Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCOCC1.C(OC([N:13]1[C@H:17]([CH:18]([OH:27])[C:19]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[CH:21][N:20]=2)[CH2:16][C@H:15]([S:28][C:29]2[C@H:30]([CH3:46])[C@@H:31]3[C@@H:41]([C@H:42]([OH:44])[CH3:43])[C:40](=[O:45])[N:32]3[C:33]=2[C:34]([O:36]CC=C)=[O:35])[CH2:14]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1COCC1.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.ClCCl.C(OCC)(=O)C>[OH:44][C@@H:42]([C@H:41]1[C:40](=[O:45])[N:32]2[C:33]([C:34]([OH:36])=[O:35])=[C:29]([S:28][C@H:15]3[CH2:16][C@@H:17]([CH:18]([OH:27])[C:19]4[N:26]5[C:22]([S:23][CH:24]=[CH:25]5)=[CH:21][N:20]=4)[NH:13][CH2:14]3)[C@H:30]([CH3:46])[C@H:31]12)[CH3:43]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4ncc5sccn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Morpholine (0.026 ml) and 6.5 mg of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 65.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-5-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) and 12 mg of triphenylphosphine in a mixture of 0.55 ml of anhydrous THF with 0.55 ml of dry methanol, and the mixture is stirred in an argon atmosphere at room temperature for 30 min. Ethyl acetate (5 ml) and 1 ml of dichloromethane are added thereof, and the resultant precipitate is further washed with 5 ml of ethyl acetate and 1 ml of dichloromethane, followed by drying in vacuo to give 48.4 mg of a colorless powder. The colorless powder is successively purified by column chromatography on Cosmosil 40C18-PREP (water:methanol=5:1 to 3:1) and on Cosmosil 5C18-MS (water:methanol=3:1) to give 3.3 mg of the title compound as a colorless flocculent material.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Br:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1.CN(C=O)C>CCOC(C)=O.O>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]2)=[C:36]([C:41]([F:44])([F:42])[F:43])[CH:35]=1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
tert-Butyl 4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidine-1-carboxylate (2.65 g) and potassium carbonate (2.0 g) were added to a mixture of 4-bromo-2-(trifluoromethyl)benzenethiol (1.8 g) and DMF (20 mL) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was further stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, water (50 mL) and EtOAc (30 mL) were added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 80:20), whereby tert-butyl 4-(2-{[4-bromo-2-(trifluoromethyl)phenyl]sulfanyl}ethyl)piperidine-1-carboxylate (2.83 g) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:19])([C:8]1([OH:18])[CH:15]2[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:17][CH:9]1[CH2:10]3)[CH2:14]2)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl.[Cl-].[C:24]1([S+:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.O1CCOCC1>[F:1][C:2]([F:19])([C:8]1([OH:18])[CH:9]2[CH2:17][CH:13]3[CH2:12][CH:11]([CH2:16][CH:15]1[CH2:14]3)[CH2:10]2)[C:3]([O-:5])=[O:4].[C:37]1([S+:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)C(F)(F)C1(O)C2CC3CC(C2)CC1C3
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C([O-])C(F)(F)C1(O)C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 3.9 g of ethyl difluoro-(2-hydroxyadamantan-2-yl)acetate, prepared in Synthesis Example 1-8, 20 g of 1,4-dioxane, and 4.8 g of 25 wt % sodium hydroxide was stirred for 2 hours. To the reaction solution, 1.5 g of 35 wt % hydrochloric acid was added, and then 24 g of an aqueous solution of triphenylsulfonium chloride and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 4.7 g of the target compound, triphenylsulfonium difluoro-(2-hydroxyadamantan-2-yl)acetate as white crystals (yield 63%).
Reaction SMILES: C(O)C.[OH-].[Na+].[N+](C1C=CC(C([O:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](\[CH3:35])/[CH2:24][CH2:25]/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28])\[CH3:19])=O)=CC=1)([O-])=O>O.C1(C)C=CC=CC=1>[CH2:25]([CH2:24][C:23](=[CH:22][CH2:21][CH2:20]/[C:18](=[CH:17]/[CH2:16][OH:15])/[CH3:19])[CH3:35])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
100 g of ethanol, 7.88 g of sodium hydroxide and 30 g of water were added to 75 g of geranylgeranyl p-nitrobenzoate (containing 0.98 g of geranylneryl p-nitrobenzoate and 67.35 g of geranylgeranyl p-nitrobenzoate) obtained as a cake in Example 7. The reaction mixture was stirred at 50°C. for 2 hours and cooled down to room temperature, to which 300 g of toluene and 200 g of water were added. The resulting organic phase was separated and washed twice with 200 g of water, and concentrated under reduced pressure to give 55 g of crude geranylgeraniol. This crude product was subjected to simple distillation (154°C., 0.5 mmHg) to give 42.1 g of a main fraction. The results of the analysis of the obtained fraction with gas chromatography under the same conditions as in Example 14 revealed that it contained geranylgeraniol with a purity of 97.8% and geranylnerol with a purity of 1.2%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[N:13](CC3C=CC(OC)=CC=3)[C:12]([C:25]([NH:27]CC3C=CC(OC)=CC=3)=[O:26])=[C:11]([Cl:37])[CH:10]=2)[CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.CO>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[C:14](=[O:15])[NH:13][C:12]([C:25]([NH2:27])=[O:26])=[C:11]([Cl:37])[CH:10]=2)[CH:3]=1
Reactant: COc1ccc(CNC(=O)c2c(Cl)cc(Nc3cc(N)ncn3)c(=O)n2Cc2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1[nH]c(=O)c(Nc2cc(N)ncn2)cc1Cl
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide (6, 0.40 g, 0.77 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (20 mL) and trifluoromethanesulfonic acid (1 mL) at 0° C. The reaction mixture was stirred at 70° C. for 2 h. After completion, the reaction mixture was concentrated and basified by aq. ammonia at 0° C. The precipitate obtained was collected by filtration, washed with water and dried to obtain the crude. The crude was stirred with methanol, filtered, washed with pentane and dried to afford 5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (Cpd. No. 214) as yellow solid. Yield: 0.035 g, 16%; MS (ESI) m/z 281.05 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 6.53 (s, 2H), 6.18 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:112])[CH2:7][N:8]([CH2:104][C:105](=[O:111])[O:106][C:107]([CH3:110])([CH3:109])[CH3:108])[C:9](=[O:103])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:77][C:78]1[N:79]([CH2:83][C:84](=[O:102])[N:85]([CH2:94][C:95](=[O:101])[O:96][C:97]([CH3:100])([CH3:99])[CH3:98])[CH2:86][C:87](=[O:93])[O:88][C:89]([CH3:92])([CH3:91])[CH3:90])[CH:80]=[CH:81][N:82]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([C:41](=[O:76])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:48][C:49](=[O:68])[NH:50][C@H:51]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:23]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:23][C@H:22]([C:41](=[O:76])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[NH:48][C:49](=[O:68])[NH:50][C@H:51]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:52][CH2:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:77][C:78]1[N:79]([CH2:83][C:84]([N:85]([CH2:86][C:87]([O:88][C:89]([CH3:90])([CH3:91])[CH3:92])=[O:93])[CH2:94][C:95](=[O:101])[O:96][C:97]([CH3:98])([CH3:99])[CH3:100])=[O:102])[CH:80]=[CH:81][N:82]=1)[CH2:16][C:12]1[N:11]([CH2:10][C:9]([N:8]([CH2:104][C:105]([O:106][C:107]([CH3:109])([CH3:108])[CH3:110])=[O:111])[CH2:7][C:6](=[O:112])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:103])[CH:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of the above product, (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate in DMF (1.0 mL) was added piperidine (0.50 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 5% MeOH to 50% MeOH in DCM to afford (7S,14S,18S)-tri-tert-butyl 7-amino-1-(1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (40 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3) 6.96 (s, 2H), 6.83 (d, 2H), 6.37 (brs, 1H), 6.33 (brs, 1H), 5.05 (s, 4H), 4.87 (brs, 2H), 4.27-4.24 (m, 2H), 4.18 (s, 4H), 4.10 (s, 4H), 3.88 (d, J=15.2 Hz, 2H), 3.62 (d, J=15.2 Hz, 2H), 3.14-3.12 (m, 1H), 2.30-1.24 (m, 83H); MS (ESI), 674.1 (M/2+H)+.
Reaction SMILES: C(O)CCCCCCCO.FC1C=CC=CC=1CBr.[F:20][C:21]1[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=1[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33].FC1C=CC=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH2:74])[CH2:70][N:71]([CH3:73])[CH3:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH:74][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][C:22]1[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=1[F:20])[CH2:70][N:71]([CH3:72])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCOCc1ccccc1F
Agent: Cl
Agent: Fc1ccccc1CBr
Agent: O=C(O)CCCCCCCOCc1ccccc1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccccc1F

Procedure:
The title compound, m/e=397.4 ([M+H]+), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2-fluorobenzyl bromide, leading to 8-(2-fluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2-fluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2-fluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH2:17])[CH:5]=1.CCN(CC)CC.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([NH:17][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(-c2ccc(Cl)cn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
3-Amino-5-(5-chloro-pyridin-2-yl)-benzoic acid methyl ester (1.5 g, 5.71 mmol, from Preparation 2) and Et3N (2.39 mL, 17.13 mmol) were dissolved in 30 mL methylene chloride, and isobutyryl chloride (72 mL, 6.85 mmol) was added. The reaction mixture was stirred at room temperature for two hours, and then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.29 g of 3-(5-chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester, MS (M+H)=333.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].IC>O.CCOC(C)=O>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C=O)c1Br
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-3-hydroxybenzaldehyde (0.5 g, 2.4 mmol) was added potassium carbonate (0.77 g, 5.6 mmol), and the mixture was stirred for 5 minutes. Iodomethane (0.17 mL, 2.7 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with H2O (30 mL) and EtOAc (30 mL), and the organic layer was washed with 1N aqueous NaOH, then brine, dried over Na2SO4, decanted, and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:17])[S:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[C:11]1([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:23])=[CH:20][CH:19]=2)=[O:17])[S:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2cccs2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C(=O)N2CCc3ccoc3C2)cc1)c1cccs1
Reaction time: 8 h

Procedure:
To a solution of 0.173 g (1.084 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.38 g (1.6 mmol) of 4-(2-thenoyl)benzoic acid and 0.60 ml (4.3 mmol) of triethylamine in 30 ml of dichloromethane, 0.25 ml (1.6 mmol) of diethyl cyanophosphonate was added dropwise at room temperature, followed by overnight stirring. This mixture was poured into aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][OH:25])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][O:25][S:36]([CH3:35])(=[O:38])=[O:37])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of 8-[2,6-dichloro-3-(N-hydroxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (200 mg) and triethylamine (99.9 mg) in dry dichloromethane (2 ml) was added methanesulfonyl chloride (62.2 ml) under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was washed with water, saturated sodium bicarbonate solution and brine,dried over magnesium sulfate and concentrated in vacuo to give 8-[2,6-dichloro-3-(N-methanesulfonyloxyacetyl-N-methylamino)benzyloxy]-2-methylquinoline (220 mg) as colorless amorphous.
Reaction SMILES: [O-:1]Cl.[Na+].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C@:14]([CH3:21])([CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH:13]=[CH:12][C:11]=2[CH:22]=1)([O-:6])=[O:5]>ClCCl>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C@:14]([CH3:21])([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C@H:13]3[O:1][C@H:12]3[C:11]=2[CH:22]=1)([O-:6])=[O:5]
Reactant: [O-]Cl
Reactant: COC(OC)[C@]1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.05 M Na2HPO4 aqueous solution (16.6 ml) was added to 0.55 M NaOCl aqueous solution (41.5 ml, 22.8 mmol) at 0° C. To the aqueous solution was slowly added the solution of (2S)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (1.5 g, 5.7 mmol) and (S,S)-Mn(III) salen, catalyst (155 mg, 0.28 mmol) for an enantioselective epoxidation developed by Jacobsen in dichloromethane (8.5 ml). The solution was stirred at the room temperature for 12 hours. After the reaction was completed, the reaction mixture was filtered to remove the catalyst and the filtrate was extracted with dichloromethane (200 ml). The dichloromethane layer was washed with saturated brine solution, dried over anhydrous magnesium sulfate and concentrated to remove the dichloromethane. The crude product was purified by chromatography (developing solvent—n-hexane:ethyl acetate=4:1) to give (2S,3S,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran, the compound of formula 2 (1.4 g, yield: 88%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[OH:8][S:9]([O-:11])=[O:10].[OH-].[Ca+2:13].[OH-]>>[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[CH:5]1[C:4]([OH:7])=[CH:3][CH:2]=[C:1]([S:9]([O-:11])(=[O:10])=[O:8])[CH:6]=1.[Ca+2:13]
Reactant: O=S([O-])O
Reactant: Oc1ccccc1
Agent: [Ca+2]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(O)cc1

Procedure:
To 1000 g of 5% phenol sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium phenolsulfonate aqueous solution.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([OH:33])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl.CN(C)C=O>[N:40]1([C:31](=[O:33])[CH2:30][C:24]2([CH2:23][CH2:22][N:19]3[CH2:20][CH2:21][CH:16]([N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[O:10])[CH2:17][CH2:18]3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: C1COCCN1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)N4CCOCC4)CCCCC3)CC2)nc1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a solution of [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Example 3A-3) (300 mg) in dichloromethane (4 mL) was added N,N-dimethylformamide (1 drop) dropwise and then oxalyl chloride (0.087 mL) under ice cooling. The solution was stirred under ice cooling for 2 hours. A 2 mL aliquot of the reaction solution was taken and it was added to a solution of morpholine (288 mg) in dichloromethane (4 mL) dropwise under ice cooling. The solution was stirred under ice cooling for 1.5 hours. NH silica gel was then added to the reaction solution and it was concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1:1)] to give the title compound (60 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:24])[CH:8]=[C:7]1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(C)=O

Procedure:
To a solution of Example 179B (0.15 g, 0.5 mmol) in benzene (5 mL) was added celite (0.15 g), pyridinium dichromate (0.75 g, 2.0 mmol), and a solution of 70% t-butyl peroxide in water (0.25 mL, 2.0 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (10 mL), washed with 5% Na2S2O5 (10 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (5% to 15% ethyl acetate/hexane gradient) affored the product as colorless oil (0.12 g, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1 H), 0.76 (m, 7 H), 1.35 (m, 1 H), 1.73 (s, 3 H), 1.80 (m, 1 H), 2.09 (m, 1 H), 3.84 (s, 3 H), 4.51 (m, 2 H), 5.97 (s, 1 H), 7.43 (m, 2 H), 7.59 (m, 1 H), 8.20 (d, J=7.72 Hz, 1 H); MS m/z 317.1 (M+H)+.