Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=O)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=O.[BH4-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH2:26][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1
Reactant: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)Nc2ccccc2SCc2ccccc2Br)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC[C@H]2CNc2ccccc2SCc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (1531 g, 1327 ml) was added over ten minutes to a stirred, ice-cooled solution of (2S)-(N-[2-(2-bromophenylmethylthio)phenyl])carbamoyl-1-(4-methoxyphenylacetyl)pyrrolidine (see Preparation 23) (1750 g) and sodium borohydride (306.2 g) in tetrahydrofuran (8.73 L). The mixture was stirred at room temperature for one hour, heated under reflux for two hours, cooled, evaporated under reduced pressure to reduced volume to remove the tetrahydrofuran, quenched by the cautious addition of water and further evaporated under reduced pressure. The residue was treated with 40% aqueous sodium hydroxide solution (5 L) and the mixture was heated under reflux for two hours, cooled to room temperature by the addition of ice, acidified to pH 6-7 with concentrated hydrochloric acid and extracted with dichloromethane. The combined organic extracts were washed with 1M aqueous sodium hydroxide solution followed by water, dried over magnesium sulphate and evaporated under reduced pressure to give the desired compound (1589 g, 96%) as a brown oil which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[CH2:14]([O:13][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N+:1]([O-:21])=[CH:2][CH:3]=[CH:4]2)=[O:12])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc2ncccc2c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
To ethyl quinoline-6-carboxylate (3.2 g, 16 mmol) in dichloromethane (120 mL) was added meta-chloroperoxybenzoic acid (4.9 g, 0.024 mol) portionwise. The reaction was stirred at room temperature for 4 hours. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium carbonate (3×30 mL) and brine (2×40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (2.45 g, 71%) as a brown solid. 1H NMR (400 MHz, CDCl3, δ): 8.81-8.79 (d, 1H), 8.62 (s, 2H), 8.35-8.33 (d, 1H), 7.87-7.85 (d, 1H), 7.39 (s, 1H), 4.49-4.44 (q, 2H), 1.47-1.43 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([O:1][C:20](=[O:29])[N:21]([CH3:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=1
Reactant: Cc1cc(O)nc2ccccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
A mixture of 2-hydroxy-4-methylquinoline (0.48 g, 3.00 mmol) ), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours followed by heating at 50° C. for 4 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.24 g, 27% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH3:3]>[Pd]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCOc1ccc(CCCCCCC(=O)O)cc1
Yield: 93.1 %

Procedure:
This compound was synthesized from 7-(p-propoxyphenyl)-6-heptenoic acid (1.31 g, 5 mmol) by hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.23 g, 93%) as white crystals (mp: 49-50° C.). IR: 3450-2550, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.37 (m, 4H), 1.60 (m, 4H), 1.79 (m, 2H), 2.36 (t, 2H), 2.53 (t, 2H), 3.87 (t, 2H), 6.95 (q, 4H), 9.80 (bs, 1H). Anal. Calcd. for C16H24O3 : C, 72.69, H, 9.15%; Found: C, 72.79, H, 9.16%.
Reaction SMILES: C(Cl)(=O)C.[C:5]([S:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=O)C>>[CH3:5][S:8][C:9]1[CH:10]=[C:11]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(SC(C)=O)c1
Solvent: CC(=O)Cl
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(SC)c1

Procedure:
When an equimolar amount of acetyl chloride is used in place of dimethyl sulfate in the above reaction, then the product prepared is ethyl 3-acetylthio-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])([CH3:3])[CH3:2].[S:12](N)(N)(=[O:14])=[O:13]>N1C=CC=CC=1>[CH:1]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][S:12]1(=[O:14])=[O:13])([CH3:3])[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Nc1ccccc1N
Solvent: c1ccncc1
Product: CC(C)N1c2ccccc2NS1(=O)=O
Yield: 81.1 %

Procedure:
To a solution of N-isopropyl-1,2-phenylenediamine (7.52 g, 50.0 mmol) in pyridine (200 mL) was added sulfamide (7.21 g, 75 mmol, 1.5 equiv.) and the mixture was refluxed for 1 hour. After cooling, pyridine was removed under reduced pressure. Residual pyridine was removed by azeotrope evaporation using toluene. The black residue was dissolved in chloroform (150 mL) and the solution was washed with an aqueous hydrochloric acid solution (2 N, 2×50 mL), water, brine, dried (anhydrous sodium sulfate), and concentrated to give a crude black oil, which was purified by Isco CombiFlash Companion column chromatography (silica gel, 0-40% ethyl acetate/hexane, with 1% formic acid additive) to give 8.61 g (81%) of 1-isopropyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous brown liquid.
Reaction SMILES: CCOC(C)=O.[OH:7][N:8]=[CH:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CN1C(=O)CCC1.C1C(=O)N([Cl:36])C(=O)C1>O>[Cl:36][C:9](=[N:8][OH:7])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(Cl)=NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 294.3 %

Procedure:
To an AcOEt (270 ml) solution of the (S)-t-butyl 2-((hydroxyimino)methyl)pyrrolidine-1-carboxylate (32.0 g) obtained in Example 2-(1), NMP (43.1 ml) was added and after adding NCS (21.94 g) in three divided portions at 20- to 30-min intervals at 30 to 40° C., the resulting mixture was stirred at room temperature for 0.5 hour. The same reaction was carried out in a total of four runs using the same quantities. To the reaction mixture, water (400 ml) was added and the organic layer was separated. The separated organic layers were combined, washed with water (1.2 L×2), dried (MgSO4), filtered and concentrated to give a crude product (pale yellow solid, 174 g), which was washed with AcOEt/hexane (AcOEt/hexane=140 ml/840 ml) and dried to give the titled compound (109.3 g, colorless solid.)
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[N:19]([O:20][CH3:21])[CH3:18])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
A solution of 30 g (130.9 mmol) of Boc-isonipecotic acid in 1.5 1 CH2Cl2 was treated with 20.42 g (209.3 mmol) of N,O-dimethylhydroxylamine hydrochloride, 23.1 ml (209.3 mmol) of N-methylmorpholine and at 0° C. with 32.6 g (170.1 mmol) of EDCI and 3.53 g (26.2 mmol) of HOBT. The reaction was stirred overnight at room temperature and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to give 37.54 g (quantitative) of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 273(MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])[C:3]=1[CH3:16].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.CC(C)([O-])C.[K+].O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]2[C:18](=[O:20])[NH:12][C:10](=[O:11])[C:9]([CH:13]3[CH2:15][CH2:14]3)=[C:4]2[C:3]=1[CH3:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(C(C(N)=O)C2CC2)ncc(F)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a −60° C. solution of 2-(4-chloro-5-fluoro-3-methylpyridin-2-yl)-2-cyclopropylacetamide (2.7 g, 11.0 mmol (Example 1)) and triphosgene (7.2 g, 24.0 mmol) in dichloromethane (250 mL) was added portionwise potassium tert-butoxide (4.5 g, 40.0 mmol). After the addition was complete, the mixture was stirred at −50° C. for 30 minutes. Water was then added at this temperature. The organic layer was separated, washed with brine (3×), dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography (7:3 ethyl acetate/hexanes) to afford the title compound (2 g). 1H NMR (200 MHz, CDCl3) δ 8.95 (bs, 1H), 8.16 (d, 1H), 2.66 (s, 3H), 1.75-1.71 (m, 1H), 1.11-1.01 (m, 2H), 0.46-0.37 (m, 2H). MSCI: m/z=269 (MH+).
Reaction SMILES: [CH2:1]([P:3]([CH:10]=[CH:11][CH3:12])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:15]>C(O)(C([O-])=O)=O.C(O)(C([O-])=O)=O.O.O=[Ti].[K+].[K+]>[CH2:1]([P:3]([CH:10]=[CH:11][CH3:12])(=[O:9])[O:4][CH2:5][CH2:6][OH:15])[CH3:2]
Reactant: OCCO
Reactant: CC=CP(=O)(CC)OCCCC
Agent: O=[Ti]
Agent: O=C([O-])C(=O)O
Agent: [K+]
Solvent: O
Product: CC=CP(=O)(CC)OCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To 570 g (3.0 mol) of butyl ethylpropenylphosphinate (produced as in Example 6) are added 248 g (4 mol) of ethylene glycol and 0.4 g of potassium titanyl oxalate followed by stirring at 100° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 506 g (98% of theory) of 2-hydroxyethyl ethylpropenyl-phosphinate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:19]1([S:25][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCCCC3)c(C)o2)cc1
Yield: 57.5 %

Procedure:
A solution of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (6.0 g, 22.64 mmol, 1.00 equiv), cyclohexanethiol (3.9 g, 33.62 mmol, 1.50 equiv) and cesium carbonate (11.1 g, 34.05 mmol, 1.50 equiv) in N,N-dimethylformamide (60 mL) was stirred under nitrogen overnight at 50° C. The reaction was then quenched by the addition of 30 mL of water. The precipitate was collected by filtration and washed with 3×10 mL of hexane to give 4.5 g (58%) of methyl 4-(4-(cyclohexylthiomethyl)-5-methyloxazol-2-yl)benzoate as a white solid after drying under vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:4]=[CH:5][CH:6]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1-c1cccc(COS(C)(=O)=O)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the product from Step C (1 g, 4.42 mmole) in dichloromethane (10 mL) was added triethylamine (0.54 g, 5.3 mmol) followed by methanesulfonyl chloride (0.6 g, 5.3 mmol) dropwise. The mixture was stirred at room temperature for 3-4 h. It was then washed with water and brine, and dried over magnesium sulfate, and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:16](O)([CH:17]([CH3:19])[CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1)=[O:5])C.C(O)(=O)C.Cl.C(=O)([O-])O.[Na+]>O>[CH:17]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7][C:6]=1[C:4]([OH:5])=[O:3])([CH3:19])[CH3:18]
Reactant: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1c(C(=O)O)oc(=O)c2ccccc12
Temperature: 0 °C
Yield: 40 %

Procedure:
A stirred mixture of crude 3,3-bis(ethoxycarbonyl)-4-hydroxy-4-isopropyl-3,4-dihydroisocoumarin (76 g), glacial acetic acid (500 ml) and concentrated hydrochloric acid (800 ml) was refluxed for 18 hours. The cooled mixture was added to ice/water (3500 ml) and the precipitated solid filtered off and washed with water to give an off-white solid. This was treated with a solution of sodium hydrogen carbonate (40 g) in water (400 ml) and the resultant solution was extracted with diethyl ether (150 ml). The aqueous phase was acidified to pH1 with concentrated hydrochloric acid and the white precipitate filtered off, washed with water and dried at 70° C. to give 4-isopropylisocoumarin-3-carboxylic acid (20.16 g) in the form of a white solid [Elemental analysis: C, 67.4; H, 5.2%; calculated: C, 67.2; H, 5.17%; NMR (in DMSO-d6): 1.45 (6H, d, J=8 Hz), 3.85 (1H, sept, J=8 Hz), 7.6-8.4 (4H, m)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of tert-butyl 4-((4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (Intermediate 20; 1.60 g; 2.97 mmol) in THF (10 mL) was added conc. aqueous HCl (5 mL; 36%). The reaction mixture was stirred for 1 hour and concentrated, neutralized with saturated aqueous Na2CO3 (500 mL), extracted with EtOAc (200 ml×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed phase flash chromatography to afford 1.08 g (83%) of the title compound as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([NH:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([SH:16])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>>[SH:16][C@@H:14]1[CH2:13][N:12]([S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])[C@H:11]([C:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:30])=[O:2])=[O:10])[CH2:15]1
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1C[C@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1)C(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)[C@@H]1C[C@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1)C(=O)O

Procedure:
(S)-2-[[(2S,4S)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-3-methyl-butyric acid methyl ester was treated with 0.1M LiOH according to general procedure 5.2. to yield (S)-2-[[(2S,4S)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-3-methyl-butyric acid as white foam, MS: 437 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([C:10]2[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[N:3]=1.[CH3:19][C:20]1[N:21]=[C:22]([Sn](CCCC)(CCCC)CCCC)[S:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([C:10]2[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[N:3]=[C:2]([C:22]2[S:23][CH:24]=[C:20]([CH3:19])[N:21]=2)[CH:7]=1
Reactant: COc1cc(Cl)nc(-c2nc(C(F)(F)F)cs2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(C)cs2)nc(-c2nc(C(F)(F)F)cs2)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of compound 21 (4.17 mmol) in DMF (15 mL) were added 4-methyl-2-(tributylstannyl)thiazole (5 mmol), dichlorobis(triphenylphosphine) palladium (II) chloride (0.417 mmol), and K2CO3 (5 mmol). The reaction mixture was stirred at 110° C. under microwave irradiations for 1 hr. The solution was concentrated in vacuo and H2O and DCM were added. The layers were separated and the organic layer was concentrated. The crude was purified by silica gel chromatography (eluent: DCM) to give compound 22 in quantitative yield. MS (ESI, EI+): m/z=357.87 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CCc1ccncc1C
Reactant: Clc1ccc(CCCBr)cc1Cl
Product: Cc1cnccc1C(C)CCCc1ccc(Cl)c(Cl)c1
Yield: 37.2 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl-4-ethylpyridine and 4.05 g (15.1 mmol) of 1-bromo-3-(3,4-dichlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.73 g of the desired compound (yield:37.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C=Cc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CCc2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 99.1 %

Procedure:
3.46 g of 4-[2-(4-fluoro-phenyl)-vinyl]-phenylamine is dissolved in 100 ml of tetrahydrofuran, treated with 350 mg of palladium 10% on charcoal and hydrogenated at room temperature and normal pressure for about 4 h. The catalyst is filtered off and the filtrate concentrated to yield 3.46 g (99%) of a yellow solid. MS: m/e=216.9 (M++H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
DIPEA (939 μL, 5390 μmol) was added to a mixture of ethyl 7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.00 g, 3594 μmol) and glycine tert-butyl ester hydrochloride (723 mg, 4312 μmol) in dioxane (25 mL). The reaction mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (590 mg). MS (m/e)=308.1 (M+H-tBu)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[NH:5].N1C=CC=CC=1.[C:36]1([O:42]C(Cl)=O)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:36](=[O:42])[O:7][N:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C

Procedure:
138 mg of 2-Fluoro-N-hydroxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzamidine were dissolved in 2 ml dichloromethane. 35 μl pyridine and 53 μl phenylchloroformate were added and the mixture stirred at room temperature for thirty minutes. The mixture was diluted by the addition of 20 ml ethyl acetate, washed with brine and dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 2 ml acetonitrile and 105 μl 1,8-Diazabicyclo[5.4.0]undec-7-ene was added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 70 mg 3-{2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazole-5-one as an amorphous lyophilisate.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
In tetrahydrofuran (8 ml), 6-chloro-N-methoxy-N-methylnicotinamide (500 mg) was dissolved, followed by the dropwise addition of diisobutylaluminum hydride (a 0.95M hexane solution, 2.88 ml) at −78° C. in an argon gas atmosphere. The resulting mixture was stirred for 3 hours and then, at room temperature, for 2 hours. After the reaction mixture was cooled to −20° C., saturated saline (2 ml) was added thereto, followed by stirring for 30 minutes. The insoluble matter was filtered off. The residue was washed with ethyl acetate. The filtrate and the washing were combined together. The mixture was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, whereby the title compound (346 mg, 98%) was obtained as a crude product. The product was provided for the subsequent reaction without purification.