Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH3:15]>>[CH2:17]([N:16]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH3:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC1CO1
Reactant: CCCNCCCCCCNCCC
Product: CCCCCCCCCC(O)CN(CCC)CCCCCCN(CCC)CC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and N,N'-dipropylhexamethylenediamine affords N,N'-(1,6-hexylene)-bis[N-propyl-2-hydroxyundecylamine] (I: R= CH3 (CH2)8, R'=CH3 (CH2)2, X= (CH2)6, Z= H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17](C(OC(C)(C)C)=O)[CH3:18])=[CH:9][CH:8]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][CH3:18])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(NC)c2ccccc12

Procedure:
To 3.90 g (10.9 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-naphthalen-1-yloxy]-acetic acid ethyl ester, dissolved in 110 ml of CH2Cl2, was added via dropping funnel within 15 Min. 27.9 ml of TFA. After additional 30 Min. at RT, the bulk of the solvents was removed i. V. and the residue distributed between NaHCO3 and AcOEt. Washing with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), gave 2.25 g of the title compound as off-white crystals.
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][NH:30]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2]>N1CCCCC1.CN(C=O)C>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:28]=[C:26]([CH3:27])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:29][NH2:30])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: Cc1cn([C@H]2C[C@H](ONC(=O)OCC3c4ccccc4-c4ccccc43)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3′-O-(Fmoc)amino-thymidine-5′-triphosphate is dissolved in 20% piperidine in DMF (0.5 mL). The mixture is stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue is redissolved in triethylammonium acetate buffer (aqueous, 10 mM; pH 7; 2 mL) and purified by rp-HPLC (C18, gradient 0-21% acetonitrile in 10 mM triethylammonium acetate over 27 minutes) to give 3′-O-amino-thymidine-5′-triphosphate as a colorless foam. The purity of the product is confirmed by analytical ion-exchange chromatography (DEAE, gradient 0-1 M triethylammonium bicarbonate in water over 30 minutes). 1H-NMR (D2O; 300 MHz): δ (ppm)=1.80 (s, 3H); 2.18 (m, 1H); 2.34-2.39 (m, 1H); 4.03-4.09 (m, 2H); 4.25 (m, 1H); 4.45 (m, 1H); 6.17 (dd, J=6.0, 9.1 Hz, 1H); 7.66 (s, 1H). 31P-NMR (D2O; 162 MHz): δ (ppm; H3PO4=0)=−14.1 (br s, IP); −16.3 (br s, IP); −27.7 (br s, 1P). MS-ESI−: [M-H]− calcd. for C10H17O14N3P3, 496.0; found, 496.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([Cl:18])=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCN(c2ccncc2)CC1
Reaction time: 3 h

Procedure:
To a stirring suspension of 1-(4-pyridinyl)piperidin-4-ylcarboxylic acid (0.8 g, 3.88 mmol) in dichloromethane (75 mL) at reflux was added thionyl chloride (0.45 mL, 5.82 mmol). After 3 h, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (75 mL), giving a solution of the title compound, approximately 0.05 M.
Reaction SMILES: CON=[CH:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11].[CH2:12]([NH2:15])[CH2:13][NH2:14].[CH3:16]COCC>C(O)C>[NH:14]1[CH2:13][CH2:12][N:15]=[C:16]1[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11]
Reactant: NCCN
Reactant: CON=CCN1CCOC1=O
Reactant: CCOCC
Solvent: CCO
Product: O=C1OCCN1CCC1=NCCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A mixture of 25.8 g (0.15 mol) of N-[2-(methoxyimino)ethyl]oxazolidinone 22 and 9 g (0.15 mol) of ethylenediamine in 50 mL of absolute ethanol was refluxed for 30 min. After cooling to room temperature, the mixture was treated with ether until crystals separated and then was refrigerated for 3 days. The colorless crystals were filtered and dried to give 19.9 g (73%) of 23: mp 118°-123° C.; 1H NMR (CDCl3) δ 2.54 (t, 2, --CH2 --C(=N) 3.57 (s, 4, =NCH2CH2 --NH), 3.62 (m, 4, --CH2NCH2), 4.32 (m, 2, --OCH2), 4.57 (b, NH). Anal. C8H13N3O2): C, 52.25; H, 7.15; N, 22.80.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:25][I:26]>ClCCCl>[I-:26].[CH3:24][N+:20]1([CH3:25])[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][CH2:17][N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCCC1CCN(c1ccccc1)C1Cc2ccccc2C1
Reactant: CI
Solvent: ClCCCl
Product: C[N+]1(C)CCCC1CCN(c1ccccc1)C1Cc2ccccc2C1
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 19 (0.1 g, 0.31 mmol) in DCE (3 mL) was added methyl iodide (0.058 mL, 0.94 mmol) and the resulting mixture was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressures and the crude material was purified by column chromatography on neutral alumina eluting with 1% methanol-DCM to provide 1,1-dimethyl-2-[2-((indan-2-yl)(phenyl)amino)ethyl]pyrrolidinium iodide.
Reaction SMILES: FC1C=CC(C2N=C(C(=O)C)SN=2)=CC=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1.Cl[C:27]([S:29]Cl)=[O:28]>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:22][C:27](=[O:28])[S:29][N:23]=2)=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(Cl)SCl
Agent: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Product: O=c1oc(-c2ccc(F)cc2)ns1

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluorobenzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][C@H:10]([NH:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:17]([F:20])([F:19])[F:18])[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][S:8][CH2:9][C@H:10]([NH:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:17]([F:20])([F:18])[F:19])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)[C@H](CSCc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](CSCc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of methyl 3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionate (0.64 g, 1.59 mmol) in methanol (9 mL) was added 1N sodium hydroxide (4.77 mL). The resulting solution was stirred for 2 h at ambient temperature and then methanol was removed in vacuo. The residue was portioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were dried over magnesium sulfate. Removal of the solvents provided 3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (0.410 g, 1.06 mmol) as a white solid which was a mixture of diastereomers. 3-(Pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid was converted to of N-(1-cyano-cyclopropyl)-3-(pyridin-2-ylmethylsulfanyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)-ethylamino]propionamide by proceeding as described in Example 2, Step 8 above. N-(1-Cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenyl-ethylamino)propionamide (95 mg) was obtained from the diasteriomeric mixture by flash chromatography and was converted to the title compound (50 mg) by proceeding as described in Example 1, Step 6 above.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2]
Reactant: CCNc1nc(Nc2ccccc2)ncc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCNc1nc(Nc2ccccc2)ncc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of (4-ethylamino-2-phenylamino-pyrimidin-5-yl)-methanol (173 mg, 0.71 mmol) in 15 mL of chloroform was added manganese oxide (600 mg, 6.89 mmol). After stirring at room temperature overnight, the mixture was filtered through a pad of celite, washing with chloroform. The filtrate was concentrated in vacuo to give 170 mg (99%) of 4-ethylamino-2-phenylamino-pyrimidine-5-carboxaldehyde, mp 155-157° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][C:21](=[O:23])[CH3:22])[C:14]=3[Cl:24])[C:5]2=[N:4][C:3]=1[CH3:25].[H-].[Na+].Br[CH2:29][C:30]([O:32]CC)=[O:31].O>CN(C)C=O.C(O)C.[OH-].[Na+]>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH2:29][C:30]([OH:32])=[O:31])[C:21](=[O:23])[CH3:22])[C:14]=3[Cl:24])[C:5]2=[N:4][C:3]=1[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)N(CC(=O)O)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 59.7 %

Procedure:
To a solution of 3-bromo-8-(2,6-dichloro-3-acetylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (222 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (24 mg, 60% oil dispersion) at ambient temperature. The mixture was stirred for half an hour at the same temperature and then ethyl bromoacetate (100 mg) was added thereto in one portion. The mixture was stirred for 2 hours at the same temperature and poured into water. The separated oil was extracted with dichloromethane. The extract was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give an oil, which was dissolved in a mixture of ethanol (10 ml) and 1N sodium hydroxide solution (2 ml). The solution was refluxed for one and half hour. The organic solvent was removed under reduced pressure. The aqueous layer was adjusted to pH 4 with diluted hydrochloric acid to give 3-bromo-8-[2,6-dichloro-3-(N-carboxymethyl-N-acetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Nc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
To a stirred solution of 2-aminopyridin-4-ol (500 mg, 4.5 mmol) in DMF (5 mL) at rt was added K2CO3 (940 mg, 6.8 mmol). The resulting mixture was stirred at rt for 20 min before allyl bromide (393 μL, 4.5 mmol) was added. The mixture was then stirred at rt overnight and heated at 60° C. for 2 h. After cooling to rt, the mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in hexanes to give 4-(allyloxy)pyridin-2-amine (110 mg, 16%) as a white solid. LCMS (ESI) m/z 151 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:34]/[C:35](/[CH3:41])=[CH:36]\[C:37]([O:39][CH3:40])=[O:38]>C(O)(C)C>[CH3:16][C:14]1[NH:34][C:35]([CH3:41])=[C:36]([C:37]([O:39][CH3:40])=[O:38])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCN1CCN(Cc2ccccc2)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(Cc3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 86 %

Procedure:
A mixture of m-nitrobenzaldehyde, 2-(4-benzyl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzyl-1-piperazinyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 106°-108° C. (sintering). Yield 86.0%. IR(Nujol)cm-1 : 3325. NMR(CDCl3) δ: 2.33(6H,s, ##STR33## 3.46(2H,s,C6H5CH2 --), 3.61(3H,s,COOCH3), 4.14(2H,t,J=6,--COOCH2CH2 --), 5.09(1H,s,C(4) --H), 5.82(1H,s,NH).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:15](/[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH3:10])[CH:13]=2)\[C:16]#[N:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(Br)cc1
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)cc2)cc1OC
Yield: 78.6 %

Procedure:
4-Bromobenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.9 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (2.9 g, yield: 78%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=1[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[O:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=1[O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc([N+](=O)[O-])c(Oc2ccccc2OCC(=O)OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 21.5 %

Procedure:
A mixture of 2-fluoro-4-(methoxymethoxy)-1-nitrobenzene (9.25 g, 0.046 mol), methyl (o-hydroxyphenoxy)acetate (8.5 g, 0.047 mol) and potassium carbonate (6.44 g, 0.047 mol) in N,N-dimethylformamide is stirred at 100° C. for 18 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange gum. Flash chromatography of the gum using silica gel and a 35% ethyl acetate in hexanes solution gives the title product as a yellow oil (3.6 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: O=C1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5]C(C#N)=C1.S(=O)(=O)(O)[OH:29].[O:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[O:5]=[C:6]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:34][C:35]=2[O:36][C:37]([C:38]([OH:33])=[O:29])=[CH:11]1
Reactant: O=S(=O)(O)O
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C#N)oc2c1
Reactant: C1COCCO1
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A suspension of 1.0 parts of 4-Oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2carbonitrile in 50 parts of dioxane and 50 parts of 35% v /v sulphuric acid was heated on a steam can for eighteen hours. The solid obtained on cooling was collected, washed with water and crystallised from acetone to give 0.09 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 161°-163°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH2:8]
Reactant: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1nc(-c2cccnc2)sc1N
Reaction time: 2 h

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:20][CH:19]3[O:21][CH:15]([CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18]3)[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH:19]12[O:21][CH:15]([CH2:16][NH:17][CH2:18]1)[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:20]2
Reactant: CC(C)(C)OC(=O)N1CC2CN(CCCCc3ccc(C#N)cc3)CC(C1)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCCCN2CC3CNCC(C2)O3)cc1
Reaction time: 3 h
Yield: 102.7 %

Procedure:
A 2 L three-necked flask was equipped with a magnetic stirrer, a thermometer and an addition funnel. The flask was charged with tert-butyl 7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (34 g, 88 mmol, from step (iv) above) and dichloromethane (440 mL). Trifluoroacetic acid (132 mL) was added slowly at room temperature. The solution was stirred for three hours at which point TLC analysis showed complete consumption of starting material. The contents were transferred to a single-necked flask and concentrated under vacuum. The residue was dissolved in dichloromethane (500 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over magnesium sulfate and concentrated under vacuum to afford 25.8 g (100% yield) of sub-title compound as an off-white solid. The crude material was used in the next step without farther purification.
Reaction SMILES: [CH3:1][OH:2].N1C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22]Cl)[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]>C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22][O:2][CH3:1])[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]
Reactant: CO
Reactant: CN1C(=O)C(=NSCl)N(c2ccccc2F)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COSN=C1C(=O)N(C)C(=O)N1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (0.1 mole) methanol and 7.9 g (0.1 mole) pyridine in 20 ml of methylene chloride was added dropwise to a solution of about 0.1 mole of 1-(2-fluorophenyl)-3-methyl-5-chlorothioimino-2,4-imidazolidinedione in 100 ml of methylene chloride at 0°C. The resulting reaction mixture was stirred for about 30 minutes at 0°C., washed with water, washed with sodium bicarbonate, dried over magnesium sulfate, and evaporated under reduced pressure to give a yellow solid residue. The solid was washed with isopropyl alcohol to give the product as a pale yellow solid, m.p. 124°-127° C. Elemental analysis showed:
Reaction SMILES: C(Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]([CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:15])#[N:11].C(N(C(C)C)CC)(C)C>O1CCCC1>[S:23]([OH:24])(=[O:25])(=[O:8])[CH3:26].[C:10]([CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:33][CH2:34][NH:35][C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:28][CH:27]=1)(=[O:24])=[O:25])=[O:15])#[N:11]
Reactant: O=C(Cl)c1ccncc1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCN)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCNc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of isonicotinoyl hydrochloride (20 mg, 0.112 mmol) and trans-N-cyanomethyl-2-[4-(aminoethylsulfanyl)benzenesulfonylmethyl]cyclohexanecarboxamide (50 mg, 0.102 mmol) in tetrahydrofuran (1 mL) was added diisopropylethylamine (71 μL, 0.407 mmol). The reaction mixture was stirred overnight at room temperature, then purified directly on a short plug of silica gel (5-10% methanol/dichloromethane) to give the title compound. MS [ESI, (M+H)+] m/z=501 amu.