Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11](Br)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.O.C(Cl)Cl.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>[CH2:1]([C:8]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([F:28])[CH:21]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Cn1c(Cc2ccccc2)ncc(Br)c1=O
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: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(Cc3ccccc3)n(C)c2=O)cc1F
Temperature: 25 °C

Procedure:
2-Benzyl-5-bromo-3-methyl-3H-pyrimidin-4-one (Step 3, 11.1 g, 39.9 mmol), 4-methoxy-3-fluorophenylboronic acid (10.12 g, 59 mmol) and Pd(PPh3)4 (2.3 g, 1.9 mmol) in 2 M Na2CO3 (100 mL) and dioxane (150 mL) were heated to 90° C. for 1 h. The reaction was cooled to RT, and diluted with H2O and CH2Cl2. The organics were separated and washed with brine, dried (Na2SO4) and filtered through a plug of silica. The filtrate was concentrated under reduced pressure. Et2O/hexane (1:1) were added and the reaction was concentrated under vacuum to a brown solid. The solid was triturated with 20% Et2O/hexane to afford the title compound as a yellow solid. MS (ESI pos. ion) m/z: 325.2. Calc'd for C19H17FN2O2: 324.13.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=O)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:26].O>C(O)(=O)C.O1CCOCC1>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:26][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(-c2cn3c(Br)ccc3c(=O)[nH]2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 5-bromo-1-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.15 g, 0.43 mmol) and ammonium acetate (170 mg, 2.21 mmol) in glacial acetic acid (2 mL) was heated at 130° C. overnight. The reaction was stopped, and the recovered starting material was suspended in 1,4-dioxane (2 mL), treated with ammonium acetate (170 mg, 2.21 mmol) and then was heated in a sealed tube at 120° C. for 5 h. At this time, the reaction was treated with additional ammonium acetate, and the mixture continued stirring at 120° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water (2×) and dried in vacuo to afford 6-bromo-3-(4-methoxy-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (78 mg, 55%) as red solid. 1H NMR (DMSO-d6) δ ppm 7.54-7.63 (m, 4H), 7.03 (d, J=9.0 Hz, 2H), 6.96 (d, J=1.3 Hz, 1H), 3.80 (s, 3H). LC-MS calcd. for C14H12BrN2O2 [(M+H)+] 319, obsd. 319.0.
Reaction SMILES: C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O.[OH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]3[S:28][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][N:25]3[C:24]=2[CH:36]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH:19]([C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]3[S:28][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][N:25]3[C:24]=2[CH:36]=1)=[O:18]
Reactant: CCOC(=O)c1cn2c(nc3ccc(CO)cc32)s1
Agent: O=C([O-])O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c(nc3ccc(C=O)cc32)s1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Triethylamine (39.02 ml) and sulfur trioxide-pyridine mixture (55.71 g) were added to a DMSO (300 ml) solution of ethyl 6-hydroxymethylthiazolo[3,2-a]benzimidazole-2-carboxylate (19.34 g). The reaction mixture was stirred for 2 hours accompanied by exothermic reaction. After completion of the reaction, the reaction mixture was carefully added to saturated sodium bicarbonate aqueous solution. The insoluble matter was collected by filtration, washed with water and then dried by heating under a reduced pressure to obtain the pale ivory-colored title compound (19.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Br)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 4-bromo-2-methoxy-6-methyl-benzaldehyde (1.25 g, 5.45 mmol) in tert-butanol (21.7 ml) is added a solution of sodium chlorite (0.98 g, 10.9 mmol) and monosodium phosphate (4.25 g, 27.3 mmol) in water (11 ml). To the solution is added 2-methyl-2-butene (4.63 ml, 43.7 mmol). The resulting homogeneous solution is stirred at RT for 30 min. After completion of the reaction, the solvent is evaporated and the residue is diluted with water and acidified with 1 M hydrochloric acid to pH=1 and extracted with methyl tert-butyl ether (3×40 ml). The combined organic layers are extracted with 1 M sodium hydroxide solution which is further acidified with 6 M hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer is washed with brine (40 ml), dried over sodium sulfate and concentrated to yield 4-bromo-2-methoxy-6-methyl-benzoic acid (1.2 g, 4.89 mmol, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[CH3:11][C:12](OC(C)=O)=[O:13].[C:18]([O-])(=[O:20])[CH3:19].[Na+]>>[C:12]([N:1]([C:18](=[O:20])[CH3:19])[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1)(=[O:13])[CH3:11]
Reactant: Nc1nsc2ccccc12
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)N(C(C)=O)c1nsc2ccccc12
Reaction time: 48 h

Procedure:
A mixture consisting of 11.7 g of 3-aminobenzisothiazole, 126 ml of acetanhydride and 0.2 g of sodium acetate is stirred for 48 hours at 100°-110? C. After concentration by evaporation and then chromatography (silica gel; eluant: hexane/diethyl ether 2:1), the product is recrystallised from hexane/diethyl ether to thus obtain the compound No. 1 of the formula ##STR10## having a melting point of 65°-67° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:26][C:27]#[N:28])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][C:16]=2[CH3:17])=[N:8][CH:9]=1)([O-])=O.CN1CCCC1=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:28][C:27]1[S:26][C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][C:16]=3[CH3:17])[N:8]=[CH:9][C:4]=2[N:1]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc2nc(N)sc2n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of the above-mentioned crude product of tert-butyl {3-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]-4-methylphenyl}carbamate in ethanol (120 mL)/1-methylpyrrolidin-2-one (80 mL) were added reduced iron (6.68 g, 120 mmol) and aqueous solution (20 mL) of calcium chloride (13.3 g, 120 mmol), and the mixture was stirred at 100° C. for 16 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added water (350 mL), and the mixture was extracted with ethyl acetate (200 mL, 2×80 mL). The combined organic layer was washed with saturated brine (50 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (5.24 g, 35%) as a gray solid.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@@H:2]1O>O.C(O)(=O)C>[OH:10][C@@H:3]1[C@@H:4]([OH:9])[C@H:5]([OH:8])[C:6](=[O:7])[CH:1]=[CH:2]1
Reactant: O=C1C[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Yield: 33 %

Procedure:
0.15 g of 2-deoxy-scyllo-inosose synthesized according to the method described in WO 2006/112000 was added to 1.35 mL of 0.5 N acetic acid water, and the resulting mixture was heated at 120 degrees centigrade for 1 hour. After the completion of the reaction, a quantitative analysis was carried out using HPLC and as a result, (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one was obtained at a yield of 33%. At this time, 44% of the raw material of 2-deoxy-scyllo-inosose was collected.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:20])=[O:9]
Reactant: COC(=O)c1ncccc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1c(C)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of methyl 3-methylpicolinate (2 g, 14.8 mmol) and m-CPBA (3 g, 17.8 mmol) in DCM (35 mL) was stirred at RT overnight. Then the mixture was washed with NaHSO3 (a.q.) and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH=200:1) to give the product of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (1.89 g, yield: 79%). 1H-NMR (CDCl3, 400 MHz) δ 8.05 (d, J=6.0 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.23 (s, 3H). MS (M+H)+: 168.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13].[Cl:89][C:90]([Cl:94])([Cl:93])[C:91]#[N:92]>C(Cl)Cl>[Cl:89][C:90]([Cl:94])([Cl:93])[C:91](=[NH:92])[OH:14].[C:12]([O:15][C@@H:16]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@H:19]([CH3:30])[O:18][C@H:17]1[O:31][C@@H:32]1[C@@H:38]([OH:39])[C@H:37]([CH3:40])[O:36][C@@:34]([C@H:41]2[O:70][C@H:69]([CH2:71][O:72][CH2:73][C:74]3[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=3)[C@@H:60]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C@H:51]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C@H:42]2[O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([OH:35])[C@@H:33]1[O:80][C:81](=[O:88])[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=1)(=[O:14])[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](O[C@@H]2[C@@H](O)[C@H](C)O[C@](O)([C@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: N=C(O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DBU (100 μL) was added at 0° C. to a solution of the hemiacetal 522 (3.8 g, 3.58 mmol) in DCM (40 mL) containing trichloroacetonitrile (4 mL). The mixture was stirred for 30 min at 0° C., and volatiles were evaporated. Flash chromatography (solvent B, 7:3+0.2% Et3N) of the crude material gave the donor 505 (3.9 g, 90%) as a while solid; 1H NMR (α anomer): δ 8.75 (s, 1H, NH), 8.13-7.12 (m, 25H, Ph), 6.40 (d, 1H, J1,2=2.4 Hz, H-1C), 5.54 (br s, 1H, H-2B), 5.49 (dd, 1H, J2,3=2.9 Hz, H-2C), 5.26 (d, 1H, J1,2=2.8 Hz, H-1E), 5.20 (dd, 1H, J2,3=J3,4=10.0 Hz, H-3B), 5.17 (br s, 1H, H-1B), 4.96 (dd, 1H, H-4B), 4.99-4.41 (m, 8H, OCH2), 4.34 (m, 1H, H-3C), 4.14-4.02 (m, 3H, H-3E, 5E, 5C), 3.87 (m, 1H, H-4C), 3.78 (dq, 1H, J4,5=9.5, J5,6=6.1 Hz, H-5B), 3.70 (m, 2H, H-6aE, 6bE), 3.65 (dd, 1H, J2,3=3.4, J3,4=9.8 Hz, H-2E), 3.57 (pt, 1H, J2,3=J3,4=9.4 Hz, H-4E), 1.86, 1.83 (2s, 9H, CH3CO), 1.42 (d, 3H, J5,6=6.2 Hz, H-2C), 0.98 (d, 3H, H-6B); 13C NMR (α anomer): δ 170.3, 170.1, 169.9, 166.1 (4C, C═O), 160.7 (C═NH), 139.2-127.8 (Ph), 100.2 (C-1B), 98.1 (C-1E), 94.8 (C-1C), 91.2 (CCl3), 82.4 (C-4C), 82.0 (C-3E), 81.2 (br s, C-2E), 78.5 (br s, C-3C), 78.3 (C-4E), 75.9, 75.4, 74.3, 73.3 (4C, CH2Ph), 71.8 (C-5E), 71.7 (C-2C), 71.3 (C-4B), 70.8 (br s, C-5C), 70.0 (C-2B), 69.3 (C-3B), 69.2 (C-6E), 67.6 (C-5B), 21.3, 21.0, 20.9 (3C, CH3CO), 18.9 (C-6C), 17.1 (C-6B). Anal. Calcd. for C61H66Cl3NO18: C, 60.67; H, 5.51; N, 1.16%. Found: C, 60.53; H, 5.48; N, 1.38%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:22]([O-:25])([O-])=[O:23].[K+].[K+]>CC(C)=O>[CH2:17]([O:15][C:12]1([O:23][C:22]2([O:25][CH2:11][CH2:10][CH2:9][CH2:14][CH3:13])[CH:21]=[CH:20][C:19]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:18][CH2:17]2)[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH2:13]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOC1(OC2(OCCCCC)C=CC(OCc3ccccc3)=CC2)C=CC(OCc2ccccc2)=CC1
Temperature: 80 °C

Procedure:
30 g (150 mmol) 4-(benzyloxy)phenol and 22.35 g 1-bromo-pentane (150 mmol) were dissolved in 250 ml acetone. The solution was heated to 80° C. and stirred with a mechanical stirrer. At this temperature, 118.5 g K2CO3 (1.09 mol) was added in one portion. The resulting heterogeneous solution was allowed to stir at 80° C. for 16 hours. The reaction was monitored by TLC until completion. Excess K2CO3 and the byproduct KBr were removed by filtration. The solution was then acidified with concentrated HCl. Evaporation of the solvent resulted in a light yellow colored oil. No further purifications were needed to obtain the 1-pentyloxy-4-(benzyloxy)phenyl ether intermediate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13]([O-:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+].O>C(O)C>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][S:20][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C=Cc1cnc(C)c(O)c1CSC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 65 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine in 1 liter of ethanol under nitrogen there was added 96 g. of potassium thiobenzoate in 200 ml. of water over 30 minutes. After 1 hour, the ethanol was evaporated at 40° C. and the aqueous solution was extracted with 4 × 300 ml. of ethyl acetate. The extract was washed with 1 × 75 ml. of water, dried over magnesium sulfate and concentrated to dryness to give 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=[C:11]([CH:23]=[O:24])[CH:10]=1.[Cl:25]N1C(=O)CCC1=O.O>O1CCCC1.CN(C)C=O>[Cl:25][C:12]1[N:13]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[CH:10][C:11]=1[CH:23]=[O:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cc(-c2c(F)cccc2F)n(S(=O)(=O)c2cccnc2)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2c(F)cccc2F)n(S(=O)(=O)c2cccnc2)c1Cl
Reaction time: 15 h
Yield: 58.2 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.06 g) and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-yellow oil (yield 160 mg, 58%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26]([NH:25][C@H:16]([C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:20][CH:19]=2)=[O:36])[CH2:29]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirred mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (200 mg, 0.34 mmol) and cesium carbonate (330 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL) was added ethyl bromoacetate (75 μL, 0.67 mmol). After stirring at ambient temperature for 2 h, the reaction was diluted with ethyl acetate (50 mL), washed with water (3×40 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by silica gel chromatography (60:40; ethyl acetate:hexane) to afford the title compound (162 mg, 71%) as a white foam. 1H NMR (DMSO-d6): δ 0.78 (6H, dd), 1.16 (3H, t), 1.17-1.43 (2H, m), 1.92 (1H, m), 2.35 (1H, t), 2.64-2.78 (3H, m), 2.88-3.01 (2H, m), 3.24-3.29 (1H, m), 3.40-3.60 (4H, m), 3.70 (1H, t), 3.78-3.82 (1H, m), 4.10 (2H, q), 4.65 (2H, s), 4.81 (1H, q), 5.00 (1H, d), 5.46 (1H, d), 6.12 (2H, s), 6.73 (2H, d), 7.02-7.07 (3H, m), 7.20-7.28 (3H, m); MS: 679 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]([CH3:20])[C:10]=2[CH:21]=1.[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:1][C:2]2[CH:24]=[CH:23][CH:22]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:13]=[C:12]([NH:14][C:15]([CH:17]5[CH2:19][CH2:18]5)=[O:16])[N:11]([CH3:20])[C:10]=4[CH:21]=3)[CH:3]=2)=[O:34])[CH2:28][CH2:29]1)#[N:26]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(N)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cc21
Yield: 26.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide (168 mg, 522 μmol) produced in Example C4(vi), 3-(1-cyanocyclopropyl)benzoic acid (303 mg, 1.62 mmol), pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 1.99 mmol) and N,N-dimethylpyridine-4-amine (39.1 mg, 320 μmol) as starting materials, and in the same manner as in Example C4(vii), the title compound (67.4 mg, 26%) was obtained as colorless crystals.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:29])[CH2:23][O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=3)[C:15]([OH:17])=O)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:33]1[N:38]=C(OC)N=C(OC)[N:34]=1.C[N:44]1[CH2:49][CH2:48]OC[CH2:45]1.CNN1C=CC=N1>O.C(#N)C>[N:1]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C@@H:22]([CH3:29])[CH2:23][O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:20]=3)[C:15]([NH:38][C:33]3[CH:48]=[CH:49][N:44]([CH3:45])[N:34]=3)=[O:17])=[CH:30][CH:31]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: CN1CCOCC1
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Agent: CNn1cccn1
Solvent: CC#N
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)phenoxy]-5-[(1S)-2-tert-butoxy-1-methylethoxy]benzoic acid (6.18 mmol, 2.64 g) and acetonitrile (18.5 mL) were charged to a vessel. The contents were stirred and cooled to 0° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (6.78 mmol, 1.19 g) was added to the slurry followed by an addition of N-methylmorpholine (8.11 mmol, 0.82 g), added over 20 minutes. The reaction was held for approximately 1 hour at 0° C. and allowed to warm up to ambient. N-methylaminopyrazole (6.79 mmol, 0.66 g) was added over 20 minutes and the reaction held at ambient temperature until the reaction was complete. Water (7 mL) was added to the reaction mixture and the acetonitrile removed by distillation at reduced pressure. Ethyl acetate (32 mL), water (7 mL) and sodium bicarbonate solution (10% by weight, 26 mL) were added to the resultant slurry. The bi-phasic liquor was separated and the ethyl acetate phase sequentially washed with further sodium bicarbonate (10% by weight, 13 mL), water (13 mL), 2M hydrochloric acid (2×13 mL), and then with water (2×13 mL). The washed organic phase was azeodistilled at reduced pressure, removing water and solvent, to give a light brown foam (2.9 g, 90% yield).
Reaction SMILES: O=[C:2]([C:14]1[S:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]2[S:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCc1ccc(C(=O)CCCCCc2ccccc2)s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: O=C(O)CCCCc1ccc(CCCCCCc2ccccc2)s1

Procedure:
This compound is prepared analogously to Example 1b from: 22.8 g of methyl 5-[5-(1-oxo-6-phenylhexyl)-thien-2-yl]-valerate, 11.1 g of potassium hydroxide, 250 ml of triethylene glycol and 7.0 g of hydrazine hydrate.