Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([F:53])[CH:52]=1)[C:47]([OH:49])=O>>[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([F:53])[CH:52]=1)[C:47](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:49]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3cc(F)cc(Cl)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 38.5 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-chloro-5-fluorobenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-chloro-5-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (38.5% yield). MS m/z=585.4 [M+H], calc 585.11 for C30H38ClFN6O3.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.O>[NH:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)NCC1CCNC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
TEA (1.05 mL, 7.5 mmol) was added to a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (1 g, 5 mmol) in DCM (25 mL) at 0° C. Methanesulfonyl chloride (0.43 mL, 5.5 mmol) was then added. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water. The organic phase was separated, dried (MgSO4), filtered and concentrated. The crude material was treated with 1M HCl in MeOH (25 mL) at RT and stirred at RT for 20 h. The volatiles were removed under reduced pressure to afford 0.95 g of 72 as a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25][C@H:26]2[O:83][C@H:82]([CH2:84][O:85]C(=O)C)[C@@H:37]([O:38][C@H:39]3[O:56][C@H:55]([CH2:57][O:58][C@H:59]4[O:76][C@H:75]([CH2:77][O:78]C(=O)C)[C@@H:70]([O:71]C(=O)C)[C@H:65]([O:66]C(=O)C)[C@H:60]4[O:61]C(=O)C)[C@@H:50]([O:51]C(=O)C)[C@H:45]([O:46]C(=O)C)[C@H:40]3[O:41]C(=O)C)[C@H:32]([O:33]C(=O)C)[C@H:27]2[O:28]C(=O)C)[C@@H:18]([CH2:89][O:90]C(=O)C)[O:17][C@H:6]1[O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)C.[Na].C(Cl)(Cl)Cl.CO.O>CO>[C@H:59]1([O:58][CH2:57][C@H:55]2[O:56][C@H:39]([O:38][C@@H:37]3[C@@H:82]([CH2:84][OH:85])[O:83][C@H:26]([O:25][C@@H:19]4[C@@H:18]([CH2:89][OH:90])[O:17][C@@H:6]([O:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@H:5]([OH:4])[C@H:20]4[OH:21])[C@H:27]([OH:28])[C@H:32]3[OH:33])[C@H:40]([OH:41])[C@@H:45]([OH:46])[C@@H:50]2[OH:51])[O:76][C@H:75]([CH2:77][OH:78])[C@@H:70]([OH:71])[C@H:65]([OH:66])[C@H:60]1[OH:61]
Reactant: COC(=O)CCSCCO[C@@H]1O[C@H](COC(C)=O)[C@@H](O[C@H]2O[C@H](COC(C)=O)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCSCCO[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 9 h
Yield: 83.9 %

Procedure:
Compound 94 (3.0 g, 2.2 mmol) was dissolved in methanol (25 ml) and added to a solution of sodium (1 mg) in methanol (75 ml). The reaction mixture was monitored by TLC (chloroform:methanol:water 65:35:10, lower phase). After 9 h at room temperature and 30 min at 40°, the solvent was removed and the residue was chromatographed (SiO2, chloroform:methanol:water, 65:35:10, lower phase) to give 98 (1.50 g, 84%). [α]D25 +113° (c 0.7, water). 1H-NMR (D2O, TSP) δ 5.41 (d, 2H, J=3.5 Hz, H1' and H1"), 4.98 (d, 1H, J=3.6 Hz, H1"'), 4.53 (d, 1H, J=7.9 Hz, H1), 3.75 (s, 3H, MeO). 13C-NMR (D2O, TSP) δ 177.4 (CO), 104.3 (Cl), 102.0, 101.6, 100.2 (Cl', Cl", Cl"'), 79.3, 79.1, 78.3, 76.7, 75.4, 75.2, 75.1, 73.9, 73.8, 73.6, 73.5, 73.3,,71.6, 71.5, 71.1, 68.0, 62.8, 62.7, 62.6, 62.6, 54.5, 36.3, 32.9, 28.6.
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][Cl:21])[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(OCC)(=O)C.Cl.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][OH:40]>>[ClH:21].[C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][O:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCO
Reactant: CCCC(=O)c1sc(NC(=O)c2ccnc(CCl)c2)nc1-c1ccco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC(=O)c1sc(NC(=O)c2ccnc(COCCN(C)C)c2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Compound 387 (247 mg, 0.635 mmol) was dissolved in 2-(dimethylamino)ethanol (3 mL), and 55% sodium hydride (55.0 mg, 1.27 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The precipitated solid was collected by filtration to afford a free form of the entitled Compound. An ethyl acetate solution of 4 mol/L hydrogen chloride was added to the resulting free form, and the precipitated solid was collected by filtration to afford the entitled Compound 389 (248 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][C:5](=[O:18])[C:4]=2[CH:3]=1
Reactant: BrCCCCCCCCCBr
Reactant: CNC
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: CN(C)CCCCCCCCCOc1ccc2oc(-c3ccccc3)cc(=O)c2c1

Procedure:
The compound was prepared by a method similar to Example 2 from 6-hydroxyflavone, 1,9-dibromononane and dimethylamine: mp 52°-53° C.
Reaction SMILES: Cl.[CH3:2][C@:3]([C:7]([OH:9])=[O:8])([CH2:5][SH:6])[NH2:4].[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]#N.C(N(CC)CC)C.[OH-].[K+]>C(O)C.O>[OH:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[C:13]1[S:6][CH2:5][C@:3]([CH3:2])([C:7]([OH:9])=[O:8])[N:4]=1
Reactant: N#Cc1ccc(O)cc1O
Reactant: C[C@@](N)(CS)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: C[C@]1(C(=O)O)CSC(c2ccc(O)cc2O)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
4.00 g (S)-2-methylcysteine hydrochloride (23.3 mmol, 1.0 meq) and 3.14 g 2,4-dihydroxy benzonitrile (23.3 mmol, 1.0 meq) were suspended in 40 mL ethanol. After degassing this mixture with nitrogen (30 min) 4.95 g triethylamine (6.8 mL, 48.9 mmol, 2.05 meq) were added. The obtained suspension was heated under reflux in an atmosphere of nitrogen for 20 hours and then cooled to room temperature. From this suspension ethanol was evaporated under reduced pressure until an oil (20% of the initial volume) was obtained. This oil was dissolved in 50 mL water. The solution was adjusted to pH 7.5 with 1.20 ml 20% KOH and was extracted two times each with 20 mL methyl t-butyl ether (MTBE). The aqueous layer was separated, adjusted with 20% KOH to pH 11 and again extracted two times each with 20 mL MTBE. After separating the aqueous layer the pH was set with concentrated HCl to 7.5 and traces of MTBE were distilled off. Then the aqueous solution was acidified with 1.50 mL concentrated HCl to pH 1.5. The product precipitated. This suspension was stirred at 4° C. for 1 hour. Then the precipitate was filtered, washed two times each with 10 mL water (5° C.) and dried at 45° C. under vacuum. The reaction yielded 5.17 g (87.6%) of crude 4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid product. 1H-NMR showed no significant impurity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.C(Cl)(Cl)Cl>CN(C)C=O>[Cl:23][C:20]1[N:19]=[C:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(Cl)ccc1Cl
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(Cl)nc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 30.8 %

Procedure:
4-Methoxythiophenol (0.927 ml; 7.55 mmol) and 1.14 g (8.26 mmol) of potassium carbonate were added, at room temperature, to a solution (70 ml) of 1.70 g (6.86 mmol) of the resulting ester compound in N,N-dimethylformamide followed by stirring for 1 hour. Chloroform was added to the reaction solution followed by washing with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution, drying and concentrating in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 743 mg (yield: 31%) of tert-butyl 6-chloro-3-(4-methoxy-phenylsulfanyl)-2-pyridinecarboxylate as a colorless oily substance.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:26]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Reactant: O[C@H]1CCNC1
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CC[C@H](O)C3)cc2n1C
Yield: 25 %

Procedure:
The title compound was prepared as a white solid in 25% yield (30 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (100 mg, 0.30 mmol, STEP 2 of Example 11) and (S)-(+)-3-pyrrolidinol (77 mg, 0.63 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: C([N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[C:6]([Br:12])=[N:5]1)(=O)C.N1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.CCOC(C)=O>[Br:12][C:6]1[C:7](=[O:11])[N:8]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[C:9](=[O:10])[NH:4][N:5]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)n1nc(Br)c(=O)[nH]c1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1c(=O)[nH]nc(Br)c1=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
2-acetyl-6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (P6, 2.47 g, 10.56 mmol) was dissolved in 1,4-Dioxane (18 ml) and pyridine (2.56 ml, 31.7 mmol). The solution was cooled to 5° C. then benzoyl chloride (1.470 ml, 12.67 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The day after the reaction mixture was diluted with AcOEt and washed with 0.5N HCl aq solution. Organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. Crude product (brown oil) was purified by flash chromatography (SiO2, eluent: Cy to Cy/AcOEt 6:4) affording 6-bromo-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (1.46 g, 4.93 mmol, 46.7% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:45])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: NCCCN1CCCC1=O
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCCN3CCCC3=O)n2)s1
Yield: 80 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.20 g, 0.37 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.52 ml, 3.7 mmol) the title compound was obtained (0.20 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.15-7.64 (m, 7H), 5.81-5.98 (m, 1H), 3.21 (t, J=6.6 Hz, 2H), 3.07-3.16 (m, 2H), 2.21 (t, J=8.0 Hz, 2H), 1.92 (quin, J=7.4 Hz, 2H), 1.66 (br. s., 2H), 1.40 (s, 9H). MS (ES+): 645 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(N(CC)C(C)C)(C)C.[C:22](Cl)(=[O:24])[CH3:23].CCOC(C)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:24])[CH3:23]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)O)cc1OC(C)=O
Reaction time: 0.08 h
Yield: 61.7 %

Procedure:
To a suspension of 600 mg (3.57 mmol) of 3-hydroxy-4-methoxybenzoic acid (Aldrich Chemical Company, Milwaukee, Wis.) in 5 mL of anhyd CH2Cl2 was added 1.31 mL (7.50 mmol) of N,N-diisopropylethylamine and the mixture stirred until homogeneous (ca. 5 min). Acetyl chloride (305 μL, 4.28 mmol) was added dropwise over 2 min followed by 2.0 mg ((0.016 mmol) of 4-dimethylaminopyridine. After stirring at room temperature for 1 h, the mixture was poured into 50 mL of EtOAc and washed with 1 M HCl (3×25 mL). The organic phase was extracted with saturated NaHCO3 (6×15 mL) and the combined extracts saturated with solid NaCl and acidified to pH 2 with conc HCl. The resulting suspension was extracted with EtOAc (3×20 mL) and the combined extracts were dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light beige powder (463 mg, 62%). 1H-NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, J=8.7, 2.0 Hz), 7.79 (d, 1H, 2.0 Hz), 7.00 (d, 1H, 8.7 Hz), 3.91 (s, 3H), and 2.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:22]/[CH:23]=[CH:24]\[CH2:25]Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH:24]=[CH:23][CH2:22]2)[CH:7]=1
Reactant: COC(=O)Cc1cc(F)cc(OC)c1
Reactant: ClC/C=C\CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cc(F)cc(OC)c2)CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a stirred solution of methyl 5-fluoro-3-methoxyphenylacetate (708 mg, 3.6 mmol) in THF (10 ml) was added a 1.0M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) at -30° C. over 0.25 hr. After stirring for 1 h at the same temperature, a solution of cis-1,4-dichlorobut-2-ene (526 mg, 4.0 mmol) in THF (2 ml) was added dropwise and the reaction mixture was warmed to room temperature over 2 hr period. The reaction mixture was cooled to -30° C., and 1.0M solution of potassium t-butoxide in THF (4.0 ml, 4.0 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 150 g; hexane/ethyl acetate (20/1)) afforded 495 mg (55%) of methyl 1-(5-fluoro-3-methoxyphenyl)cyclopent-3-ene-1-carboxylate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1.C(O)(=O)C>[Fe].O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:13])[O:6][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2Cl)nc1CCOc1ccc(N)cn1
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of 2-[2-[5-methyl-2-(2-chlorophenyl)-4-oxazolyl]ethoxy]-5-nitropyridine (1.69 g), iron dust (787 mg), acetic acid (25 ml) and water (8 ml) was stirred at 65°-70° C. for 3 hours. Insolubles were filtered off and the filtrate was evaporated under reduced pressure. To the residue was added water. The mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel chromatography. From the fraction eluted with methanol-chloroform (1:25, v/v), 5-amino-2-[2-[5-methyl-2-(2-chlorophenyl)-4-oxazolyl]ethoxy]pyridine (1.50 g, 97%) was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].COCCOC.[H-].[Na+].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]Cl>O>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9]
Reactant: ClCCOCCOC1CCCCO1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)COCCOCCOC1CCCCO1
Reaction time: 1 h
Yield: 9.4 %

Procedure:
In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.4 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:18][CH:17]2[N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]([CH2:11][C:12]3[NH:13][N:14]=[CH:15][C:16]=32)[CH2:9]1)=[O:7])C>C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:19]2[CH:10]3[CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:18][CH:17]2[C:16]2[CH:15]=[N:14][NH:13][C:12]=2[CH2:11]3)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (0.5 mL, 3 N solution) was added to a solution 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid ethyl ester (8) (321 mg, 0.783 mmol) in THF (2 mL). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc (2×5 mL) and the combined organic phases were dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-10-carboxylic acid (9) as a white solid. Retention time (min)=1.316, method [1], MS (ESI) 382.0 (M+H); 1H NMR (CDCl3) δ 7.56 (d, J=8.7 Hz, 2H), 7.30-7.22 (m, 3H), 5.30-5.25 (m, 1H), 4.54-4.45 (m, 1H), 2.80 (dd, J=17.0, J=7.7 Hz, 1H), 2.50 (d, J=17.0 Hz, 1H), 2.42-2.30 (m, 1H), 2.24-1.85 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[CH:19]=[CH2:18])=[CH:7][N:6]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Amino-2,4-dichloropyrimidine (Chempacific; 100 mg, 0.610 mmol) in THF (2 mL) was added triethylamine (170 μL, 1.22 mmol) followed by 3-Chloropropionyl Chloride (Aldrich; 64 mL, 0.671 mmol) The reaction was stirred at room temperature for 18 hrs.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:27]([O:29][P:30]([O:34]CC)[O:31][CH2:32][CH3:33])[CH3:28]>>[CH2:27]([O:29][P:30]([CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O:31][CH2:32][CH3:33])=[O:34])[CH3:28]
Reactant: CCOC(=O)C(Cc1ccccc1CCCBr)(NC(C)=O)C(=O)OCC
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)C(Cc1ccccc1CCCP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Yield: 49 %

Procedure:
A solution of 7.5 g (17.5 mmol) of ethyl 3-[2-(3-bromopropyl)phenyl]-2-acetamido-2-carboethoxypropanoate in 20 mL of freshly distilled triethylphosphite was stirred at reflux for 6 h. The excess P(OEt)3 and the volatile by-products were removed from the mixture by distillation under vacuum. The remaining viscous oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure to yield 4.2 g (49%) of the product as a viscous yellow oil. IR(neat): 1746, 1680 cm-1 (C=O). 1H NMR(CDCl3) δ 1.1-2.1 (complex m, 19H); 2.4-2.7 (t, 2H); 3.6 (5, 2H); 3.8-4.3 (m, 8H); 6.55 (s, 1H); 6.9-7.2 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH3:7])[C@@H:4]([C:8]([OH:10])=O)[O:3]1.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@H:4]1[O:3][C:2](=[O:1])[NH:6][C@@H:5]1[CH3:7])=[O:10])([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: C[C@H]1NC(=O)O[C@@H]1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: C[C@H]1NC(=O)O[C@@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 14.9 %

Procedure:
Following a procedure similar to that described in Example 1, but using 167 mg of (4R,5S)-2-oxo-4-methyloxazolidine-5-carboxylic acid, 234 mg of N-(2-nitrooxyethyl)amine nitrate and 0.30 ml of diphenylphosphoryl azide, 40 mg of the title compound were obtained as a colorless oil.