Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3C=CC(Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.[NH:41]1CC[CH2:44][CH2:43][CH2:42]1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.CC1C=CC(O)=NC=1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:18]=[CH:19][C:43]([CH3:44])=[CH:42][N:41]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C1CCNCC1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: Cc1ccc(O)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(O[C@@H](C)[C@H]2CCN(C(=O)C3CCN(c4ccc(C#N)cn4)CC3)C[C@@H]2c2ccc(Cl)cc2)nc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 5-methyl-pyridin-2-ol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous light yellow oil. MS (m/e): 544.4 [(M+H)+].
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[N:24]([CH:30]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[CH2:23]3)=[O:17])=[CH:11][C:10]=1[CH3:38])(C(C)(C)C)(C)C.Cl>C(Cl)Cl.CCOCC>[O:37]=[C:31]1[CH:30]([N:24]2[CH2:23][C:22]3[C:26](=[CH:27][CH:28]=[C:20]([CH2:19][NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH3:38])[CH:11]=4)=[O:17])[CH:21]=3)[C:25]2=[O:29])[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1
Reactant: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
To a solution of the product from Step 3 (0.5 g, 0.9 mmol) in methylene chloride (20 mL) was added 2N HCl in ether (2 mL). The mixture stirred for 16 h at ambient temperature. The precipitated product was isolted by filtration, and was rinsed with methylene chloride (20 mL) and dried under vacuum, providing 0.4 g of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-hydroxy-3-methylphenyl)urea as an off-white solid, in quantitaive yield; HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 1.88 min (96.94%); mp 210-212° C.; 1H NMR (DMSO-d6) δ 1.94-2.18 (m, 4H), 2.30-2.51 (m, 1H), 2.58-2.72 (m, 1H), 2.87-3.06 (m, 1H), 4.25-4.56 (m, 4H), 5.15 (dd, J=5.0, 13.3 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 7.02 (dd, J=2.5, 8.6 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.73 (d, J=7.7 Hz, 1H), 8.32 (br. s., 1H), 11.02 (s, 1H); 13C NMR (DMSO-d6) δ 16.15, 22.51, 31.20, 42.77, 47.12, 51.56, 114.47, 117.11, 121.32, 121.83, 122.88, 123.61, 126.86, 130.22, 131.72, 142.35, 145.17, 150.10, 155.58, 170.99, 172.85; LCMS MH=423; Anal. Calcd for C22H22N4O5+0.25 CH2Cl2: C, 60.23; H, 5.11; N, 12.63. Found: C, 60.14; H, 5.43; N, 12.54.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28]COC(C)=O.[N+](=C[Si](C)(C)C)=[N-].C(O)(=O)C>CO>[CH3:28][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:22])[NH:14][CH2:15][CH:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
Combined ethyl 5-hydroxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (0.6 g, 1.603 mmol), EtOAc (30 mL), and MeOH (10 mL) then added (diazomethyl)trimethylsilane, 2.0 M solution in hexanes (2.60 mL, 5.21 mmol) at 23° C. over 20 minutes. The reaction mixture was stirred at 23° C. for 1 hour, quenched with acetic acid (0.206 mL, 3.61 mmol), and the mixture was stirred for 2 hours at 23° C. The reaction mixture was concentrated to give an orange-brown oil which was purified by medium pressure chromatography using an eluent of 100% EtOAc on a 25 g silica gel column (Single Step™) to give the title compound (408 mg, 65.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16-1.27 (m, 2H) 1.31 (t, J=7.07 Hz, 3H) 1.62 (dd, J=12.88, 2.02 Hz, 2H) 1.81 (ttd, J=11.13, 11.13, 7.31, 7.31, 3.79 Hz, 1H) 3.20 (t, J=6.44 Hz, 2H) 3.27 (td, J=11.68, 2.15 Hz, 2H) 3.85 (dt, J=9.35, 2.27 Hz, 2H) 4.14 (s, 3H) 4.27 (q, J=7.07 Hz, 2H) 7.79 (dd, J=8.34, 0.76 Hz, 1H) 8.03 (s, 1H) 8.38-8.43 (m, 1H) 8.78 (t, J=5.81 Hz, 1H) 8.98 (dd, J=2.53, 0.76 Hz, 1H). MS m/z [M+H]+ 389.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][C:10]=1[CH3:18].C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[C:10]([CH3:18])[CH:11]=3)=[O:17])[CH2:30][C:29]=12
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a stirred solution of 2′-methoxy-2-methyl-biphenyl-4-carboxylic acid (0.250 g; 1.032 mmol) in dichloromethane (20 mL) was added one drop of N,N-dimethylformamide followed by dropwise addition of oxalyl chloride (0.144 mL; 1.65 mmol). After stirring for one hour, the mixture was thoroughly evaporated to give the crude acid chloride as a brown oil. The acid chloride then was dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo [2,1-c][1,4] benzodiazepine (0.57 g, 3.10 mmol) and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane (15 mL). After stirring for 1 hour, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography using a solvent gradient of 5 to 15% ethyl acetate in hexane yielded a white foam which crystallized upon sonication in ethanol/hexane to give 0.42 g of the desired title product as a white solid, m.p. 133-135° C. MS [(+)ESI, m/z]: 409 [M+H]+. Anal. Calcd. for C27H24N2O2: C, 79.39; H, 5.92; N, 6.86. Found: C, 79.16; H, 5.87; N, 6.90.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][OH:9]
Reactant: CCOC(=O)c1cccc(OCCF)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(OCCF)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Thirty grams of ethyl 3-hydroxybenzoate, 14.9 g of 1-fluoro-2-chloroethane and 37.4 g of anhydrous potassium carbonate were added to 130 ml of dimethylformamide. With stirring, the reaction was carried out at 120° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure to give 32.6 g of crude ethyl 3-(2-fluoroethoxy)benzoate. The resulting crude ethyl 3-(2-fluoroethoxy)benzoate (32.6 g) was added at 40° to 45° C. to a solution of 6.0 g of lithium aluminum hydride in 200 ml of dry tetrahydrofuran, and the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature. Ethanol and water in this order were added to the mixture to decompose the unreacted lithium aluminum hydride. Water was then added, and the mixture was extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was removed to give 26.0 g of crude 3-(2-fluoroethoxy)benzyl alcohol This compound was chlorinated to give 30.0 g of 3-(2-fluoroethoxy)benzyl chloride.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([C:12]1[O:16][CH:15]=[N:14][C:13]=1[CH2:17]Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:19][N:20]=[C:21]=[S:22]>>[CH3:19][NH:20][C:21]([NH:3][CH2:2][CH2:1][NH:4][CH2:17][C:13]1[N:14]=[CH:15][O:16][C:12]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:22]
Reactant: ClCc1ncoc1Cc1ccccc1
Reactant: NCCN
Reactant: CN=C=S
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolymethyl)-ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxaxzolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine
Reaction SMILES: [CH3:1][O:2][C:3](=O)O.OC[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1CCCCC1>[CH3:13][O:12][CH2:11][CH2:10][N:9]1[CH2:14][CH2:1][O:2][CH2:3][CH2:8]1
Reactant: OCCN1CCOCC1
Reactant: COC(=O)O
Solvent: C1CCCCC1
Product: COCCN1CCOCC1

Procedure:
Using the apparatus employed in Examples 15-27, a 20 percent (volume) solution of 4-(2-hydroxyethyl)morpholine methyl carbonate Prepared in Example 30 in cyclohexane was passed through 6.0 grams of Catalyst J at a temperature of 300° C. and a liquid feed rate of 0.27 milliliters per minute. A total of 7.4 grams of product was recovered. Capillary gas chromatographic analysis (area percent) of this material showed 67.7 percent selectivity to 4-(2-methoxyethyl)morpholine at 100 percent 4-(2-hydroxyethyl)morpholine methyl carbonate conversion.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([NH:11][C:9]([NH:8][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[N:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH:7]=[CH:6][N:5]=1)=[O:10])[CH3:13]
Reactant: CCNC(=O)Nc1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCNC(=O)Nc1cc(-c2ccc(F)nc2)ccn1
Yield: 84.3 %

Procedure:
N-(4-bromopyridin-2-yl)-N′-ethylurea (Intermediate 33, 0.40 g, 1.64 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.057 g, 4.92 mmol), tetrakis triphenyl phosphine palladium (0.189 g, 0.16 mmol), and cesium carbonate (1.16 g, 4.92 mmol) were taken in a microwave vial and degassed with nitrogen. A dioxane:water (4:1, 10 mL) solution was added to the vial and the mixture was microwaved at 110° C. for half an hour. The palladium was filtered off, and the reaction was partitioned between water and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, water and brine, then dried over magnesium sulfate, and concentrated. The residue obtained was washed with acetonitrile to give the title compound as a white solid (360 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:49]=[CH:48][C:6]([CH2:7][C:8]2[CH:9]=[C:10]([C:24]3([O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]3[O:27][C:28](=[O:30])[CH3:29])O)[CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[C:13]=2[CH3:14])=[CH:5][CH:4]=1)[CH3:2].OO.C(OCC)(=[O:54])C.[OH2:58]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:13]([CH3:14])=[C:12]([OH:54])[CH:11]=[C:10]([C:24]3([O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]3[O:27][C:28](=[O:30])[CH3:29])[OH:58])[CH:9]=2)=[CH:48][CH:49]=1)[CH3:2]
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(B3OC(C)(C)C(C)(C)O3)c2C)cc1
Reactant: O
Reactant: CCOC(C)=O
Agent: OO
Solvent: CC(=O)O
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(O)c2C)cc1

Procedure:
A solution of 3-(4-ethylbenzyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (0.64 g) in acetic acid (3 mL) is treated with hydrogen peroxide solution (0.2 mL, 35% in water) for 3 h. Then, ethyl acetate and water are added. The organic layer is separated and washed with aqueous NaHCO3 solution, water and brine. After drying (magnesium sulphate) of the organic solution, the solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1->1:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Br)c1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
To a mixture of 0.50 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.58 g of 65% m-chloroperbenzoic acid was added. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 3-bromo-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 28”).
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].[CH2:14](N(CC)CC)C>ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:5]1[S:1][N:2]=[N:3][C:4]=1[CH3:14])=[O:7]
Reactant: O=C(Cl)c1cnns1
Reactant: CNOC
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1snnc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 1,2,3-thiadiazole-5-carbonyl chloride (10.00 g, 61.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.20 g, 73.8 mmol) in dichloromethane (200 ml) was added triethylamine (20.6 ml, 147.6 mmol) at 0° C. After stirring for 2 h at room temperature, the mixture was diluted with dichloromethane (300 ml), washed with water (200 ml×2) and dried (MgSO4). Removal of solvent gave 11.31 g (98%) of the title compound as brown crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>CN(C=O)C.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 mL) and THF (1 mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature under N2. After 30 min of stirring, the reaction mixture was cooled to 0° C. and 2-chloro-N,N-dimethylacetamide (11 mL, 0.14 mmol) was added. The reaction mixture was stirred for 5 min at 0° C. and then for 10 h at room temperature. The mixture was purified by preparative HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of Pd—C (10 mg). The mixture was stirred open to the atmosphere overnight at room temperature. The reaction mixture was filtrated and purified by preparative HPLC providing 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS (ESI) (M+H+) 462.0.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1C.[CH3:17]C1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:33]1[N:34]([C:38]2[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=2[C:40](O)=[O:41])[N:35]=[CH:36][CH:37]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[CH3:17][C:4]1[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:40]([C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[N:34]4[N:35]=[CH:36][CH:37]=[N:33]4)=[O:41])[CH2:15]3)[CH2:10]2)=[N:6][CH:7]=[CH:2][N:3]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1ncc(N2C[C@@H]3CCNC[C@@H]32)nc1C
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1nccnc1N1C[C@@H]2CCN(C(=O)c3ccccc3-n3nccn3)C[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(3-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 31) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.1 [M+H]+. 1H NMR (CD3OD): 8.08-8.01 (m, 1H), 7.98-7.88 (m, 2H), 7.84-7.78 (m, 1H), 7.70-7.38 (m, 4H), 4.55-3.84 (m, 4H), 3.75-3.11 (m, 3H), 2.70-2.29 (m, 4H), 2.22-1.48 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11]=2[O:10][CH:9]=1)(=O)=O.[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([SH:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:22][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[C:11]2[O:10][CH2:9][CH:8]([CH2:7][CH2:6][S:31][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:30])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CC(S)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c(CCOS(C)(=O)=O)coc12
Product: COC(=O)COc1cccc2c1OCC2CCSC(C)(c1ccccc1)c1ccccc1
Yield: 79.9 %

Procedure:
The same process as Example 17 was repeated except that methyl (3-(2-(methanesulfonyloxy)ethyl)benzofuran-7-yloxy)acetate (284 mg) and 1,1-diphenylethanethiol (240 mg) were used to obtain the object compound (310 mg, yield 95%).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11](O)([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@:11]2([CH3:45])[O:8][C:7](=[C:9]([CH3:47])[CH2:10]2)[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@]2(C)CC(C)=C(O2)[C@H](C)[C@@H](O)[C@]1(C)O
Yield: 71 %

Procedure:
A solution (710.0 mL) of EMA (erythromycin A; 104.4 g, 16.90 mmol) in glacial acetic acid was stirred at room temperature for 2 hr, and aqueous NaHCO3 solution was slowly added to neutralize the solution. The reaction mixture was extracted with CHCl3, and the organic layer was dried over Na2SO4. The residue was filtrated, and the filtrate was concentrated to give a crude product (99.30 g). The obtained crude product was dissolved in CHCl3 (250 mL), and the solution was recrystallized by adding hexane (50 mL) to give EM201 (74.50 g, 71%) as a white powder.
Reaction SMILES: CS(C)=O.[CH3:5][O:6][C:7](=[O:38])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@@H:14]1[C@@H:18]([C@@H:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)/[CH:20]=[CH:21]/[C:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:17]([CH3:36])[CH2:16][CH:15]1[OH:37].C(N(CC)CC)C>[Cl-].[Na+].O>[CH3:5][O:6][C:7](=[O:38])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][C@@H:14]1[C@@H:18]([C@@H:19]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)/[CH:20]=[CH:21]/[C:22]([CH3:27])([CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:17]([CH3:36])[CH2:16][C:15]1=[O:37]
Reactant: CCCCC(C)(C)/C=C/[C@H](OC1CCCCO1)[C@H]1[C@H](C)CC(O)[C@@H]1C/C=C\CCCC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCC(C)(C)/C=C/[C@H](OC1CCCCO1)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC

Procedure:
A DMSO (60 mL) solution of the crude optically active (5Z,11alpha,13S,14E)-13-(2-tetrahydropyranyloxy)-11,16,16-trimethyl-9-hydroxyprosta-5,14-dien-1-oic acid methyl ester (11.1 g) was treated with triethylamine (22 mL) and then dropwise with a DMSO (60 mL) solution of sulfur trioxide pyridine complex (11.1 g) during 30 minutes while stirring. After 31/2 hours, the reaction mixture was poured into a slush of ice and brine (600 mL) and extracted with hexane (3×150 mL). The combined extracts were washed with 2N HCL, water, NaHCO3 solution, and brine, then dried over sodium sulfate and stripped of solvent. The crude optically active (5Z,11alpha,13S,14E)-13-(2-tetrahydropyranyloxy)-11,16,16-Trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester was obtained as a yellow oil weighing 10.55 g (95.4%).