the solution was stirred for 30 minutes at 80° C. The reaction solution was added with 0.5 ml of water and stirred for 10 hours at 80° C. After cooling, the solution was filtered. The benzene layer of the filtrate was extracted three times with 20 ml of 1N hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 100 g) using chloroform as the developing solvent to give 0.69 g of 3-(3-diethylaminopropylamino)-5-aminoindazole having the following analytical values in a yield of 44%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.F[C:10]1[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>O1CCCC1.CN1CCCC1=O.C1(C)C=CC=CC=1>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([C:10]2[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=2)[CH:8]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (12.18 g, 55-65% m/m, Fluka 71620) is suspended in tetrahydrofuran (60 mL) and a solution of 4-methylimidazole (24.5 g) in tetrahydrofuran (65 mL) is slowly added to the stirred suspension at 20-25° C. Gentle cooling is necessary to maintain the temperature at 20-25° C. during the addition. After completion of the addition, the reaction mixture is stirred for additional 15 minutes at 20-25° C., until gas evolution had ceased. A solution of 3-fluoro-5-trifluoromethyl-phenylamine (XIX) (25 g) in 1-methyl-2-pyrrolidone (125 mL) is added slowly to the reaction mixture and the mixture is stirred for additional 15 minutes at 20-25° C. Then, the reaction mixture is heated at an oil bath temperature of 100° C. to distill off the volatile solvent (tetrahydrofuran). Finally, the temperature is raised to 165° C. (oil bath) and the reaction mixture is stirred for 22 hours at this temperature. For work up, the reaction mixture is poured onto water (500 mL) and the water phase is extracted with t-butyl methyl ether (2×500 mL). The t-butyl methyl ether phases are combined and are extracted with water (2×500 mL). The organic layer is dried on anhydrous magnesium sulfate (19 g) and the solvent is evaporated at 45° C. under reduced pressure to obtain crude 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as a yellowish solid. The crude product is contaminated with at least 1 regioisomer. The crude product is dissolved in toluene (93.4 g) at 80-90° C. and the solution is allowed to cool down to room temperature. Crystallization occurred at ca. 35-40° C. The suspension is stirred for additional 2 hours at room temperature and the product is isolated by filtration. The filter cake is washed with ice-cold toluene (25 mL) and dried in vacuo at 50° C. to obtain pure 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (I). GC-MS: m/z 241, 222, 213, 200, 186, 172, 160.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.Cl.[F:17][C:18]1([F:25])[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]1([F:25])[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(NC2CCC(F)(F)CC2)c2cccc([N+](=O)[O-])c2n1
Yield: 69.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-15, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 200 mg, 0.896 mmol), 4,4-difluorocyclohexanamine hydrochloride (228 mg, 1.345 mmol), and K2CO3 (370 mg, 2.68 mmol) in CH3CN (4 mL) to afford 200 mg of the title product. MS [M+H]+: 323.23.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].CCO>[Fe].O>[NH2:16][C:15]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[N:11][C:12]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]#[N:27])=[CH:23][CH:24]=2)=[N:13][CH:14]=1
Reactant: N#CCc1ccc(-c2ncc([N+](=O)[O-])c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(-c2ncc(N)c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Yield: 24.1 %

Procedure:
To a solid mixture of 2-(4-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-nitropyrimidin-2-yl)phenyl)acetonitrile 45 mg, 0.125 mmol, 1 equivalent) and NH4Cl (3.6 g, 1.375 mmol, 11 equiv) was added EtOH (4 ml) and H2O (2 mL). The reaction mixture was heated to reflux under nitrogen atmosphere and iron powder (25 mg, 0.438 mmol, 3.5 equiv.) was added. The resulting mixture was continued to reflux for 0.5 h. The mixture was filtered immediately with a hot filter under reduced pressure. EtOH and water were removed under reduce pressure. The residue was washed by water. The title compound 2-(4-(5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)phenyl) acetonitrile (Compound 92) (10 mg, 24.4%) was obtained. LC-MS (m/z)=332.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.71 (s, 2H), 0.93 (s, 2H), 1.92 (s, 1H), 3.83 (s, 2H), 5.30 (s, 2H), 6.21 (s, 2H), 7.04 (s, 1H), 7.21 (d, J=6.0 Hz, 1H), 7.53 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.78 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1F>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])[CH2:6]1
Reactant: Fc1ccccc1Cl
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccccc2Cl)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.6 ml of dimethylsulfoxide were added to 65 mg of sodium hydride in the form of a 50% oil dispersion and the mixture was held at 25° C. for 30 minutes and was then heated to 60° C. and then cooled to 25° C. 205 mg of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and after standing at room temperature for 15 minutes, 0.15 ml of o-chlorofluorobenzene was added thereto. The mixture was heated at 80° C. for 30 minutes and then was cooled to 20° C. and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 370 mg of cis N,N-dimethyl-5-[2-chlorophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>C1COCC1>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C. was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resulting mixture was stirred at −25° C. for 30 min and an amine or an amine salt, e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was then added. The mixture was allowed to gradually warm to rt. After 16 h, the solvents were removed. The residue was dissolved in AcOEt, washed twice with NH4Cl saturated solution, then twice with 10% NaHCO3 solution. The organic layer was dried over Na2SO4, filtrated and concentrated to afford the desired product, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][N:20]2[CH3:25].C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH3:14])[N:20]([CH3:25])[CH:19]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=CCOCc1ccccc1
Reactant: COc1cccc2c1ccn2C
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COc1cccc2c1c([C@@H](CC=O)COCc1ccccc1)cn2C
Yield: 93.7 %

Procedure:
Prepared according to the general procedure from 4-benzyloxy-but-2-enal (285 mg, 1.50 mmol), 4-methoxy-1-methyl-1H-indole (80.5 mg, 0.500 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −87° C. for 19.5 h to provide, after silica gel chromatography (20:80 EtOAc/hexanes), the title compound as a colorless oil (158 mg, 90% yield, 94% ee). IR (film) 3081, 2961, 2850, 2730, 1719, 1608, 1582, 1548, 1501, 1466, 1454, 1424, 1381, 1334, 1321, 1274,1261, 1180, 1116, 1073, 1026, 782, 714 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.78 (dd, J=2.4, 2.4 Hz, 1H, CHO), 8.03-8.01 (m, 2H, ArH), 7.59-7.53 (m, 1H, ArH, 7.47-7.41 (m, 2H, ArH), 7.16 (t, J=8.4 Hz, 1H, ArH), 6.92 (dd, J=0.6, 8.4 Hz, 1H, ArH), 6.83 (s, 1H, NCH), 6.52 (d, J=7.5 Hz, 1H, ArH), 4.71 (dd, J=5.1, 10.5 Hz, 1H, CH2O), 4.50 (dd, J=8.4, 10.5 Hz, 1H, CH2O), 4.35 (m, 1H, ArCH), 3.94 (s, 1H, OCH3), 3.71 (s, 3H, NCH3), 2.98 (d, J=2.4 Hz, 1H, CH2CO); 2.96 (d, J=2.7 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 202.5, 166.3, 154.2, 133.0, 130.3, 129.6, 128.6, 128.4, 125.4, 122.9, 116.8, 113.6, 102.8, 99.4, 68.8, 55.3, 47.3, 33.2, 32.2; HRMS (CI) exact mass calcd for (C21H21NO4) requires m/z 351.1471, found m/z 351.1466. [α]D=−13.9 (c=1.0 CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (4:96 ethanol/hexanes, 1 mL/min); S isomer tr=58.7 min and R isomer tr=47.5 min.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C(Cl)Cl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([Cl:30])=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
The title compound 390 (0.72 g, 2.2 mmol) and the oxalyl chloride (0.58 mL, 6.6 mmol) were mixed in DCM (10 mL) and few drops of DMF was added. The reaction mixture was stirred for 30 minutes and the solvent was evaporated (and stripped with toluene twice) to afford title compound 391 that was used crude for next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].Cl[CH2:13][CH2:14][CH2:15][CH2:16]Cl>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH3:2]
Reactant: CCOC(=O)Cc1cccs1
Reactant: ClCCCCCl
Product: CCOC(=O)C1(c2cccs2)CCCC1

Procedure:
Thiophen-2-yl acetic acid ethyl ester (1) was dialkylated as described in Example 1, Step 1, using 1,4-dichlorobutane to obtain the title compound (31).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>O1CCCC1.[Cl-].[Na+].O>[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([N:13]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:16])([F:1])[F:17])=[CH:10][C:11]([CH:14]=[O:15])=[CH:12]2)(=[O:44])=[O:43])[CH:37]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2C(F)(F)F)n(S(=O)(=O)c2cccnc2)c1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution (36 mL) of 5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (240 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 201 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (1.11 g) was added dropwise and the mixture was stirred for 30 min. Pyridine-3-sulfonyl chloride hydrochloride (537 mg) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:3) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 380 mg, about 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:20][C:19]=3[CH3:31])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Li+].O1CCCC1.Cl>C(OCC)(=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[CH3:31])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)C(C)c1ccc(-c2ccc(-c3ccc(OC(C)C)c(C#N)c3)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(C)C(=O)O)ccc1-c1ccc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 55 °C

Procedure:
Ethyl (4-(5-(3-cyano-4-(2-propyloxy)phenyl)-thien-2-yl)-3-methylphenyl)propanoate (from STEP E) was combined with 200 mg of lithium hydroxide, 3 mL of tetrahydrofuran and 1 mL of water. The reaction mixture was heated to 55° C. for 6 h, combined with 50 mL of ethyl acetate, 50 mL of 1 M solution of hydrochloric acid. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated. The title compound was isolated by flash chromatography on silica gel using 10% methanol in dichloromethane as the eluant: 1H NMR (CDCl3) 7.81 (d, J=2.0, 1H), 7.74 (dd, J=2.0, 9.0, 1H), 7.38 (d, J=8.0, 1H), 7.22 (d, J=4.0, 1H), 7.16 (d, J=1.0, 1H), 7.11 (dd, J=1.0, 8.0, 1H), 7.03 (d, J=4.0, 1H), 7.00 (d, J=8.0, 1H), 4.70 (sep, J=1.0, 1H), 3.00 (t, J=1.5, 2H), 2.75 (t, J=1.5, 2H), 2.47 (s, 3H), 1.42 (d, J=1.0, 6H); HPLC A 3.78 min; ESI-MS (m/z)=406.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1.[CH3:19][N:20]1CCCC1=O>C(N)CN>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=[O:18])[NH:9]2)=[CH:4][CH:3]=1)#[N:20]
Reactant: O=C1Cc2ccccc2C(c2ccc(Br)cc2)N1
Reactant: CN1CCCC1=O
Solvent: NCCN
Product: N#Cc1ccc(C2NC(=O)Cc3ccccc32)cc1
Yield: 68 %

Procedure:
A solution of 1-(4-bromophenyl)-1,4-dihydroisoquinol-3-one (15.1 g, 50 mmol) and cuprous cyanide (8.95 g, 100 mmol) in N-methylpyrrolidinone (150 ml) was heated under reflux under a nitrogen atmosphere for 2 h. The solution was cooled and diluted with 10% aqueous ethylenediamine solution (1000 ml), then extracted with ethyl acetate (4×250 ml). The combined extracts were washed with water (4×250 ml) and brine (250 ml), then dried (MgSO4) and evaporated to dryness to leave a pale brown solid which was crystallised from ethyl acetate to give the title compound (8.43 g, 68%), m.p. 165°-168° C. (ethanol).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](O)=[O:26]>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[O:26])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1ccccn1
Yield: 54.7 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and pyridine-2-carboxylic acid (41 mg, 0.33 mmol) as starting materials. The title compound (66 mg, 46.8%) was isolated as off white solid; MS (ESI): 366 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si](C(C)(C)C)(C)C)[CH:26]=2)[C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4].O>O1CCCC1>[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
3 N HCl (7 mL) was added to the solution of 4- {(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl) [3-(tert-butyl-dimethylsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide (1.3 g) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature overnight. Water (15 mL) was added to the reaction. The reaction mixture was extracted with diethyl ether (25 mL×3). The remaining water layer was neutralized by 10% aqueous NaOH to pH=8-9 and then extracted with ethyl acetate (30 mL×3). The combined ethyl acetate layers were washed with water (20 mL×3) and brine (20 mL), dried over sodium sulfate and concentrated to give 0.83 g of crude product. The crude product was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 7% MeOH in CH2Cl2) to give 4-[(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide (720 mg; 70%). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H, J=8.5 Hz), 7.35 (d, 2H, J=8.5 Hz), 7.14 (dd, 1H, J=8.0, 8.0 Hz), 6.89 (bs, 1H), 6.85 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0, 2.5 Hz), 5.83 (1H, m), 5.24-5.12 (m, 3H), 3.32 (dd, 1H, J=13.5, 5.0 Hz), 2.86 (dd, 1H, J=13.5, 8.0 Hz), 2.78 (dd, 1H, J=11.5, 3.0 Hz), 2.72 (s, 6H), 2.65 (dd, 1H, J=11.0, 2.5 Hz), 2.51 (m, 2H), 2.14 (dd, 1H, J=11.5, 9.0 Hz), 1.81 (dd, 1H, J=11.0, 9.5 Hz), 1.16 (d, 3H, J=6.0 Hz), 0.98 (d, 3H, J=6.0 Hz); MS (FAB, glycerol) m/z: 444 (M++H), 290, 153. Found: C, 58.32; H, 6.66; N, 8.18. Calc. (C24H33N3O3S 0.8 CH2Cl2): C, 58.23; H, 6.82; N, 8.21.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCOCCOC)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: COCCOCCOc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12
Agent: COCCOCCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: COCCOCCOc1cccc2cc(C(=O)Nc3ccccc3N)oc12

Procedure:
was prepared from [2-({7-[2-(2-Methoxy-ethoxy)-ethoxy]-benzofuran-2-carbonyl}-amino)-phenyl]-carbamic acid tert-butyl ester (32) in an analogous manner to that described for the preparation of (27) example 11, step 2; exact MW [M+H] calc'd: 371.16; MW found [M+H]: 371.2.