Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O:19][C:20](=O)[CH2:21][C:22]([CH3:24])=O)C>>[CH2:15]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:19])[CH2:21][C:22]([CH3:24])=[N:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:6])[CH3:16]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCN(CC)S(=O)(=O)c1ccc(NN)cc1
Product: CCN(CC)S(=O)(=O)c1ccc(N2N=C(C)CC2=O)cc1

Procedure:
From the reaction of N,N-diethyl-4-hydrazinobenzenesulfonamide and ethylacetoacetate: yields N,N-diethyl-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide. Subsequent reaction with 2-methoxyaniline yields N,N-diethyl-4-(4,5-dihydro-4-(2-methoxyanilinomethylene)-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide, Mp: 191° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([S:13]([CH3:15])=O)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.N1C=CC=CC=1.C(=O)=O>CC(C)=O>[Cl:19][CH2:15][S:13][C:7]1[C:6](=[O:16])[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]([CH3:12])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Agent: O=C=O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cn1cc(SCCl)c(=O)c2ccc(F)cc21
Temperature: -5 °C
Yield: 74 %

Procedure:
3.59 g (5 mmole) of racemic flosequinan (1) were added (over the course of one minute) to a mixture of thionyl chloride (12 ml) and pyridine (3 ml) with efficient stirring and gentle cooling in a bath of dry ice and acetone, to keep the temperature in the range of 0° C. to 6° C. The mixture was stirred at approximately 0° C. for 5 minutes, cooled to −5° C. and poured as a thin stream into 350 ml of ice-water with efficient stirring. After 10 minutes of stirring at 0° C., a solid was filtered off, washed with water and dried over phosphorous pentoxide, under high vacuum producing 2.82 g (74% yield) of 95% pure (by 1H NMR) 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone (6). 1H NMR, CDCl3, δ=8.50 dd, 1H, J=6.6 & 9.0 Hz, H at C5; 8.01 s, 1H, H at C2; 7.18 ddd, 1H, J=2.1 & 9.0 & 10.2 Hz, H at C6; 7.09 dd, 1H, J=2.1 & 10.2 Hz, H at C8; 5.01 s, 2H, CH2; 3.83 s, 3H, N—CH3.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6](OC3C=CC=CC=3)[C:5]=2[N:19]=1.C([O-])(=O)C.[NH4+:36]>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([NH2:36])[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(N)c2nc(C)n(CCOCCCc3cccnc3)c2c1C
Temperature: 25 °C
Reaction time: 46.5 h

Procedure:
Under a nitrogen atmosphere, 2,6,7-trimethyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridine (4 g) from Part D and ammonium acetate (40 g) were heated in a sealed tube to 150° C. After 46.5 hours, NMR analysis indicated that only 7% of the starting material remained. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, and washed 3 times with IN potassium hydroxide and once with water. The organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was triturated with 90/10 diethyl ether/toluene and the filtered solids were dried under vacuum at 45° C. The pale yellow solid was dissolved in 10% hydrochloric acid and extracted 3 times with dichloromethane (DCM). Potassium hydroxide was added to the aqueous layer to bring the pH to 14, and this was subsequently washed 3 times with DCM. The combined organic layers were washed once with water, 3 times with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The oil was purified by column chromatography over silica using 97/3 DCM/methanol as the eluant. The oil was then triturated with diethyl ether/toluene and the resulting solid was recrystallized from ethyl acetate/hexane to yield 2,6,7-trimethyl-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 108.6-109.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].C([O-])(O)=O.[Na+].C(OCC)(=O)C>COCCOC.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]([O:41][C:40]([NH:39][C:25]1[CH:26]=[CH:27][C:28]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[CH:29][C:24]=1[O:23][CH3:22])=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I16) (474 mg, 1.43 mmol), tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (I17) (500 mg, 1.43 mmol) and Pd(PPh3)4 (165 mg, 0.143 mmol) in DME (15 mL) was added a solution of 3.5 M aqueous NaHCO3 (2.00 mL, 5.0 eq) and the resulting suspension was heated at 80° C. for 16 hours. On cooling to room temperature ethyl acetate (70 mL) was added and the resulting solution was washed with water (50 mL). The organic layer was dried (MgSO4) and evaporated to dryness. The residue was chromatographed (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I18) (520 mg, 90%) as a pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.96 (dd, J=8.4, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 5.98 (s, 1H), 4.08 (d, J=1.9 Hz, 2H), 3.89 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.52 (s, 2H), 1.54 (s, 9H), 1.51 (s, 9H). LCMS Method C: rt 6.87 min; m/z 349.1 [M-t-Bu+2]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[ClH:14].[H][H]>[Pd].O>[OH2:1].[ClH:14].[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Nc1cc(C(=O)O)ccc1O
Temperature: 95 °C

Procedure:
To a 5-liter, 3-necked, round-bottom flask is added 160 g of 4-hydroxy-3-nitrobenzoic acid, 150 cc hydrogen chloride, 3 liter of distilled water and 25 g of 5 percent palladium on carbon. The reaction mixture is heated to 95° C. with vigorous stirring and hydrogen gas is passed into the reaction mixture. Upon completion, the reaction is cooled to room temperature under nitrogen gas and the catalyst is recovered by filtration. The resulting solution is poured into two 4-liter beakers and acidified with concentrated hydrochloric acid to a normality of 4 and allowed to cool to 0° C. The resulting solid is isolated by filtration and dried under vacuum to afford 176 g of crude 3-amino-4-hydroxybenzoic acid hydrochloride monohydrate with a melting point of 300° C. decomposition.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH2:4][CH3:5].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.[CH3:30]N(C=O)C>>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][C:20]([CH2:19][N:10]2[C:9]3[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:8]=3[N:7]=[C:6]2[CH2:3][CH2:4][CH3:5])=[CH:21][CH:22]=1)[CH3:30]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CN(C)C=O
Reactant: CCCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2cc([N+](=O)[O-])ccc2n1Cc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride, 60% dispersion in oil (1.0 g; 25 mmol) in DMF (30 mL), a solution of 2-propyl-5-nitrobenzoimidazole (4.2 g; 20 mmol) in DMF (30 mL) was added dropwise over 10 minutes. After addition, the reaction mixture was stirred at ambient temperature for 30 minutes, then methyl 4- (bromomethyl)benzoate (4.7 g; 20 mmol) was added. The reaction mixture was heated at 80° C. for 18 hours, then concentrated to a thick oil. The oil was extracted with ethyl acetate and water. The ethyl acetate layer was concentrated to dryness. The residue (1.3 g) was subjected to flash chromatography on silica gel (hexane/EtOAc; 7:3) to obtain 365 mg of yellow solid. Recrystallization from hexane/EtOAc gave the title compound, m.p. 136°-138° C. Anal. Calcd. for C20H21N3O4 : C, 65.38; H, 5.74; N, 11.44.. Found: C, 65.15; H, 5.75; N, 11.26. Mass spectrum (EI; M+) m/z 367. 1H-NMR (DMSO-d6 ; 400 MHz) δ 8.5 (d, 1H), 8.1 (dd, 1H), 7.9 (d, 2H), 7.7 (d, 1H), 7.2 (d, 2H), 5.7 (s, 2H), 4.3-4.3 (q, 2H), 2.8 (t, 2H), 1.7-2.0 (m, 2H), 1.24-1.3 (t, 3H), and 0.90-0.95 ppm (t, 3H).
Reaction SMILES: N[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([OH:17])(=[O:16])[CH2:9]CCCC(C)C>N1C=CC=CC=1>[CH3:8][C:3]([CH2:2][C:5]([OH:7])=[O:6])=[O:4].[C:3]([O:17][C:8](=[O:16])[CH3:9])(=[O:4])[CH3:2]
Reactant: CC(C)CCCCC(=O)O
Reactant: N[C@@H](CO)C(=O)O
Solvent: c1ccncc1
Product: CC(=O)CC(=O)O
Product: CC(=O)OC(C)=O

Procedure:
BU-3862T exhibits strong absorptions at 3300 (hydroxy), 1720 (carbonyl), 1650 and 1530 cm-1 (amide) in the IR spectrum indicating a peptide structure for the antibiotic. The 13C-NMR spectrum demonstrated 20 carbons which were identified as two C--CH3, one =C--CH3, eight --CH2, three --CH, one >C<, one >C=CH2 and three C=O carbons. The molecular formula of BU-3862T was established as C20H34N2O6 based on the microanalysis, mass spectral data ((M+H)+ : m/z 399) and 13C-NMR spectral analysis. Thirty-four protons were observed in the 1H-NMR spectrum. The two doublet protons (δ7.03 and 6.48 ppm, in CDCl3) gradually disappeared by the addition of deutrium oxide were assigned to two --NH--CO groups. The broad two singlet protons (δ4.83 and 4.79) and the AB type doublet protons (δ3.35 and 3.12, J: 5.0 Hz) were assigned to exomethylene(--(CH3)C=CH2) and epoxide ##STR6## protons, respectively. The connectivities of these protons were determined by 1H-1H COSY experiments leading to the partial structures as shown below. Further connectivities of the partial structures were established by the 13C-1H COSY and 13C-1H long range COSY experiments. They were analyzed as shown below and thus the total structure of BU-3862T was determined. Further evidence for the structure was provided by its mass spectrum and degradation experiment. The EI-MS spectrum exhibited abundant fragment ions at m/z 127 (iso-octanoyl), 214 (iso-octanoyl-seryl) and 325 (iso-octanoyl-seryl-4,5-didehydroleucyl) supporting the structure. Upon acid hydrolysis, BU-3862T gave an amino acid and a fatty acid. The amino acid isolated was identified as L-serine by HPLC and the fatty acid as iso-octanoic acid by gas chromatography of its methyl ester. BU-3862T afforded the diacetate derivative upon treatment with acetic anhydride in pyridine. When hydrogenated over palladium carbon, BU-3862T afforded two reduction products, dihydro-BU-3862T and tetrahydro-BU-3862T, whose structures were determined based on their spectral data. The diacetate and the dihydro compound retained the biological activity but the tetrahydro derivative was devoid of the activity.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)(C)CI.[C:33](=O)([O-])[O-:34].[K+].[K+]>CN(C)C=O>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][CH:33]=[O:34])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CC(C)(C)CI
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
150 mg (0.406 mmol) of 2-[4-(5H -dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride, 80.5 mg (0.406 mmol) of 2,2-dimethyl-1-iodopropane and 84.3 mg (0.610 mmol) of potassium carbonate were dissolved in 1 ml of N,N-dimethylformamide, and the obtained solution was stirred at 120° C. overnight. The product was purified by the silica gel chromatography (hexane: ethyl acetate=9:1 to 2:3) to obtain the title compound.
Reaction SMILES: N12CCC(CC1)CN2.[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:18](=[CH2:19])[C:17]([O:21][CH3:22])=[O:20]
Reactant: O=Cc1ccccc1
Reactant: C=CC(=O)OC
Agent: C1CN2CCC1CN2
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 70.7 %

Procedure:
Diazabicyclo[2.2.2]octane (5.2 g, 0.046 mol, 0.15 eq) was added to a mixture of benzaldehyde (31.5 mL, 0.309 mol, 1 eq) and methyl acrylate (42 mL, 0.464 mol, 1.5 eq). The reaction mixture was then allowed to stir at room temperature for 7 days. The reaction mixture was purified by column chromatography (eluent: hexane/ethyl acetate=95:5) to give the desired product as colorless oil (42 g, 77%). Rf 0.5 (hexane/ethyl acetate=7:3). 1H NMR δ (DMSO-d6) 3.6 (s, 3H), 5.43 (m, 1H), 5.73 (m, 1H), 5.98 (s, 1H), 6.19 (s, 1H), 7.29 (m, 5H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].Br[CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.[CH:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:42]3[CH2:43][CH2:44][N:39]([C:36]4[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=4)[CH2:40][CH2:41]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(CN5CCN(c6ccccc6)CC5)cc4)cc3)n(C)c(=O)c12
Yield: 13.6 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)quinazolinone (1.03 g), 4,4'-bis (bromomethyl)benzophenone (1.75 g), phenylpiperazine (810 mg), and 1N-sodium hydroxide/water (5.5 ml) in DMF (35 ml) was stirred at 60° C. for 1 hour. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=4:1:1) and crystallized from isopropyl ether to provide the title compound as colorless solid (372 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH2:17]([NH2:29])[CH2:18][C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[CH3:23][O:22][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][NH:29][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH:28]=[CH:27][C:24]=1[O:25][CH3:26]
Reactant: O=C(NCCCCl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNCCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Product: Cl
Yield: 23.6 %

Procedure:
A solution of 10.62 g (44 mmol) N-(3-chloropropyl)-4-nitrobenzamide (D3), 8.1 g (45 mmol) homoveratrylamine and 6.26 ml triethylamine in 200 ml methylene chloride was refluxed for 48 h. The solvent was then concentrated in vacuo and the residue dissolved in water. The aqueous phase was first washed with methylene chloride, then made basic with aqueous NaOH and finally extracted twice with methylene chloride. This second organic phase was dried over MgSO4 and concentrated in vacuo affording 12 g of a crude residue. This residue was purified by chromatography on silicagel using CH2Cl2 /MeOH/NH4OH: 85/10/5 to afford 4.4 g of the title compound as an yellow oil (free base).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](Cl)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([N:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[O:24])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of 100 mg (0.22 mmole) of N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-N-pentylcarbamoyl chloride (from Example 2, Step B), 0.2 mL (1.15 mmole) of N,N-diisopropylethylamine, and 44 mg (0.33 mmole) of 1,2,3,4-tetrahydroquinoline in 2.5 mL of toluene was stirred at 110° C. for two days. After cooling to room temperature, volatiles were removed by rotary evaporation, and the residue was flash chromatographed over silica gel (gradient elution using 10% to 12.5% EtOAc in hexane) to give 81 mg (66%) of the desired product as an oil, homogeneous by TLC (4:1 hexane-EtOAc), FAB-MS m/e 548 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-])=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)C([S:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:35]=1[NH2:36])=S)(C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:13]=[C:8]([CH:7]=[C:6]([C:14]2[S:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:35]=3[N:36]=2)[CH:5]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)N(C(=S)Sc1cnccc1N)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2nc3ccncc3s2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
Mono-methyl 5-nitro-isophthlate (1.25 g, 5.58 mmol) was suspended in 25 mL of CH2Cl2 and oxalyl chloride (0.49 mL, 5.58 mmol) was added. After 3 drops of DMF was added, the reaction mixture was stirred at room temperature until all gas evolution had ceased and all the solids had dissolved. This freshly prepared solution of the acid chloride was then added dropwise to a solution of 4-aminopyridin-3-yl diisopropylcarbamodithioate (1.5 g, 5.58 mmol) and triethylamine (0.77 mL, 5.58 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 1 hour. It was then quenched with 25 mL of brine and the two layers were separated. The organic layer was dried (Na2SO4) and concentrated. The resulting residue was suspended in 25 mL of 2 N HCl and stirred under reflux for 30 min. It was then cooled to room temperature and the solids were collected by filtration and dried to afford 1.0 g of methyl 3-nitro-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate. This material was then mixed with 20 mL of methanol and 3 mL of water along with 1 g of sodium hydrosulfide hydrate and stirred under reflux for 2 hours. The resulting reaction mixture was cooled and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 150 mg of methyl 3-amino-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate (MS, M++H=286).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:35]([S:38][CH2:39][CH:40]([CH3:44])[C:41](O)=[O:42])(=[O:37])[CH3:36]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[N:9]([C:41](=[O:42])[CH:40]([CH3:44])[CH2:39][S:38][C:35](=[O:37])[CH3:36])[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: COC(=O)C1NCCS1
Reactant: CC(=O)SCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)C1SCCN1C(=O)C(C)CSC(C)=O
Temperature: 0 °C

Procedure:
2-Thiazolidinecarboxylic acid methyl ester (C.A. 53, 12,281d) (4.4 g.) and 3-hydroxybenzotriazole (4.0 g.) are dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After fifteen minutes stirring in the ice bath, and sixteen hours at room temperature, the precipitate is filtered off and the filtrate is washed neutral. The organic layer is dried and concentrated to dryness in vacuo to give 3-(3-acetylthio-2-methylpropanoyl)-2-thiazolidinecarboxylic acid methyl ester.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:32]([CH:34]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=1)[C:35](OC)=O)=[O:33].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:23][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]([F:20])([F:22])[F:21])=[N:17][CH:18]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:35]=[C:34]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([O:46][CH3:47])=[N:44][CH:45]=2)[C:32](=[O:33])[N:24]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 100 °C

Procedure:
To the solution of 3-fluoro-4((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (50 mg, 0.109 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (30 mg, 0.134 mmol) in 1,4-dioxane (1 mL) was added K2CO3 (60 mg, 0.434 mmol). The mixture was heated with a microwave reactor at 100° C. for 0.5 h. Purification via MDAP then afforded the title compound (13.5 mg, 23.82 yield). LCMS: rt=2.97 min, [M+H+]=519
Reaction SMILES: N[C:2]1[N:6]2[CH:7]=[C:8](SC3C=CC=CC=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.COC(Cl)=O>C(N(CC)CC)C>[N:4]1[CH:3]=[CH:2][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccn2ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio)imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamideethane yields pure 3-(methoxycarbonylamino) 6-phenylthio)imidazo [1,2-a] pyridine m.p. 211°-215° C.