Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][S:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: COC(=O)c1cc2sccc2[nH]1
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: COC(=O)c1cc2sccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 4-(7-fluoro-naphthalen-1-ylmethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 324.4 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:34])=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].I[CH3:36].[OH-].[K+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:34])=[C:22]4[C:26]=3[N:25]([CH3:36])[CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc(F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D47) (450 mg) and iodomethane (0.91 mL) in dimethyl sulfoxide (DMSO) (15 mL) at room temperature was added potassium hydroxide (218 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc for 3 times. The organic phase was washed with brine, dried over anhydrous sodium sulphate and evaporated in vacuo to afford the crude product. Purification by column chromatography affords ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1-methyl-1H-indol-3-yl]propanoate (D130) (349 mg). MS (ES): C26H25FN4O4 requires 476; found 477.3 (M+H+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[N:9]=1.[OH:16][C:17]1[CH:26]=[C:25]([CH3:27])[C:20]2[NH:21][C:22](=[O:24])[O:23][C:19]=2[CH:18]=1.O>CN(C=O)C>[Cl:14][C:12]1[N:11]=[C:10]([CH3:15])[N:9]=[C:8]([O:16][C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH:13]=1
Reactant: Cc1cc(O)cc2oc(=O)[nH]c12
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.724 mmol) potassium carbonate and 110 mg (0.655 mmol) 4,6-dichloro-2-methyl-pyrimidine were added to 100 mg (0.575 mmol) 6-hydroxy-4-methyl-3H-benzoxazol-2-one in 1.5 mL DMF and the mixture was stirred for 2 h at RT. Then 15 mL water were added and the mixture was stirred overnight at RT. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Br:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[Br:28][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Br)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of of 2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 ml of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The mixture was stirred at −78° C. for 30 min and N-bromosuccinimide (2.2 eq.) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hr. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 7-bromo-2-(4-fluorophenyl)-3-pyridin-4-ylpyrazolo[1,5-α]pyridine as a yellow solid. 1H NMR (CDCl3): δ 8.65 (d, 2H, J=5.0 Hz), 7.56–7.68 (m, 3H), 7.31 (d, 2H, J=5.0 Hz), 7.11–7.30 (m, 4H; MS m/z 368 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[N:14]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:20]2[S:22][CH:2]=[C:3]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)[N:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)N1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(N3CCCCC3)n2)cc1
Yield: 77.2 %

Procedure:
4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.28 g, 0.95 mmol). 1H NMR (DMSO-d6, 400 MHz,) δ 7.93 (4H, m), 7.40 (1H, s), 3.48 (4H, m), 1.60 (6H, m).
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][C:22]1[C:23](=[O:51])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH:40][C:41]([C:43]4[S:44][C:45]([Cl:48])=[CH:46][CH:47]=4)=[O:42])[O:36][C:35]3=[O:49])=[CH:30][C:29]=2[CH3:50])[CH:25]=[CH:26][CH:27]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO.ClCCl>[Cl:48][C:45]1[S:44][C:43]([C:41]([NH:40][CH2:39][C@@H:37]2[O:36][C:35](=[O:49])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([N:24]4[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][OH:19])[C:23]4=[O:51])=[C:29]([CH3:50])[CH:30]=3)[CH2:38]2)=[O:42])=[CH:47][CH:46]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CCO)c1=O
Reaction time: 1 h

Procedure:
With ice-cooling, 400 ml of 1.25N hydrochloric acid in methanol are added to 43.8 g (60.3 mmol) of the compound from Example 27A. After 1 h, the mixture is diluted with dichloromethane, and the aqueous phase is then removed. The organic phase is washed twice with water, dried over sodium sulphate and, after filtration, concentrated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 19.6 g (66% of theory) of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[CH:11]1([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:14])=[O:2])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: COC(=O)Cc1ccc(C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Methyl(4-cyclopropylphenyl)acetate (710 mg, 3.73 mmol) was dissolved in 5 mL THF, 5 mL MeOH, and aqueous 1N NaOH (7.46 mmol) and the resulting mixture was heated at 45° C. overnight. After cooling to ambient temperature, the reaction was concentrated in vacuo and the residue was diluted with water (50 mL). The aqueous material was acidified with 1N HCl to pH˜3. A light brown precipitate formed which was collected by filtration and dried in a vacuum oven for 3 days to give (4-cyclopropylphenyl)acetic acid (SM-1ag, 395 mg, 60%). MS (ES−) 175.2 (M−H). 1H NMR (DMSO-d6) δ 0.57-0.61 (m, 2H), 0.86-0.91 (m, 2H), 1.81-1.88 (m, 1H), 3.45 (s, 2H), 6.97 (d, 2H), 7.08 (d, 2H), 12.20 (br s, 1H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Pd]>[NH2:1][C@@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CNC(=O)[C@H](N)Cc1ccccc1
Yield: 97.7 %

Procedure:
CBZ-D-Phe-Gly-OMe (9.5 9. 26 mmol) was dissolved in MeOH (150 ml) and subjected to hydrogenolysis in the presence of 10% Pd/C (1 g) and H2 -atmosphere (balloon filled with H2) for 4 h at room temperature. At the end, the catalyst was removed by filtration through a celite bed and the removal of MeOH under reduced pressure gave 6 g of D-Phe-Gly-OMe (≈100%, crude yield).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[CH3:19][Si](C[Li])(C)C.C(Cl)(=O)C>C1COCC1.CCCCC.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C:5](=[CH2:19])[C:4]=2[CH:3]=1
Reactant: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: [Li]C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCCCC
Product: C=C1c2cc(Br)ccc2Oc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-7-methoxy-9H-xanthen-9-one (2.035 g, 6.7 mmol) in THF (67 ml) contained in a 250-mL RBF was cooled in a dry ice/acetone bath for 10 min to give a milky-white mixture. Trimethylsilyl methyllithium (10 ml of a 1.0 M solution in pentane, 10 mmol) was added dropwise over 5 min to give a clear orange solution. The mixture was stirred for 15 min, then acetyl chloride (0.76 ml, 11 mmol) was added dropwise, resulting in the formation of a clear, bright-yellow solution. The mixture was warmed to RT for 3 h, then an additional portion of acetyl chloride (0.25 mL) was added. The mixture was stirred for an additional 30 min before being diluted with saturated aqueous sodium bicarbonate solution (100 mL). The biphasic mixture was extracted with EtOAc (2×50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give a yellow solid that was used without further purification. MS m/z=303.0 [M+H]+. Calc'd for C15H12BrO2: 303.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([S:23][CH3:24])=[N:16][C:17]([CH3:22])=[CH:18][C:19]=2[S:20][CH3:21])=[O:12])[CH2:6][CH2:5]1)(=[O:35])=[O:34]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCOS(C)(=O)=O)CC1
Reaction time: 0.75 h

Procedure:
To a solution of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (93 mg, 0.251 mmol) in THF (2 ml) were added triethylamine (51 mg, 0.502 mmol) and 4-(dimethylamino)pyridine (3 mg, 0.025 mmol), and then dropped methanesulfonyl chloride (43 mg, 0.377 mmol) with ice-cooling. The mixture was stirred for 45 minutes. The reaction solution was concentrated in vacuo to provide crude 2-[4-(2-methanesulfonyloxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[CH:7]=[C:6]([CH3:19])[C:5]=1[OH:20])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:29])C=1.O.[OH-].[Na+]>C(Cl)Cl>[CH3:19][C:6]1[C:5]2[O:20][CH:2]([CH2:3][OH:29])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(C)cc2c(-c3ccccc3)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(-c3ccccc3)noc2c2c1OC(CO)C2
Temperature: 0 °C
Yield: 96.4 %

Procedure:
To the ice-cooled solution of 7-allyl-6-hydroxy-5-methyl-3-phenyl-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml), 7.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the solution was subsequently refluxed for 3 hours. After cooling the solution, water and 50 ml of an aqueous solution of 2N sodium hydroxide were added, and the mixture was subjected to extraction with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 4.6 g of 7,8-dihydro-5-methyl3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 130°-133° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 281.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C1(=O)O[CH2:28][CH2:27][O:26]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:28][CH2:27][OH:26])=[C:18]([CH2:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1OCCO1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(CC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OCCO)c(CC)c1
Temperature: 155 °C
Yield: 24.5 %

Procedure:
A solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-4-hydroxy-phenyl)-acetate (400 mg, 1.23 mmol) described in Example 180.1, ethylene carbonate (110 mg, 1.23 mmol) and tetrabutylammonium bromide (264 mg, 1.23 mmol) in DMF (0.6 ml) was heated to 155° C. for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, hexane/EtOAc 9:1). Ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-4-(2-hydroxy-ethoxy)-phenyl]-acetate (111 mg, 24%) was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: COC(=O)Cc1n[nH]c2ncccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
Methyl 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetate (250 mg, 1.31 mmol), cesium carbonate (850 mg, 2.61 mmol), were added into 30 mL tetrahydrofuran, and stirred at room temperature for 15 minutes. Then 4-nitrobenzyl bromide (283 mg, 1.31 mmol) was added, and reacted at room temperature for 12 hours. It was filtered to remove the solid. The filtrate was rotate evaporated to dryness, and chromatographed on a column (PE:EA=10:1) to obtain a light yellow solid 75 mg, at a yield of 17.6%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C(O)=O>CS(C)=O.C1C=CC=CC=1.CO.O.C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:29])[CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CO
Product: O=C(CSc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(phenylthio)ethyl]pyrrolidine (908 mg) was dissolved in DMSO (3 ml) and benzene (3 ml), and thereto were added pyridine (162 μl), trifluoroacetic acid (78 μl) and DCC (1.24 g) in order, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 ml) was added to the reaction mixture, and oxalic acid (540 mg) in methanol (5 ml) was added thereto, followed by stirring for 30 minutes. Water (50 ml) was added to the reaction mixture and the resultant dicyclohexylurea was filtered off. The filtrate was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in order, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 714 mg of (2S)-1-(N-benzyloxycarbonyl-L-prolyl)-2-[(Phenylthio) acetyl]pyrrolidine (See Table 1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4](/[CH:5]=[N:23]/[S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.5 %

Procedure:
To a stirred suspension of 2-chloro-3-fluoroisonicotinaldehyde (0.75 g, 4.70 mmol) and Cs2CO3 (2.297 g, 7.05 mmol) in DCM (20 mL) was added a solution of (R)-2-methylpropane-2-sulfinamide (0.570 g, 4.70 mmol) in DCM (20 mL) dropwise for 10 min. The solution was then stirred for 3.5 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo to give (R,E)-N-((2-chloro-3-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.13 g, 91%) as a yellow oil which solidified upon standing. MS (ESI) m/z: 263.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([C:14](O)=[O:15])=[CH:11][S:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:24]>CCOCC>[ClH:24].[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1ccc(Oc2cscc2C(=O)O)cc1N
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: Cc1ccc(Oc2cscc2CO)cc1N

Procedure:
When the hydrochloride (XI) in water is stirred with acetic anhydride and sodium acetate trihydrate is added, the product is collected and recrystallized from acetone-hexane to provide N-ethyl-6'-[4-(hydroxymethyl)-3-thienyloxy]-m-acetotoluidide (XII). When 4-(2-amino-p-tolyloxy)-3-thiophenecarboxylic acid (IX) and lithium aluminum hydride in ether is refluxed for 16 hours and the product is treated with alcoholic hydrochloric acid, 4-(2-amino-p-tolyloxy)-3-thiophenemethanol hydrochloride (XIII) is obtained.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:41])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)=[CH:32][CH:31]=2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[OH:23][B:15]1[C@@H:14]([NH:28][C:29](=[O:41])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:37][CH:38]=[CH:39][N:40]=3)=[CH:32][CH:31]=2)[CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:44])[C:8]=2[O:16]1
Reactant: COc1c(CC(NC(=O)c2ccc(-c3ncc[nH]3)cc2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(N[C@H]1Cc2cccc(C(=O)O)c2OB1O)c1ccc(-c2ncc[nH]2)cc1

Procedure:
Prepared from 3-[2-[4-(1H-Imidazol-2-yl)-benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 378 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][C:69]1[CH:82]=[CH:81][C:72]([CH2:73][S:74][CH2:75][C@H:76]([C:78]([OH:80])=[O:79])[NH2:77])=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:77][C@@H:76]([C:78]([OH:80])=[O:79])[CH2:75][S:74][CH2:73][C:72]3[CH:81]=[CH:82][C:69]([CH3:68])=[CH:70][CH:71]=3)=[O:36])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CSC[C@@H](N)C(=O)O)cc1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(CSC[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (19.9 mg, 0.037 mmol) in DMF (2.0 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.4 mg, 0.045 mmol) was added and the mixture was stirred at 30° C. for 45 minutes. S-(4-methylbenzyl)-D-cysteine (10.5 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 1 hour. The formation of the ketone of the title compound was confirmed. M/z: 748.02 (M+1). Methanol (2 ml) and sodium borohydride (14.7 mg, 0.39 mmol) were added the mixture was stirred for 30 minutes. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV-detection 240/260 nm. A gradient from 20 to 50% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (8.7 mg, 31.5%). H-NMR (400 MHz, DMSO-d6): 2.24 (s, 3H), 2.60-2.68 (m, 1H), 2.72-2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.68 (s, 2H), 3.82 (d, 2H), 4.25 (d, 0.5H), 4.27 (d, 0.5H), 4.39-4.46 (m, 1H), 4.52 (s, 2H), 4.67-4.77 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.67 (bs, 1H), 6.98 (d, 2H), 7.05-7.18 (m, 8H), 7.20-7.25 (m, 2H), 4.30-4.39 (m, 4H), 8.23-8.32 (m, 2H), 12.80-12.95 (bs, 1H). M/z: 748.04 (M−1).