Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[S:34][C:35]2[CH2:62][CH2:61][CH2:60][CH2:59][C:36]=2[C:37]=1[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][CH:50]=2)=[CH:43][CH:42]=1)=[O:39]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:32][C:33]1[S:34][C:35]2[CH2:62][CH2:61][CH2:60][CH2:59][C:36]=2[C:37]=1[C:38]([NH:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:57][CH:58]=2)=[CH:45][CH:46]=1)=[O:39])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 319 mg of 3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid, 0.10 mL of oxalyl chloride, 2.5 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 2.5 mL of dichloromethane was added to a mixture of 0.050 mL of pyridine, 250 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of dichloromethane, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 320 mg of methyl 4-(2-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow foamed solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+].CC1N(C(N(C)C)=O)C1.I[C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([N+:42]([O-:44])=[O:43])[CH:36]=2>[Cu](I)I.O>[N+:42]([C:37]1[CH:36]=[C:35]2[C:40]([CH:41]=[C:32]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[CH:33]=[N:34]2)=[CH:39][CH:38]=1)([O-:44])=[O:43]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc2cc(I)cnc2c1
Agent: I[Cu]I
Agent: CC1CN1C(=O)N(C)C
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: O
Product: O=[N+]([O-])c1ccc2cc(-n3cccn3)cnc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
Pyrazole (20 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (24 μl), copper iodide (14 mg), and cesium carbonate (73 mg) were added to an N,N-dimethylpropyleneurea (2 ml) solution containing 3-iodo-7-nitroquinoline (45 mg), followed by stirring at 70° C. for 2.5 hours in a nitrogen atmosphere. Water was added to the reaction solution, an insoluble precipitate was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 0:1), and a light yellow solid of 7-nitro-3-(1H-pyrazol-1-yl)quinoline (36 mg) was thus obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16]/[CH:17]=[CH:18]/[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[C:31]([Cl:32])=[C:30]([Cl:33])[CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:14])=[CH:11][CH:12]=2)[CH:6]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:32][C:31]1[C:30]([Cl:33])=[CH:29][CH:28]=[CH:27][C:26]=1[N:23]1[CH2:24][CH2:25][N+:20]([O-:42])([CH2:19]/[CH:18]=[CH:17]/[CH2:16][NH:15][C:13](=[O:14])[C:10]2[CH:11]=[CH:12][C:7]([C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)=[CH:8][CH:9]=2)[CH2:21][CH2:22]1
Reactant: O=C(NC/C=C/CN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NC/C=C/C[N+]1([O-])CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of PG01037, see U.S. 2006/0106030 (288 mg, 0.60 mmol) in 10 mL dichloromethane was treated at 0° C. with meta-chloroperbenzoic acid (0.16 g, 77%, 0.72 mmol). After stirring for 16 h at room temperature, the reaction mixture was successively washed with saturated sodium bicarbonate solution, H2O and brine and dried with sodium sulphate. The volatiles were removed in vacuo and the residue was purified by preparative thin layer chromatography. Yield: 93 mg (32%). Mp. (hydrochloride): foam. 1H NMR (CD3OD): δ 3.23-3.29 (m, 4H), 3.50-3.61 (m, 4H), 3.99 (d, J 6.5, 1H), 4.13 (d, J 4.6, 1H), 6.04-6.18 (m, 2H), 7.18 (dd, J 7.8, 3.9, 1H), 7.24-7.28 (m, 2H), 7.40 (m, 1H), 7.91-7.93 (m, 2H), 7.99 (d, J 8.4, 2H), 8.06 (d, J 8.7, 2H), 8.64 (dt, J 4.8, 1.2, 1H). 13C NMR (CDCl3): δ 41.0, 45.5, 63.5, 72.0, 119.3, 120.0, 121.6, 123.1, 125.4, 127.0, 127.3, 127.7, 128.0, 133.8, 134.6, 137.8, 137.9, 142.2, 149.3, 150.1, 156.4, 168.3. Anal. (C26H26Cl2N4O2:2HCl.0.5H2O) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23]C)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1O
Temperature: -78 °C

Procedure:
Methyl 5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-methoxybenzoate (1.485 g, 3.66 mmol) was dissolved in dichloromethane (DCM) (10 mL) and this was cooled to −78° C. A solution of boron tribromide in DCM (1M, 18.31 mL, 18.31 mmol) was then added dropwise and the reaction stirred under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight. Water (20 mL) was added dropwise to the reaction mixture and the crude product extracted to the organic phase of an aqueous work up between DCM and water. The aqueous phase was washed twice with DCM. The organic phase was then dried and concentrated in vacuo to give the crude product. LCMS [LCMS2] Rt 1.42 min, m/z (ES+) 392 (M+H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:26]2[C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:26]2[C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[CH2:22][O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Nc1cccc2c1C(=O)c1ccccc1CO2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1ccccc1CO2)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
In dimethylacetamide (3 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.17 g, 1.1 mmol), and thionyl chloride (80 μl, 1.1 mmol) was added thereto at -15° C., followed by stirring at -15 to -5° C. for one hour. To this reaction mixture was added 1-amino-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 4 (0.17 g, 0.77 mmol), and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (20 ml). The organic layer was washed successively with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give Compound 1 (80 mg, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:12]([OH:14])=[O:13])=[O:4].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C@@H:11]([NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[C:12](=[O:14])[O:13][CH:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[CH:20][CH:19]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1sccc1NC(C(=O)O)c1ccc(OC)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1sccc1N[C@@H](C(=O)OC1CN2CCC1CC2)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a solution of 2-(2-(methoxycarbonyl)thiophen-3-ylamino)-2-(6-methoxypyridin-3-yl)acetic acid (I59) (548 mg, 1.70 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (421 mg, 2.04 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (276 mg, 2.04 mmol), and (R)-quinuclidin-3-ol (259 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, and the insoluble was removed by filtration. The organic phase was washed twice with Na2CO3 and then brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM/MeOH=95/5) collecting first diastereomer 1 of C60 (140 mg, 19 yield) and then a mixture of diastereomers 1 and 2 of C60 (100 mg, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:31][CH3:30])[CH2:35][CH2:36]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: COCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCN1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1

Procedure:
In a similar manner to Step 1, of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(2-methoxyethyl)piperazine (29 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-methoxyethyl)piperazin-1-ylmethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C1CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (18 mg, 50 μmol) in dichloromethane (2 ml) was added triethylamine (100 μl), followed by cyclopropanecarbonyl chloride (15 mg, 150 μmol). The stirring was continued for 20 min at r.t., then the solvent was removed under reduced pressure, and the product purified by semi-preparative HPLC. Yield 20 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C@H:14]3[CH:16]([OH:19])[CH:17]([OH:18])[C@H:7]([C:8]4[C:13]3=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[Cl:1][C:2]1[C:15]2[CH:14]([CH:16]=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH:17]=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1C(O)[C@H]2c3ccccc3[C@@H]1c1cccc(Cl)c12
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=CC1c2ccccc2C(C=O)c2c(Cl)cccc21
Reaction time: 0.17 h

Procedure:
To a solution of 0.54 g. of cis-1-chloro-9,10-dihydro-9,10-ethanoanthracene-11,12-diol in 5 ml. of acetic acid at 35° C. is added 1.0 g. of lead tetraacetate, portionwise. The mixture is stirred for 10 minutes, cooled in an ice-water bath and the crystals which form are collected by filtration and washed with cold acetic acid, giving the desired product as colorless crystals, m.p. 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1.[C:23]([NH2:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: [O-][n+]1ccc(Cl)c2ccc(Cl)cc21
Solvent: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc(Cl)c2ccc(Cl)cc2n1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of example 289A (10.0 g, 46.7 mmol) and benzoyl chloride (23.5 g, 168 mmol) and benzamide (5.9 g, 49.1 mmol) was heated at 180° C. for 6 hours, cooled to room temperature, filtered. Yellow solid as washed with large quantity of water and ethyl acetate (20 mL) and dried under vacuum. MS (ESI(+)Q1MS m/z 318 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])=[CH:12][CH:11]=1.C(O)(=O)C.[N:30]1[C:39]2[C:38](=O)[CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][CH2:21][NH:22][CH:38]2[C:39]3[N:30]=[CH:31][CH:32]=[CH:33][C:34]=3[CH2:35][CH2:36][CH2:37]2)[C:23]([OH:25])=[O:24])=[O:16])=[CH:12][CH:11]=1
Reactant: NCCC[C@H](NC(=O)c1ccc(CNCc2ccccn2)s1)C(=O)O
Reactant: O=C1CCCc2cccnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)s1
Reaction time: 72 h
Yield: 27 %

Procedure:
The compound obtained in Example 14-4 (18.2 mg) was dissolved in methanol (0.6 ml), and acetic acid (0.06 ml), 5,6,7,8-tetrahydroquinolin-8-one (16 mg), and sodium cyanoborohydride (7 mg) were added. After 3 days, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol=5/1). 1 mol/l hydrochloric acid was added to the resulting colorless syrup, and the mixture was concentrated and dried under reduced pressure to obtain ahydrochloride of the title compound (6.7 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:17])[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[F:17][C:2]1([F:1])[CH:10]([OH:11])[C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)C(F)(F)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]1)C(O)C(F)(F)CC2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 113j (18 g, 74.01 mmol, 1.00 equiv) in ethanol (100 mL), followed by the addition of NaBH4 (2.8 g, 74.02 mmol, 1.00 equiv) in several batches at 0° C. (FIG. 14). The resulting solution was stirred at 5° C. for 10 min, quenched by the addition of 50 mL of saturated aqueous NH4Cl, concentrated under vacuum and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 18 g (99%) of 113k as a white solid.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[C:22]([O:31][CH3:32])[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:30]=[N:29][NH:28][CH:27]=3)=[C:22]([O:31][CH3:32])[N:21]=2)[CH2:13][C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)cc2)ccc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.8 %

Procedure:
10% palladium-activated carbon (60 mg) and acetic acid (2 mL) were added to a solution of (5R)-5-{(E)-2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethenyl}pyrrolidin-2-one (122 mg) in methanol (3 mL) in a hydrogen gas stream, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure. Saturated aqueous sodium bicarbonate was added to the residue, followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of (5R)-5-{2-(4-chlorophenyl)-2-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]ethyl}pyrrolidin-2-one as a yellow oil (77 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:22](O)(=[O:26])[CH2:23][CH2:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:22]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)O
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 129.9 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (359 mg, 1.107 mmol), butyric acid (146 mg, 1.66 mmol), HATU (631 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.286 ml, 1.66 mmol) in 5.5 ml of dimethylformamide in a 20 ml round-bottomed flask, equipped with a magnetic bar, is stirred for 8 hours at 60° C. and then left overnight at room temperature. The reaction medium is extracted with ethyl acetate and washed with water and then with 0.1 N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained (567 mg of pale yellow solid) is purified by chromatography on a 40 g Biotage silica cartridge, eluting with a 9/1 toluene/isopropanol mixture. After evaporating off the solvent, 239 mg of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester are obtained (white solid) in a yield of 55%.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C:24]2[C:28](=[O:29])[CH2:27][CH:26]([OH:30])[CH:25]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][C:33]([CH3:41])([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:34][SH:35].C(NC(C)C)(C)C>>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:25]([S:35][CH2:34][C:33]([OH:32])([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C@H:26]([OH:30])[CH2:27][C:28]2=[O:29])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCC=CCC1=CC(O)CC1=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Reactant: CCCCCC(C)(O)CS
Solvent: CC(C)NC(C)C
Product: CCCCCC(C)(O)CS[C@H]1[C@H](O)CC(=O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Analogously to Example 5, by reaction of 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-hept-5-enoic acid p-benzoylaminophenyl ester with 2-hydroxy-2-methyl-heptanethiol in the presence of diisopropylamine, 11α,15-dihydroxy-15-methyl-9-oxo-13-thia-5-prostenoic acid p-benzoylaminophenyl ester is obtained.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.B(F)(F)F.[CH3:20]COCC>CCOC(C)=O>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH2:20][O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCOCC
Agent: C=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: c1ccc(COC2COCOC2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
To a mixture of 17 (100 mg, 0.55 mmol) and paraformaldehyde (17 mg, 0.55 mmol) in EtOAc (10 mL), boron trifluoride etherate (70 μL, 0.55 mmol) was added and the reaction mixture was stirred at 23° C. for 4 h. The organic phase was washed with a saturated solution of NaHCO3, dried and the solvent was removed. The residue was purified by flash-chromatography eluting with a 1:4 mixture of EtOAc and hexanes to afford 84 mg (78%) of O-benzyl-1,3-dioxan-5-ol as a colourless oil. The above compound was dissolved in EtOAc (3 mL), Pd/C was added and the resulting suspension was stirred at rt under a hydrogen atmosphere. After 12 h, the catalyst was filtered off, the filtrate was evaporated in vacuo and the residue (39 mg, 100%) was used in the next step without further purification: 1H NMR (CDCl3) δ 4.93 (d, J=6.3 Hz, 1H), 4.76 (d, J=6.3 Hz, 1H), 3.94-3.84 (m, 4H), 3.64-3.61 (m, 1H), 2.78 (bs, 1H). 13C NMR (CDCl3) δ 94.0, 71.7, 64.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][C:35]1[N:40]=[C:39]2[N:41]=[C:42]([CH2:44][CH3:45])[NH:43][C:38]2=[C:37]([CH3:46])[CH:36]=1.[Cl:47][C:48]1[CH:65]=[C:64]([CH2:66]O)[CH:63]=[C:62]([CH2:68][CH:69]=[CH2:70])[C:49]=1[O:50][CH:51]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52]([O:54][CH3:55])=[O:53]>C1COCC1>[C:52]([CH:51]([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[O:50][C:49]1[C:62]([CH2:68][CH:69]=[CH2:70])=[CH:63][C:64]([CH2:66][N:41]2[C:39]3=[N:40][C:35]([CH3:34])=[CH:36][C:37]([CH3:46])=[C:38]3[N:43]=[C:42]2[CH2:44][CH3:45])=[CH:65][C:48]=1[Cl:47])([O:54][CH3:55])=[O:53]
Reactant: C=CCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a magnetically stirred solution of 0.541 g (2.06 mmol) of triphenylphosphine in 4 mL anhydrous THF was added 406 μL (2.06 mmol) of diisopropylazodicarboxylate at -20° C. The reaction mixture was stirred for 1 hour, followed by addition of a solution of 0.301 g (1.72 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine and 0.596 g (1.72 mmol) of the product of Step C in 6 mL THF. The reaction mixture was stirred 20 min at -20° C., then warmed to room temperature and stirred an additional 1 hour. The reaction mixture was then evaporated in vacuo and applied to a silica gel flash chromatography column. Elution with 50% EtOAc-hexane, evaporation of the purified fractions and drying in vacuo afforded 0.440 g (51%) of the title compound.