Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:21])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[N:12]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>CC(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH3:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH:9]([NH2:8])[CH3:21])[N:12]=1
Reactant: Cc1nn(CC(C)NC(=O)OC(C)(C)C)c2ccccc12
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1nn(CC(C)N)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of (RS)-1-[2-(tert-butoxycarbonylamino)propyl]-3-methylindazole (1.2 g, 4.3 mmol), dichloromethane (15 mL) and trifluoroacetic acid (5 mL) was stirred for 1 h. The mixture was partitioned between aqueous sodium hydroxide solution (2 N, 30 mL) and dichloromethane (3×30 mL). The combined organic extracts were washed with brine (2×), dried (magnesium sulfate) and concentrated in vacuo to give an orange oil. 2-Propanol (5 mL) was added, the mixture was heated to boiling, then fumaric acid (0.5 g, 4.3 mmol) was added. The mixture was cooled to room temperature and filtered. The filter cake was dried in vacuo to give the title compound (0.89 g, 68%) as a pale brown solid: mp 145-147° C.; IR νmax (Nujol/cm−1) 1618, 1510, 1458, 1377, 973, 742 and 652; NMR δH (400 MHz, DMSO-d6) 1.09 (3H, d, J 6.5 Hz), 2.49 (3H, s), 3.56 (1H, m), 4.39 (2H, m), 6.47, (2H, s), 7.09-7.15 (1H, m), 7.36-7.41 (1H, m), 7.62 (1H, d, J 8 Hz) and 7.72 (1H, d, J 8 Hz).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].C[O-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CO.C1COCC1.O>[CH2:22]([N:2]([CH3:1])[S:3]([C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:5])=[O:4])[CH:23]=[CH2:24]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 313 g (1 mol) N-methylnonafluorobutanesulfonamide (3M Co., U.S. Pat. No. 6,664,354, Savu), 216 g (1 mol) 25% sodium methoxide in methanol (Aldrich), and 100 mL THF (EMD) was stirred at 50° C. for one hour and stripped. The residue was diluted with 600 mL THF and treated with 100 mL (1.15 mol) allyl bromide (Aldrich). The mixture was stirred at 40° C. for about 8 hr and then diluted with water. Extraction with methylene chloride and distillation yielded 321.7 g colorless liquid, by 75-80° C./1.1 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:8]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][CH2:10][CH2:9]1
Reactant: BrBr
Reactant: O=C1CCCSc2ccc(F)cc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(F)ccc2SCCC1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-Fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (1 equivalent) was dissolved in glacial acetic acid and stirred at room temperature. Bromine (2.5 equivalents) was added to the above mixture dropwise and stirring continued at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was then extracted with 2×25 ml ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate, and water. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a solid which was re-crystallized from ethyl acetate/hexane 1:1 v/v to afford 4-bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one: 1H NMR (CDCl3) δ 7.55 (dd, 1H, J=2.7, 9.0 Hz), 7.44 (dd, 1H, J=8.7, 5.1 Hz), 7.11 (Apparent dt, 1H, J=2.7, 4.8 Hz), 5.34 (dd, 1H, J=5.7, 10.2 Hz), 3.20-2.50 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1.S(Cl)(Cl)=O.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([NH2:42])[CH:33]=[C:34]([N:36]2[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]2)[CH:35]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:42][C:32]2[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([N:36]3[CH:37]=[N:38][C:39]([CH3:41])=[CH:40]3)[CH:33]=2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]1[N:13]=[CH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)[N:17]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
To a 1 liter reactor was fed 40 g of 4-methyl-3-(4-(pyridine-3-yl)pyrimidin-2-ylamino)benzoic acid (0.13 mol), 200 ml of N-methylpyrrolidone (NMP) (5V) and 13 ml of thionyl chloride (0.18 mol). The reactor was heated to 60° C. and maintained at 60° C. for 1.5 hr. After 1.5 hr of heating, 31.5 g of 3-(trifluoromethyl)-5-(4-methyl-1H-imidazol-1-yl)benzenamine (0.13 mol) was fed into the reactor. The reactor was then heated to 90° C., and maintained for 30 minutes at this temperature. Then 200 ml (5V) of water was added. The resulting mixture was maintained for 2 hours at 90° C. Then, an additional 240 ml (6V) of N-methylpyrrolidone was added, followed by 26.5 ml of sodium hydroxide (47% aqueous) to raise the pH to 6.5-7. The reactor was then cooled to 40° C. and maintained for 3 hours. The mixture was then filtered and the filter cake was washed with ethanol and water. The washed material was then dried in a vacuum tray oven overnight to provide dry Nilotinib base (62.1 g, Yield 90%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].[CH3:18][O:19][CH:20]([O:31][CH3:32])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](F)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:23]2[CH:22]=[C:21]([CH:20]([O:31][CH3:32])[O:19][CH3:18])[CH:26]=[CH:25][C:24]=2[N+:27]([O-:29])=[O:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1ccccc1
Yield: 54.1 %

Procedure:
A mixture of 0.250 g (1 mmole) of 2-amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (V.1), 0.215 g (1 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene, 0.488 g (1.5 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 100 degrees overnight. The cooled mixture was diluted with 30 mL of water and then extracted three times with 20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 0.240 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VIA a) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:24])[CH2:26]1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-3-ylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.91 minutes; C21H21Cl2N5O2 (446,34); mass spectrum: (M+H)+=446.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][N:13]1[C:17]3=[N:18][C:19](Br)=[CH:20][N:21]=[C:16]3[N:15]=[N:14]1)=[CH:7][CH:6]=2.C([Sn](CCCC)(CCCC)C([O:30][CH2:31][CH3:32])=C)CCC.[CH3:41][CH2:42][O:43]C(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]([C:19]1[N:18]=[C:17]2[N:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31](=[O:30])[CH3:32])=[CH:11]4)[N:14]=[N:15][C:16]2=[N:21][CH:20]=1)(=[O:43])[CH3:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2ccc(Cn3nnc4ncc(Br)nc43)cc2c1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2ccc(Cn3nnc4ncc(C(C)=O)nc43)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of 3-bromo-6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (128 mg, 0.305 mmol), Pd(PPh3)4 (51.5 mg, 0.045 mmol) and tributyl(1-ethoxyvinyl)stannane (253 mg, 0.701 mmol) in 5 mL of DMF was heated at 95° C. for 1 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with DCM/MeOH gradient to afford the title compound (74 mg, 45%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.47-9.45 (m, 2H), 8.70 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.97 (dd, 1H), 6.21 (s, 2H), 2.82 (s, 3H), 2.74 (s, 3H). LCMS (method E): [MH]+=347, tR=4.503 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 98%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8].[NH2:13][C:14]1[C:15]([CH3:39])=[C:16]2[C:20](=[C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]=1[CH3:23])[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:18][CH2:17]2.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:11]([NH:10][S:7]([NH:13][C:14]1[C:15]([CH3:39])=[C:16]2[C:20](=[C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:29])[CH3:27])[C:22]=1[CH3:23])[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:18][CH2:17]2)(=[O:9])=[O:8])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCN1CCc2c(C)c(N)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCN1CCc2c(C)c(NS(=O)(=O)NC(=O)OC(C)(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.5 h

Procedure:
tert-Butanol (0.85 mL) was dissolved in methylene chloride (17 mL) and chlorosulfonyl isocyanate (0.77 mL) was added at −18° C. The mixture was stirred at the same temperature for 30 min and N-(5-amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide (1.66 g) and triethylamine (1.24 mL) were added. The mixture was further stirred at −5° C. for 30 min. Methylene chloride (50 mL) was added, and the mixture was washed successively with 10% aqueous citric acid, saturated aqueous sodium hydrogencarbonate, and then saturated brine (50 mL) and dried over sodium sulfate. Then, methylene chloride was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as crystals (1.9 g).
Reaction SMILES: CS[C:3](=[N:6][C:7]#[N:8])SC.[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:21]([NH2:23])[CH3:22]>>[C:7]([NH:6][C:3]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Br:20])=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:23][CH2:21][CH3:22])#[N:8]
Reactant: NCCSCc1ncccc1Br
Reactant: CCN
Reactant: CSC(=NC#N)SC
Product: CCN=C(NC#N)NCCSCc1ncccc1Br

Procedure:
Sequential reaction of dimethylcyanodithioimidocarbonate with 2-((2-aminoethyl)thiomethyl)-3-bromopyridine and excess ethylamine, followed by chromatographic purification on a column of silica gel with elution by ethyl acetate and final recrystallisation from ethyl acetate-petroleum ether afforded N-cyano-N'-[2-((3-bromo-2-pyridyl)methylthio)-ethyl]-N"-ethylguanidine, m.p. 123°-124°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:15]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:16])[CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CCC1
Product: O=C(O)c1ccc(NC(=O)C2CCC2)cc1

Procedure:
4-Cyclobutanecarbonylamino-benzoic acid was prepared as described in Example 3 from 7.05 g (0.0514 mol) of p-aminobenzoic acid (PAB) and 6.4 g (0.054 mol) of cyclobutanecarboxylic acid chloride.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([O:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([O:37][CH2:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:11]=1)([CH3:22])([CH3:23])[CH3:21]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(OCCCc2ccncc2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCCc3ccncc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-(3-pyridin-4-ylpropoxy)naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[O:15][CH2:16][C:17]#[N:18]>>[C:17]([CH2:16][O:15][C:14]1[CH:13]=[C:12]([NH:11][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: N#CCOc1cccc(N)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: N#CCOc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (341 mg, 1.69 mmol) was coupled to aniline (172)(250 mg, 1.69 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(NC(=O)c2cc(N)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 5 h
Yield: 58.3 %

Procedure:
A mixture of 2-(4-tert-butylbenzoylamino)-5-nitro-N-(4-methoxyphenyl)benzamide (895 mg, 2.00 mmol), 10% palladium-on-carbon (90 mg) and ethyl acetate (5 ml) in ethanol (5 mL) was hydrogenated at one atmospheric pressure for 5 h. The reaction was degassed and a suspension of 10% palladium-on-carbon (45 mg) and ethyl acetate (3 mL) was added. This mixture was hydrogenated for 2 days at one atmosphere. The reaction was filtered through diatomaceous earth assisted by ethyl acetate/ethanol washes. The filtrate was concentrated in vacuo and chromatographed (silica gel, 10% ethyl acetate/90% methylene chloride to 35% ethyl acetate/65% methylene chloride) to give 487 mg (58%) of the title compound as a white solid; mp 212-214.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:28])[NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:20]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[S:29]1[CH2:35][C:33](=[O:34])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:30]1=[S:31].[Cl-].[NH4+].N>C(O)C>[OH2:2].[CH2:25]([O:24][C:22]([C:21](=[C:35]1[S:29][C:30](=[S:31])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:33]1=[O:34])[C:19]1[N:20]=[C:16]([NH:15][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:28])[S:17][CH:18]=1)=[O:23])[CH3:26].[OH2:2].[OH2:2].[CH2:25]([O:24][C:22]([C:21](=[C:35]1[S:29][C:30](=[S:31])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:33]1=[O:34])[C:19]1[N:20]=[C:16]([NH:15][C:14]([NH:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:28])[S:17][CH:18]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cc(OC)c(OC)c(OC)c2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2cc(OC)c(OC)c(OC)c2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.1 g of ethyl 2-[3-(3,4,5-trimethoxyphenyl)ureido]thiazol-4-ylglyoxylate. 0.48 9 of rhodanine-3-acetic acid. 0.25 g of ammonium chloride. 0.25 ml of 28% v/v aqueous ammonia and ml of ethanol, in the form of brown prismatic crystals having the following physical properties.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[N:16]12[CH2:24][C@H:20]([C:21](=O)[CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C.[C:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:33].[ClH:40]>O.C1(C)C=CC=CC=1>[ClH:40].[CH2:38]([O:37][C:35](=[O:36])[C:34](=[C:21]1[CH2:22][N:16]2[CH2:24][C@H:20]1[CH2:19][CH2:18][CH2:17]2)[C:32]#[N:33])[CH3:39]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CN2CCC[C@@H]1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(C#N)=C1CN2CCC[C@@H]1C2
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(5R)-1-Azabicyclo[3.2.1]octan-6-one (-) camphorsulfonate (61.8 g, 135.0 mmol) and triethylamine (20.4 g, 202 mmol) and ethyl cyanoacetate (61.8 g, 547 mmol) were mixed and stirred at room temperature for 6 days. Toluene (120 ml) and water (120 ml) were added to the reaction mixture and the pH was adjusted to 2 with concentrated hydrochloric acid. The phases were separated and the water phase extracted with toluene (30 ml). The combined organic phases were washed with water (20 ml). The combined water phases were adjusted to pH=9.4 with NH3 (25% in water) and extracted with toluene (1×120 ml, 1×60 ml). The combined toluene extracts were evaporated. The residue was dissolved in ethanol (120 ml) and concentrated hydrochloric acid (16 ml) was added. The title compound precipitated in 22 g yield. Upon evaporation of the mother liquor and crystallization from ethanol (40 ml) further 14.6 g of the title compound was isolated.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:9]CCN)(=[O:8])[CH3:7].[CH2:13]([N:15](CC)CC)[CH3:14].N>C(Cl)Cl>[CH3:1][S:2]([NH:15][CH2:13][CH2:14][CH2:7][C:6]([NH2:9])=[O:8])(=[O:4])=[O:3]
Reactant: CC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Product: CS(=O)(=O)NCCCC(N)=O
Reaction time: 3 h
Yield: 80.5 %

Procedure:
11.86 grams (104 mmol) of methanesulfonyl chloride was added to a solution of 10.2 grams (100 mmol) of acetylethylenediamine and 10.5 grams (104 mmol) of triethylamine in cold (0° C.) methylene chloride and the mixture was stirred for 3 hours. At the end of this period, the mixture was concentrated to obtain a residue. To the residue was added 500 milliliters of ammonia saturated chloroform, the resulting mixture was filtered to removed undesired by-product and the filtrate was concentrated to obtain 14.5 grams (80 percent yield) of 2-methanesulfonylaminoethylacetamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:18]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(NC(=O)c2ccc(OC)c(OC)c2)n1
Yield: 72.9 %

Procedure:
In 100 ml of methylene chloride, 21.3 g of 2-amino-4-ethoxycarbonyl-1,3-thiazole was suspended, followed by the addition of 24.8 g of 3,4-dimethoxybenzoyl chloride, 25.3 g of triethylamine and 0.15 g of 4-dimethylaminopyridine. The resulting mixture was refluxed for 2 hours. After the reaction mixture was allowed to cool down, methylene chloride was distilled off under reduced pressure. To the residue, 1000 ml of water was added. Crystals so precipitated were collected by filtration and then recrystallized from ethanol, whereby 30.3 g of the title compound was obtained. Yield: 73%.