Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>C(#N)C.C(OCC)C>[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][C:11]=1[N+:7]([O-:8])=[O:6]
Reactant: CCNC(=O)Nc1nc2cccc(O)c2s1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])c(O)c2s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a solution of 2-methylpyridone (0.020 mL, 0.20 mmol, 1.2 eq) in anhydrous acetonitrile (0.5 mL), nitronium tetrafluoroborate (0.045 g, 0.32 mmol, 1.9 eq) was added. The suspension was stirred at about 20° C. for about 5 minutes to get an orange solution. The solution was then transferred to a suspension of 1-(7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 8 (0.040 g, 0.17 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at about 20° C. for about 15 minutes, then taken up in diethyl ether (8 mL), and neutralized by washing with saturated sodium bicarbonate solution (1.5 mL). The organic extract was concentrated and dissolved in methanol (2 mL). LC/MS purification was followed by flash chromatography purification on silica (methylene chloride/methanol=40/1) to afford 0.005 g (10%) of the desired compound 17. 1H NMR (DMSO) δ 11.20 (br s, 1H, NH), 8.02 (d, 1H, J=9.0 Hz, ArH), 7.23 (d, 1H, J=7.5 Hz, ArH), 6.78 (br s, 1H, NH), 3.20 (m, 2H, CH2), 1.10 (t, 3H, J=7.2 Hz, CH3). LC/MS 283 (MH+); RP-HPLC RT 2.74 minutes.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2([NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NC(=O)c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)Oc2ccccc21
Temperature: 25 °C

Procedure:
Salicylamide (7.24 g), 1-benzylpiperidin-4-one (10.0 g) and p-toluenesulfonic acid hydrate (500 mg) were suspended in toluene (200 mL), and the suspension was stirred under reflux overnight while removing the water in the reaction system using a Dean-Stark tube. The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with water, ethanol and diethyl ether to give 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one as a crude product (9.7 g). The obtained crude 1′-benzylspiro[1,3-benzoxazine-2,4′-piperidin]-4(3H)-one (5.0 g) and 10% palladium-carbon (1.0 g) were suspended in ethanol (50 mL), and the suspension was stirred at 50° C. for 5 hr under a hydrogen atmosphere. The catalyst was removed by filtration through celite and the solvent was evaporated under reduced pressure. The resulting precipitate was collected by filtration, and washed with ethanol and diethyl ether to give the object product (2.7 g, 77%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[O:17][CH2:13][CH2:14][O:4]1
Reactant: CCCCO
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: N#Cc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 4 h

Procedure:
To a stirred solution of 112 parts of 4-(2-bromoacetyl)-benzonitrile in 320 parts of butanol are added 5 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene. Then there are added dropwise 46.5 parts of 1,2-ethanediol. Upon completion, sitrring is continued for 4 hours at reflux. The reaction mixture is evaporated. The oily residue is crystallized from 2,2'-oxybispropane. The product is filtered off and recrystallized from methanol, yielding 95.12 parts of 4-[2-(bromomethyl)-1,3-dioxolan-2-yl] benzonitrile; mp. 92.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:13][S:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[CH3:13][S:14][C:15]1[N:20]=[C:19]([N:8]2[C:4]3[CH:3]=[C:2]([NH2:1])[CH:10]=[CH:9][C:5]=3[N:6]=[CH:7]2)[CH:18]=[CH:17][N:16]=1
Reactant: CSc1nccc(Cl)n1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cnc3ccc(N)cc32)n1
Yield: 11 %

Procedure:
To a stirred solution of 5-aminobenzimidazole (700 mg, 5.26 mmol, 1 eq) in DMF (21 mL) was added NaH (231 mg, 5.78 mmol, 1.1 eq, (60% suspension in oil)). The mixture was allowed to stir until gas evolution ceased. To the DMF solution was added 2-methylthio-4-chloropyrimidine (0.612 mL, 5.26 mmol, 1 eq) dropwise via syringe. The mixture was allowed to stir overnight. The DMF was removed under reduced pressure and the residue was diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture was purified by preparative thin layer chromatography (cluted 2× with 3.5% MeOH/CH2Cl2) to give 149 mg 2-methylthio-4-[6-aminobenzimidazol-1-yl]pyrimidine (faster regioisomer) and 89 mg 2-methylthio-4-[5-aminobenzimidazol-i-yl]pyrimidine (slower regioisomer). 2-methylthio-4-[6-aminobenzimidazol-1-yl]pyrimidine (faster regioisomer): 1H NMR (500 MHz, CD3OD): δ8.68 (1H, s); 8.58 (1H, d, J=5.5 Hz); 7.68 (1H, d, J=2 Hz); 7.45 (2H, m); 6.81 (IH, dd, J=2 Hz, J=8.5 Hz); 2.67 (3H, s). 2-methylthio-4-[5-aminobenzimidazol-1-yl]pyrimidine (slower regioisomer): 1H NMR (500 MHz, CD3OD): δ8.81 (1H, s); 8.56 (1H, d, J=5.5 Hz); 8.11 (1H, d, J=8.5 Hz); 7.46 (1H, d, J=5.5 Hz); 7.04 (1H, d, J=2 Hz); 6.87 (1H, dd, J=2 Hz, J=8.5 Hz); 2.65 (3H, s).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4]Br.[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][N:17]=[N+:18]=[N-:19]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienyl bromide (1.5 g, 5.26 mmol) and sodium azide (0.68 g, 10.5 mmol) in DMF (20 mL) was stirred at room temperature for 0.5 hours, then poured into cold water and extracted with ether. The ethereal extract was washed with brine, dried, filtered and evaporated to yield a residue. Purification of the residue by flash chromatography on a silica gel column, using hexane as the eluant, afforded the title compound as an oil (1.2 g, 4.85 mmol, 92%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>ClCCl.O>[NH:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of alpha-bromo-4-tolunitrile (86.6 g) in dichloromethane (1000 mL) is mixed with imidazole (68.0 g). The mixture is stirred at ambient temperature for 15 hours and then diluted with water (1000 mL). Any undissolved solid is removed by filtration and the separated organic solution is then repeatedly washed with water (5×200 mL) to remove excess imidazole, and then dried (MgSO4). The crude product obtained upon evaporation of the solvent can be purified by trituration with cold diethyl ether (200 mL) to obtain 4-(1-imidazolylmethyl)-benzonitrile, m.p. 99°-101°; HCl salt, m.p. 142°-144°.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([C:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Yield: 82.6 %

Procedure:
A mixture of pyridine (15 ml), triphenyl phosphite (1.55 g, 5 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours. The reaction mixture was treated in the same manner as in Example 11 to give 2.05 g of 1-triphenylmethylimidazole as colorless needles. Yield, 82.7%. M.P., 218°-221° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([Cl:20])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:1]([N:8]1[CH2:12][C:13]2[N:14]=[CH:15][C:16]([Cl:20])=[N:17][C:18]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 2-{benzyl[(3,5-dichloropyrazin-2-yl)methyl]amino}ethanol (3.425 g) in THF (100 mL) was added potassium tert-butoxide (1.48 g) under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (2.59 g, 86%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[CH:32](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[O:13]=[S:10]1(=[O:12])[C:11]2[C:2]3[N:1]=[CH:32][O:31][C:3]=3[CH:4]=[CH:5][C:6]=2[NH:7][C:8]([C:14]2[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]3[C:22]([C:23]=2[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]1
Reactant: COC(OC)OC
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4ocnc34)N2)c(O)c2ccccc21
Yield: 22 %

Procedure:
A solution of Example 354 (0.036 g, 0.081 mmol) in dimethylformamide (2 mL) was treated with trimethyl orthoformate (1 mL) and a catalytic amount of para-toluenesulfonic acid at room temperature for 20 hours. The solvent was removed under a stream of warm nitrogen and the residue was triturated with 1:1 ethyl acetate: tetrahydrofuran, filtered, and dried to yield the title compound (8 mg, 22%). MS (ESI−) m/z 452 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.05 (d, J=6.62 Hz, 6 H) 1.93 (m, 1 H) 2.78 (m, 2 H) 6.33 (m, 1 H) 7.45 (t, J=7.54 Hz, 1 H) 7.73 (d, J=8.82 Hz, 1 H) 7.92 (t, J=7.72 Hz, 1 H) 8.00 (m, 1 H) 8.21 (m, 2 H) 9.04 (s, 1 H) 14.28 (s, 1 H).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 75 °C

Procedure:
A flask was charged with 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (38 mg, 0.110 mmol), and sodium carbonate (Na2CO3) (30 mg, 0.286 mmol) was evacuated and charged with nitrogen (N2) (3×). To this mixture was quickly added tetrakis(triphenylphosphine)palladium(0) and evacuated and charged with N2 (2×). This mixture was charged with a previously degassed solvent DME/H2O (5:1) (2 mL) and heated overnight at 75° C. The reaction mixture was filtered through an autovial (0.45 μM frit) and washed with MeOH (3×). The filtrate was concentrated in vacuo and purified by mass directed purification (MDP) resulting in the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.96-2.10 (m, 1H), 2.10-2.25 (m, 1H); 2.40-2.56 (m, 2H); 2.60-2.78 (m, 2H); 4.12-4.29 (m, 1H); 5.99 (brs, 2H); 7.42-7.58 (m, 3H); 7.84-8.05 (m, 4H); 8.18 (d, J=7.2 Hz, 2H); 8.28 (d, J=8.4 Hz, 1H); 8.39 (s, 1H); MS (ES+): m/z 393.14 (100) [MH+], HPLC: tR=3.51 min (MicromassZQ, polar—5 min).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH:13]([C@@H:16]2[CH2:18][C@@H:17]2[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:17]1[CH2:18][C@H:16]1[CH:13]1[CH2:14][CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C1CCNC1

Procedure:
To 15 ml of an ethanol solution of 547.3 mg (1.52 mmol) of 1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine (isomer A) was added 550 mg of 5% palladium-on-carbon, followed by shaking in a hydrogen stream (4 kg/cm2) for 1.5 hours. The catalyst was removed by filtration, and the solvent was removed by evaporation under reduced pressure to give 343.6 mg (quantitative) of the title compound as a brown oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:16]=1)[C:7](=[O:15])[C:8]([CH2:12][CH2:13][OH:14])=[C:9]([CH3:11])[N:10]=2.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[OH:14][CH2:13][CH2:12][C:8]1[C:7](=[O:15])[N:6]2[CH:16]=[C:2]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH3:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cc1nc2ccc(Br)cn2c(=O)c1CCO
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: Cc1nc2ccc(-c3cccs3)cn2c(=O)c1CCO
Temperature: 130 °C

Procedure:
In a round-bottom flask under a current of argon, mix 5 g of 7-bromo-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 6.2 ml of tributyl-thiophen-2-yl-stannane, 1 g of tetrakis(triphenylphosphine) palladium and 250 ml of N-methylpyrrolidone. Heat the solution at 130° C. for 2 hours and then evaporate off the solvent in vacuo; take up the residue in 200 ml of dichloromethane, wash the solution with 10% potassium fluoride solution, filter, separate off the organic phase and wash it with water. After drying over magnesium sulphate and evaporation, the residue obtained is purified by chromatography on silica gel using a mixture of dichloromethane/methanol: 95/5 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:49])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:49][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a solution of the acid (27) (75 mg, 0.36 mmol) and HOBt (54 mg, 0.40 mmol) in DMF (6 mL), was added amine 9 (135 mg, 0.40 mmol). After stirring for 5 min, EDC (84 mg, 0.42 mmol) was added and the reaction mixture was stirred for additional 4 hrs at room temperature. The reaction mixture was poured into NaHCO3 solution, extracted with EtOAc; the organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (Aquasil C-18 column, gradient MeOH/water from 60:40 to 95:5) to afford 28a (105 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.80 (s, 1H), 9.62 (s, 1H), 8.66 (d, 1H), 8.33 (s, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (m, 2H), 6.89 (m, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.66 (s, 2H). MS (m/z): 532.0 (M+H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>CN(C=O)C>[CH2:1]([N:15]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:9][CH3:10])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCC1CNCCN1
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Benzyl bromide (38.7 g, 0.22 mol) was added in portions to an ice cold (˜0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150 mL) with such a rate that the temperature did not exceed 20° C. The mixture was stirred for 1 h, the solvent was evaporated and the residue was partitioned between CHCl3/0.5 M HCl. The aqueous phase was made alkaline (11M NaOH) and extracted three times with CHCl3. The combined organic phases were dried (MgSO4) and concentrated. The resulting oil was purified by column chromatography on silica using CHCl3, followed by CHCl3/MeOH/NH4OH (95:5:0.3) as eluents to give 31.6 g (70%) of the title compound as a yellowish oil. Anal. (C13H20N2) H, N; C: calc, 76.42 found 75.85; H, N.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl[CH2:11][C:12]#[N:13]>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][C:12]#[N:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: N#CCCl
Reactant: COC(=O)C1CCCC1
Product: COC(=O)C1(CC#N)CCCC1
Yield: 38 %

Procedure:
1-(Cyanomethyl)cyclopentane carboxylic acid methyl ester was prepared from cyclopentane carboxylic acid methyl ester and chloroacetonitrile using the procedure described in example 7 to give a 38% yield. HR MS (C9H13NO2): Obs mass, Calcd mass, 167.0146 (M+).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[S:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[C:8]=2[C:20](OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[C:34]1(=O)[CH2:39][CH2:38]C[CH2:36][CH2:35]1.P(=O)(O)(O)O.C([SiH](CC)CC)C>C(O)(=O)C>[CH:20]1([C:8]2[C:9]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][C:10]=3[NH:11][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:38][CH2:39][CH2:34][CH2:35][CH2:36]1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1cc2c(C(=O)OC(C)(C)C)c(-c3ccccc3)[nH]c2s1
Agent: CC[SiH](CC)CC
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)[nH]c2s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution (0.2 M) of 4-tert-butyl 2-ethyl 5-phenyl-6H-thieno[2,3-b]pyrrole-2,4-dicarboxylate in acetic acid was treated with acetic anhydride (2.5 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. overnight, then it was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic layers were washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was dissolved in TFA and cooled to 0° C. The resulting solution (0.1 M) was treated with triethylsilane (2 eq.) and stirred at 0° C. for 1 h then solvent was evaporated to give a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (58%) as a solid.
Reaction SMILES: O.[C:2]([O-:5])([O-])=O.[Ca+2].[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1CBr>O1CCOCC1>[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:2][OH:5]
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc2ccccc2c1Br
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc2ccccc2c1Br
Yield: 84.3 %

Procedure:
Water (100 ml) and CaCO3 (18 g, 180 mmole) were added to a solution of 13 in dioxane (100 ml) and the mixture was refluxed for 10 hr. The solution was cooled and the dioxane was removed under reduced pressure and the mixture was acidified with 1N HCl and extracted with methylene chloride. The combined methylene chloride fractions were washed with saturated solution of NaHCO3, H2O, brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a white solid which when crystallized from hexane afforded 7 g of 24 (84.3%). A single component was detected by TLC (100% hexane, Rf, 0; hexane/ethyl acetate 80:20, Rf, 0.5); NMR (CDCl3) d 2.1 (m, 1H, H--O), d 5.0 (s, 2H, CH2 --OH), d 7.4-8.4 (m, 6H, naphthyl); MS (HRFAB) calcd for C11H9BrO (M+Li)+ 243.0003 found 243.0003.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.[Cl:34]N1C(C)(C)C(=O)N(Cl)C1=O>CO>[Cl:34][C:11]1[S:10][C:9]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)(=[O:26])=[O:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:13][CH:12]=1
Reactant: COc1cc(-c2nccs2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CO
Product: COc1cc(-c2ncc(Cl)s2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A solution of 1-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.100 g, 0.210 mmol) in 2 mL MeOH was treated with 1,3-dichloro-5,5-dimethylhydantoin (0.028 ml, 0.210 mmol) and was allowed to stir overnight at room temperature then was heated to reflux for two hours. LC/MS showed product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(5-chlorothiazol-2-yl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.006 g, 0.012 mmol, 5.59% yield). 1H NMR (MeCN-d3) δ: 8.60-8.64 (m, 1H), 8.52-8.56 (m, 1H), 8.10-8.13 (m, 1H), 8.05-8.09 (m, 1H), 7.95-8.00 (m, 1H), 7.91-7.95 (m, 1H), 7.87-7.91 (m, 1H), 7.74-7.78 (m, 1H), 7.66-7.74 (m, 2H), 7.57-7.61 (m, 1H), 7.42-7.47 (m, 1H), 3.76 (s, 3H); (M+H)+=510.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH2:19][CH2:20][CH2:21][OH:22]>>[NH2:16][C:11]1[NH:12][N:13]=[C:14]([CH3:15])[C:10]=1[C:8]1[S:9][C:5]2[CH:4]=[C:3]([CH2:2][NH:19][CH2:20][CH2:21][OH:22])[CH:18]=[CH:17][C:6]=2[N:7]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: NCCO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CNCCO)cc2s1

Procedure:
The title compound (10 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess 2-aminoethanol. MS (m/z, ES+): 304.1 (M+1, 10%), 243.2 (M-HOCH2CH2NH, 100%).