Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15]COC)[C:4]=1[CH2:19][CH2:20][CH2:21][S:22][S:23][CH2:24][CH2:25][CH2:26][C:27]1[C:32]([O:33][CH2:34]OC)=[C:31]([O:37]C)[CH:30]=[C:29]([O:39][CH2:40]OC)[C:28]=1[O:43]C.Cl.C(OCC)(=O)C.C1C=CC=CC=1>O1CCCC1.C(O)(C)C.CO>[CH3:34][O:33][C:32]1[C:31](=[O:37])[CH:30]=[C:29]([O:39][CH3:40])[C:28](=[O:43])[C:27]=1[CH2:26][CH2:25][CH2:24][S:23][S:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5](=[O:15])[C:6]([O:13][CH3:14])=[CH:7][C:8](=[O:9])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCSSCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: C1CCOC1
Product: COC1=CC(=O)C(OC)=C(CCCSSCCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
259.7 Milligrams of bis{3-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]propyl} disulfide was dissolved in a mixed solvent of 4 ml of tetrahydrofuran with 4 ml of isopropanol. The gas phase in the reaction vessel was replaced with argon gas three times under reduced pressure deaeration. 1 Milliliter of tetrahydrofuranisopropanol solution containing 20% (by weight) of hydrogen chloride was added to the reaction mixture, and the reaction mixture was heated at 70° C. with stirring, the reaction was completed in about 1 hour. The solvent was removed by evaporation under reduced pressure, then 5 ml of benzene was added to the residue, this mixture was further treated under reduced pressure to obtain light brawn oily substance. The crude substance was dissolved in 10 ml of methanol without being purified, and to this solution a small amount of sodium hydrogen carbonate was added, and oxygen gas was bubbled thereinto at room temperature for about 2 hours. The solvent was removed by evaporation under reduced pressure, the residue obtained was treated by means of a silica gel preparative thin layer chromatography (thickness: 1 mm, developing solvent: 50% ethyl acetate-benzene) to obtain 45.0 mg of bis[3-(3,6-dimethoxy-1,4-benzoquinon-2-yl)propyl]disulfide. Yellow oily substance.
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:33])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:19])=[O:11])C1C=CC=CC=1>C(#N)C>[OH:8][NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:31][C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=[O:33])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:19])=[O:11]
Reactant: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2ccccc2c1)NOCc1ccccc1
Solvent: CC#N
Product: O=C(CCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2ccccc2c1)NO
Yield: 7 %

Procedure:
Using an analogous method (J15F), the title compound was prepared from naphthalene-2-carboxylic acid [1-(5-benzyloxycarbamoyl-pentylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-amide (19/98). Yield 7%, foam. 1H NMR (DMSO-d6, HMDSO), δ: 1.10-1.60 (m, 6H); 1.93 (t, 2H, J=7.4 Hz); 2.95-3.30 (m, 4H); 4.65-4.83 (m, 1H); 6.92-7.10 (m, 2H); 7.23 (s, 1H); 7.30 (d, 1H, J=7.6 Hz); 7.53-7.66 (m, 2H); 7.71 (d, 1H, J=7.0 Hz); 7.84-8.04 (m, 4H); 8.09 (br t, 1H, J=5.2 Hz); 8.42 (s, 1H); 8.60 (d, 1H, J=8.2 Hz); 8.68 (br s, 1H); 10.34 (s, 1H); 10.77 (s, 1H). HPLC analysis on Symmetry C8 column: impurities 2.5% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 40:60; detector UV 220 nm; sample concentration 0.25 mg/ml, flow rate 1.5 ml/min). Anal. Calcd for C28H30N4O4*H2O: C, 66.65; H, 6.39; N, 11.10. Found: C, 66.69; H, 6.00; N, 11.01.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.Cl[C:41]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)=[O:42]>C(N(CC)CC)C>[CH:27]([O:26][C:24]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[C:4]1[S:3][C:2]([NH:1][C:41]([C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)=[O:42])=[N:6][CH:5]=1)[CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]2=[O:23])=[O:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4cccs4)s3)CSC12
Yield: 85.9 %

Procedure:
Following the procedure of Example 2, starting from 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g), triethylamine (1.23 cc) and 2-chlorocarbonyl-thiophene (1.4 g), 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(thien-2-yl-carbonylamino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.62 g) is obtained, in the form of a cream-coloured powder, after purification over Merck silica gel (0.06-0.2 mm).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]3[OH:23])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].IC.[C:30]([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH:11]3[O:23][CH3:30])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2cc(F)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1O
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CCC1n1c(C)nc2cc(F)ccc21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-hydroxy-Boc-piperidine (205 mg, 0.59 mmol) mmol) in THF (5 mL) and cooled to 0° C. under Ar. NaH (60% oil dispersion; 32 mg, 0.8 mmol) was added and the reaction mixture was stirred for 15 minutes. Iodomethane (0.8 mmol) was then added. After stirring for 3 hours at rt the reaction mixture was poured into saturated NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure yielded crude product from which 4-(5-fluoro-2-methylbenzimidazol-1-yl)-3-methoxy-Boc-piperidine (191 mg, 89%) was isolated as a waxy solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([NH:22][CH2:23][C:24]([OH:26])=[O:25])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[C:23]2\[N:22]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:26][C:24]\2=[O:25])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: COC(=O)c1c(F)cccc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cccc1/C=C1\N=C(c2ccccc2)OC1=O

Procedure:
This step was performed in five separate batches. For each batch, a solution of methyl 2-fluoro-6-formylbenzoate (3 g, 16.5 mmol), 2-benzamidoacetic acid (3.6, 20 mmol) and sodium acetate (1.62 g, 19.7 mmol) in acetic anhydride (30 mL) was heated at 100° C. in a microwave reactor (100 W, 150 psi) under nitrogen atmosphere for 2 hours. The reaction mixtures were diluted with EtOAc (100 mL) and washed with saturated aqueous Na2CO3. The combined organic layers were concentrated in vacuo to give the title compound as a brown solid, which was used without further purification (15 g). ESI-MS m/z [M+H]+ 326.2.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C>C(#N)C.CN1CCCC1=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:40][CH2:41][OH:42])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCO)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (301 mg, 0.759 mmol) in Acetonitrile (1.3 mL), N-Methylpyrrolidinone (0.44 mL) and N,N-Diisopropylethylamine (0.40 mL, 2.3 mmol) was added (2-Bromoethoxy)-tert-butyldimethylsilane (0.82 mL, 3.8 mmol), and the reaction was kept at 50° C. overnight. LC-MS showed the reaction was completed (desired peak m/z=555 (M+H)). The yellow solution was evaporated to dryness as much as possible, followed by dilution in Methylene chloride (6.0 mL) and Methanol (3.0 mL). Then, 4.0 M of Hydrogen chloride in 1,4-Dioxane (5.7 mL) was added, and the yellow solution was stirred at room temperature for 2.5 h. The solvents were removed and the residue was purified to give the final product ry (174.4 mg, 52% yield after two steps) as off-white powder: 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 4.48 (m, 1H), 4.12 (m, 1H), 3.87 (d, J=10.6 Hz, 1H), 3.75-3.48 (m, 8H), 3.40 (t, J=11.3 Hz, 1H), 3.17-3.04 (m, 2H), 2.80-2.53 (m, 6H), 1.22 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=441 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:17][NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[CH:21][CH:20]=1>C(O)C>[CH2:26]([O:25][C:23]([C:22]1[CH:30]=[CH:31][C:19]([N:18]([CH3:17])[CH:13]=[N:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:20][CH:21]=1)=[O:24])[CH2:27][CH2:28][CH3:29]
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Reactant: CCCCOC(=O)c1ccc(NC)cc1
Solvent: CCO
Product: CCCCOC(=O)c1ccc(N(C)C=Nc2ccc(C(=O)OCC)cc2)cc1

Procedure:
Ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (6.7 g, 0.03 mol) and n-butyl 4-methylaminobenzoate (6.2 g, 0.03 mol) were heated at 190° until 1.7 ml of ethanol had been collected by distillation. The solid mass which resulted upon cooling was recrystallized from hexane to yield the product, mp 83°-85° C. ##STR13##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[C:26](O)(=[O:30])[CH2:27][CH2:28][CH3:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCCC(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N
Product: CCCC(=O)N1CCC(COc2cccc3nc(C)c(C(=O)OCC)c(N)c23)CC1

Procedure:
Prepared as in Example 24a from ethyl 4-amino-2-methyl-5-(piperidin-4-ylmethoxy)-quinoline-3-carboxylate (Example 35b) and butyric acid as a yellow oil (50%). MS 414 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[CH2:23]([O:22][P:20]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)(=[O:21])[O:25][CH2:26][CH3:27])[CH3:24]
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Nc1nc(OCc2ccc(F)cc2)ncc1F)OCC
Yield: 10.8 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.42 mmol) in dry THF (5 mL) under a nitrogen atmosphere was added NaH (0.017 g of a 60 wt. % suspension, 0.42 mmol) and the mixture was stirred until bubbling ceased. Diethyl chlorophosphate (0.073 g, 0.42 mmol) was added dropwise, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc and washed saturated aqueous NH4Cl solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica (acetone/CH2Cl2 gradient) to give 0.017 g (11%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]phosphoramidic acid diethyl ester as a white solid: mp 109-111° C.; 1H NMR (300 MHz, CDCl3) δ8.10 (t, J=1.8 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 6.18 (br s, 1H), 5.35 (s, 2H), 4.25 (m, 4H), 1.38 (t, J=7.1 Hz, 6H); HPLC-MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[CH:4]=[CH:5]2
Reactant: BrBr
Reactant: O=c1ccc2ccccc2[nH]1
Solvent: CC(=O)O
Product: O=c1ccc2cc(Br)ccc2[nH]1
Temperature: 38 °C
Yield: 48.8 %

Procedure:
0.07 Mols (10.16 g) of carbostyril were put into 100 ml acetic acid in a 500 ml round bottom flask fitted with an air stirrer, thermometer and a vented dropping funnel. It was stirred and warmed to 56° C. where the carbostyril was in solution. 0.075 Mols (12.0 g) of bromine were put into 50 ml of acetic acid and added to the reaction over a one hour period. The temperature was held between 56° and 65° C. The reaction was then stirred for 13/4 hr. at 63°-65° C. It was then cooled to 38° C. and the solids filtered off. From this and the filtrate were obtained 7.65 g of 6-bromocarbostyril (product checked by IR). A second fraction of 3.9 g was also obtained which looked to be a mixture of monobromo and dibromocarbostyril.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]3[N:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[S:34][C:30]=3[CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:19][N:8]([C:6]1[N:7]=[C:2]([C:28]2[CH:40]=[CH:39][C:31]3[N:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[S:34][C:30]=3[CH:29]=2)[CH:3]=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1cccc(S(=O)(=O)N(C)c2cccc(Cl)n2)c1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(N(C)S(=O)(=O)c4cccc(C)c4)n3)cc2s1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
N-(6-chloropyridin-2-yl)-N,3-dimethylbenzenesulfonamide (0.200 g, 0.7 mmol) was dissolved in 1,4-dioxane (6 ml), then N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.300 g, 1 mmol), tetrakis (triphenylphosphine)palladium(0) (0.100 g, 0.1 mmol) and 2M sodium carbonate (1 ml, 2 mmol) was added to the mixture. The flask was fitted with a reflux condenser and placed into a pre-heated (95° C.) bath. The mixture was allowed to stir under inert atmosphere for 3 hours. The progress of the reaction was monitored by LC/MS, which showed desired product. The mixture was allowed to cool to ambient temperature and diluted with DCM and saturated sodium bicarbonate solution. The organic layer was collected by extracting with DCM (3×20 ml). Combined organic extracts, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was filtered and purified by silica-gel chromatography, in a gradient of 1-10% IPA/DCM over 30 minutes. The fractions with desired product were combined and concentrated. The crude was recrystallized from DCM/Hexanes to give N-(6-(6-(N,3-dimethylphenylsulfonamido)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.175 g, 57% yield) as a yellow crystalline solid. MS (ESI pos. ion) m/z: 453 (MH+). Calc'd exact mass for C22H20N4O3S2: 452. 1H NMR (400 MHz, DMSO-d6): 2.22 (s, 3H), 2.31 (s, 3H), 3.40 (s, 3H), 7.34-7.56 (m, 5H), 7.75 (d, J=8.53 Hz, 1H), 7.84 (d, J=7.53 Hz, 1H), 7.93 (t, J=6.53 Hz, 2H), 8.40 (s, 1H), 12.42 (s, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].C(=O)([O-])[O-].[Ca+2].Br[CH:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=O.Cl>CC(O)C>[C:20]1([C:18]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[S:10][C:17]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1cccc2ccccc12)C(Br)c1ccccc1
Reactant: NC(=S)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: c1ccc(-c2sc(-c3ccccn3)nc2-c2cccc3ccccc23)cc1

Procedure:
A 183 mg portion of pyridine-2-carbothioamide hydrochloride and 209 mg of calcium carbonate were added at room temperature to a 2-propanol solution (20 ml) of 340 mg of 2-bromo-1-(1-naphthyl)-2-phenylethanone and heated overnight under reflux. The reaction liquid was acidified by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate:n-hexane (1:9) as the elution solvent, thereby obtaining 227 mg of 2-[4-(1-naphthyl)-5-phenyl-1,3-thiazol-2-yl]pyridine as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:22].[Na+].OO.Cl>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH2:21])=[O:22])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1OC
Yield: 84 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1H-indazole-5-carbonitrile (200 mg, 0.72 mmol) in ethanol (3.5 mL) was added 6 N NaOH (0.5 mL) followed by H2O2 (2.0 mL of a 30% solution). The solution was heated to 45° C. for 1 hour when water (80 mL) was added and the pH adjusted to <1 with 3 N HCl. The reaction was then filtered and the product dried to give the title compound (180 mg, 61 mmol, 84% yield). 1H NMR (DMSO-d6) δ 13.3 (s, 1H), 8.59 (s, 1H), 8.12 (br s, 1H), 7.92 (d, 1H), 7.6–7.5 (m, 2H), 7.52 (s, 1H), 7.3 (br s, 1H), 7.13 (d, 1H), 3.87 (s, 3H), 3.84 (s, 3H); ES-MS (m/z) 298 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9].[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:9][C:8]1[CH:7]=[C:6]([CH3:10])[NH:5][C:4](=[O:11])[C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1ccc(CN2CCN(CCO)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CN3CCN(CCO)CC3)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.4 %

Procedure:
A mixture of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (70 mg, 0.46 mmol), 4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzoic acid (122 mg, 0.46 mmol), o-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and triethylamine (70 mg, 0.69 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature for 15 hours. Then the mixture was filtered and the solid was washed with water (10 mL), methanol (10 mL) and dichloromethane (10 mL) in turns to give N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)benzamide as white solid (30 mg, 16.4%). LRMS (M+H+) m/z: calcd 398.23. found 398. HPLC purity (214 nm): 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9]1.[N+]([NH:26][C:27](N)=[O:28])([O-])=O.CN(C)C=O.C(OC(C)C)(C)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]2[CH2:22][CH2:21][N:20]([C:27]([NH2:26])=[O:28])[CH2:19][CH2:18]2)=[N:9]1
Reactant: Clc1ccccc1-n1nc(N2CCNCC2)c2ccccc21
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCN(c2nn(-c3ccccc3Cl)c3ccccc23)CC1
Yield: 44.5 %

Procedure:
A mixture of 7.9 g of 1-(2-chlorophenyl)-3-(1-piperazinyl)-1H-indazole, 7.3 g of nitrourea and 100 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was flash chromatographed on silica gel eluting with chloroform/methanol (5%). Concentration of the appropriate fraction yielded a foam, which when stirred overnight with isopropyl ether afforded 4.0 g of 4-[1-(2-chlorophenyl)-1H-indazol-3-yl]-1-piperazine carboxamide as a powder. A 3.4 g sample of the free base was dissolved in diethyl ether and treated with 1.1 g of fumaric acid. The resulting salt was recrystallized from ethyl acetate to yield 2.3 g (22%) of 4-[1-(2-chlorophenyl)-1H-indazol-3-yl]-1-piperazine carboxamide hemifumarate, m.p. 156°-158°.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12](=[O:18])OC(C)(C)C)=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1.ClC([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O>Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:18])=[CH:10][C:5]=2[N:4]([CH3:19])[CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cn1cc(Br)c2cnc(NC(=O)OC(C)(C)C)cc21
Agent: Cl
Product: COC(=O)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
In a 125 ml round bottom flask, tert-butyl 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamate (3G, 0.6 g, 1.839 mmol) was dissolved in 4N HCl (15 ml) and the mixture was stirred at room temperature for 3 h. After completion, volatiles were evaporated and the mixture was re-dissolved in DMA (10 ml). To this was added methyl 4-(chlorocarbonyl)benzoate (0.44 g, 2.2 mmol) and the mixture was stirred at 50° C. for five hours. The reaction was poured into ice water. The precipitated product was collected and dried to obtain the product methyl 4-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-ylcarbamoyl)benzoate (3H, 0.6 g, 84%). Small amount of debrominated product was observed.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[CH2:20]([CH:22]1[CH2:25][CH2:24][CH:23]1[NH2:26])[CH3:21]>>[CH2:20]([CH:22]1[CH2:25][CH2:24][CH:23]1[NH:26][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19])[CH3:21]
Reactant: CCC1CCC1N
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Product: CCC1CCC1Nc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with 2-ethylcyclobutylamine to obtain 4-((2-ethylcyclobutyl)amino)-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 353.3.