Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.2 g) in acetone (5 ml) was added 6N-hydrochloric acid (5 ml) and stirred at room temperature for about 1.5 hours. After removal of the acetone, water was added to the residue and the resultant aqueous solution was extracted with ethyl acetate twice. The extract was washed with water and dried and the solvent was removed therefrom to give a reddish oil (4.2 g) of diethyl 2-methyl-4-(2-trifluoromethylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: C(O[C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])C.C(O[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](O)=O)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[OH:5][CH2:4][CH2:6][N:7]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([CH:43]2[CH2:44][CH2:45][N:40]([CH3:38])[CH2:41][CH2:42]2)=[CH:51][CH:50]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)c1
Yield: 102.8 %

Procedure:
Synthesized from pivalic acid (S)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg) according to an analogous synthesis method to the above-mentioned Preparation Example 86 and Example 337,the title compound (41 mg) was obtained.
Reaction SMILES: BrC1C(C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=CC=1.Cl.[F:28][C:29]([F:44])([F:43])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C@H:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[NH2:42])=[N:34][CH:35]=1.[CH2:45]([O:47][C:48]1[C:49]([C:55](O)=[O:56])=[N:50][C:51]([CH3:54])=[CH:52][CH:53]=1)[CH3:46]>>[CH2:45]([O:47][C:48]1[C:49]([C:55]([NH:42][C@H:38]2[CH2:39][CH2:40][CH2:41][C@@H:37]2[NH:36][C:33]2[CH:32]=[N:31][C:30]([C:29]([F:28])([F:43])[F:44])=[CH:35][N:34]=2)=[O:56])=[N:50][C:51]([CH3:54])=[CH:52][CH:53]=1)[CH3:46]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: CCOc1ccc(C)nc1C(=O)O
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Product: CCOc1ccc(C)nc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 28) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 3-ethoxy-6-methylpyridine-2-carboxylic acid (CAS number 1228188-14-4; 58 mg, 0.32 mmol) and was then purified by column chromatography (silica, 40-100% ethyl acetate/petrol) followed by partitioning between ethyl acetate and a saturated solution of sodium bicarbonate. The organics were filtered through a hydrophobic frit and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH2:11][C@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C:13]([C:15]([O:17][CH3:27])=[O:16])=[CH:12][CH2:11][C@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C(=O)O)=CC[C@H]1c1cc(F)c(F)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1=CC[C@@H](c2cc(F)c(F)cc2F)[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of Example 39A (510 mg) was dissolved in methanol (1 mL) and CH2Cl2 (1 mL). Then, (trimethylsilyl)diazomethane solution (0.4 mL, 2M in ether) was added. After ten minutes, acetic acid (0.2 mL) was added. The mixture was concentrated, filtered through a silica gel plug, and purified by chromatography (Column: Chiralcel AD, Mobile Phase: hexane/ethanol/methanol=95/2.5/2.5) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.31 (s, 9H), 2.18-2.28 (m, 1H), 2.41-2.50 (m, 1H), 2.57-2.67 (m, 1H), 2.86 (d, J=16.48 Hz, 1H), 3.10-3.18 (m, 1H), 3.76 (s, 3H), 4.02 (s, 1H), 4.37 (d, J=7.63 Hz, 1H), 6.86-6.94 (m, 1H), 6.99 (s, 1H), 7.11 (s, 1H). MS (DCI) m/z 403 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.Cl.Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:29])=[C:19]([CH:28]=1)[C:20]([NH:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:21].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[Cl:29][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:6]([C:3]2([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]2)=[O:7])=[CH:28][C:19]=1[C:20]([NH:22][C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:21]
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ncc[nH]1)c1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
To a suspension of 1-(trifluoromethyl)cyclopropanecarboxylic acid (54 mg, 0.34 mmol, 1.1 equiv) and 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (100 mg, 0.31 mmol, 1.0 equiv) in THF (1.55 mL), add DIEA (0.189 mL, 1.08 mmol, 3.5 equiv), HOBt (59.2 mg, 0.386 mmol, 1.08 equiv), EDCI (74 mg, 0.386 mmol, 1.08 equiv), and stir the reaction mixture at room temperature for three days. Concentrate under reduced pressure, and subject the crude mixture to chromatography on a C18 reversed-phase stationary phase eluting with a 5-60% (0.1% TFA in acetonitrile) in (0.1% TFA in water) gradient to give the title compound as a white solid (39 mg, 33%). 1H NMR (DMSO-d6, 400 MHz): δ 11.80 (br s, 2H), 8.41 (t, 1H, J=5.8 Hz), 7.46 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=2.1 Hz), 7.30 (dd, 1H, J=8.3, 2.1 Hz), 6.75 (br s, 2H), 4.28 (d, 2H, J=6.0 Hz), 1.33-1.20 (m, 4H). MS (m/z) (35Cl/37Cl) 387/389 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:16]1([CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)O)[CH:20]=[CH:19][N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CO.C(Cl)Cl>[N+:13]([C:3]1[C:2]([O:1][C@@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12])([O-:15])=[O:14]
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: O=C1CCCc2c1ccc(O)c2[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
To a solution of 6-hydroxy-5-nitro-1-tetralone (2.09 g, 10.1 mmol) in dry THF (50 mL) was added (R)-2-imidazol-1-yl-1-phenyl-ethanol (2.28 g, 12.1 mmol) followed by triphenylphosphine (3.18 g, 12.1 mmol). After approximately 10 min, diethylazodicarboxylate (1.9 mL, 12.1 mmol) was added slowly. The reaction became homogenous within 2 min. The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was triturated with Et2O to remove some of the phospine by-products. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over MgSO4, and concentrated to give a foam/oil. Purification by chromatography (SiO2, 10 to 20% acetone/Cl2Cl2 then 5% MeOH/CH2Cl2) afforded the title compound as a light brown foam (3.06 g, 8.1 mmol, 80%). The structure was confirmed by NMR and mass spectrometry. MS m/z 378 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24].[CH3:25][C:26]1[CH:27]=[C:28]([NH2:33])[CH:29]=[CH:30][C:31]=1[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C2OC3C(=CC=CC=3)CC=2C(P(C2C=CC=CC=2)C2C=CC=CC=2)=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1C>O1CCOCC1.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][C:26]1[CH:27]=[C:28]([NH:33][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:24])[N:2]([CH3:1])[C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1ccc(N)cc1C
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c(=O)n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1c(C)c(P(c2ccccc2)c2ccccc2)c(P(c2ccccc2)c2ccccc2)c2c1Oc1ccccc1C2
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1c(Nc2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a solution of methyl 2-methyl-1-oxo-4-{[(trifluoromethyl)sulfonyl]oxy}-1,2-dihydro-3-isoquinolinecarboxylate (0.84 g, 2.3 mmol) and (3,4-dimethylphenyl)amine (0.362 g, 2.99 mmol) in 1,4-dioxane (25 mL) under nitrogen was added cesium carbonate (1.124 g, 3.45 mmol), dimethylbisdiphenylphosphinoxanthene (0.103 g, 0.172 mmol) and Pd(OAc)2 (0.026 g, 0.115 mmol) and the mixture was stirred at 100° C. for 16 hours. The mixture was diluted with diethyl ether, filtered through Celite and the filter cake was washed with diethyl ether. The crude product was purified on silica using EtOAc/hexanes 10-30% to provide the title compound as a yellow solid (0.59 g, 74%). 1H NMR (400 MHz, CDCl3) δ ppm 8.48 (dd, J=1.2, 5.9 Hz, 1 H), 7.69-7.52 (m, 3 H), 6.89 (d, J=8.2 Hz, 1 H), 6.55-6.29 (m, 2 H), 5.66 (s, 1 H), 3.86 (s, 3 H), 3.62-3.51 (m, 3 H), 3.57 (s, 4 H), 2.14 (s, 9 H), 2.24-2.07 (m, 6 H), 1.56 (s, 3 H);); ES-LCMS: 337.3 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[S:7]1(=[O:14])=[O:13].FC(F)(F)C(O)=O>C(Cl)Cl>[F:11][C:8]1([F:12])[S:7](=[O:14])(=[O:13])[NH:6][CH2:10][CH2:9]1
Reactant: COc1ccc(CN2CCC(F)(F)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)NCCC1(F)F
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 76.4 %

Procedure:
To a 0° C. solution of 2-(2,4-dimethoxybenzyl)-5,5-difluoroisothiazolidine-1,1-dioxide (0.100 g, 0.3 mmol) in methylene chloride (6 mL) was added trifluoroacetic acid (2.182 mL, 29.4 mmol). The resulting red/purple solution was stirred at 0° C. for 3.5 hrs and concentrated in vacuo. The crude material was purified by silica gel chromatography (30-75% ethyl acetate/hexanes) to give a tan oil (0.036 g). 1H NMR (CDCl3, 300 MHz) δ 4.78 (br s, 1H), 3.46-3.40 (q, 2H, J=6.6 Hz), 2.79-2.65 (m, 2H). 19F NMR (CDCl3, 282 MHz)-105.96-106.07 (t, J=15.4 Hz).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1>>[Br:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:17][C:5](=[O:7])[CH3:6])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccc(Br)nc1
Product: CC(=O)NC(C)c1ccc(Br)nc1

Procedure:
Reagents: acetic anhydride and 1-(6-bromo-pyridin-3-yl)-ethylamine
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][N:29]2[CH3:34])#[N:2].C([O-])([O-])=[O:36].[K+].[K+].OO.O>CS(C)=O.CCOC(C)=O>[NH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:36])=[C:4]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][N:29]3[CH3:34])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1ccc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ccc3C#N)cccc21
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1ccc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4N)ccc3C(N)=O)cccc21
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-indol-4-ylamino)phenylamino)cyclohexylcarbamate (90 mg, 0.19 mmol) in DMSO (2 mL). K2CO3 (130 mg, 0.94 mmol) and H2O2 (50% aq., 0.500 mL) were added. The mixture was stirred at 100 C for 10 min. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (2 mL). After 10 min of standing, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 378.3 (M+H); UV 224.7, 291.5 nm
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[NH:6]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([S:24](Cl)(=[O:26])=[O:25])=[C:15]2[O:20][C:21](=[O:23])[CH3:22])[C:7]([CH3:9])=[O:8]>CC(C)=O>[C:1]([NH:5][S:24]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[CH:19][C:10]=2[NH:6][C:7]([CH3:9])=[O:8])[C:15]=1[O:20][C:21](=[O:23])[CH3:22])(=[O:26])=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reactant: CC(C)(C)N
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)NC(C)(C)C)ccc12
Reaction time: 8 h

Procedure:
14.5 g of t-butylamine in 50 ml of acetone were added dropwise to a solution of 18.8 g of the compound from stage 2 (0.55 mols) in 150 ml of acetone at -5° to 0° C. The mixture was further stirred overnight, filtered off from the deposit, concentrated and crystallized from ether with a little acetonitrile. Yield: 19.2 g=92% of the theoretical yield; mp: 203°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:11]/[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10].Br[C:19]([F:26])([F:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[C:19]([F:26])([F:25])[C@@:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([NH:11][S@@:12]([C:14]([CH3:16])([CH3:17])[CH3:15])=[O:13])[CH2:9][CH3:10])[CH3:24]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC/C(=N\[S@](=O)C(C)(C)C)c1ccccc1F
Product: CCOC(=O)C(F)(F)[C@](CC)(N[S@](=O)C(C)(C)C)c1ccccc1F

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(2-fluoro-phenyl)-prop-(E)-ylidene]-amide (intermediate A2F) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-2,2-difluoro-3-(2-fluoro-phenyl)-3-((R)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl ester was obtained as a colorless oil. MS (ISP): m/z=380.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:27])[C:8]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]2[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (˜8.7 mmol) in CH2Cl2 (40 mL) was added Dess-Martin periodinane (4.07 g, 9.6 mmol). After 1.5 h, a saturated solution of Na2S2O4 (20 mL) and water (20 mL) was added. The mixture was stirred vigorously for 30 min. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 3 the titled compound. 1H-NMR: 400 MHz, (CDCl3) δ: 8.22 (s, 1H), 7.70 (m, 3H), 4.41 (q, J=7 Hz, 2H), 2.47 (s, 3H), 1.39 (t, J=7 Hz, 3H). 19F-NMR: 377 MHz, (CDCl3) δ: −73.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:47][OH:48].O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:21])[NH:47][OH:48])[C:6]2=[O:17]
Reactant: NO
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (1.3 g, 2.8 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (0.7 g, 4.2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 5.6 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hours and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (1.2 g, 86%): mp 142-144° C.; 1HNMR (DMSO-d6): δ 0.87-0.89 (m, 4H, c-CH2), 1.28-1.33 (t, J=7.5 Hz, 3H, OCH2CH3), 1.78-1.83 (m, 1H, c-CH), 2.85-2.91 (m, 2H, CH2CO), 3.73 (s, 3H), 4.00 (t, J=7.5 Hz, 2H, OCH2CH3), 4.11 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.53-5.69 (m, 1H, CHN), 6.92-6.94 (m, 3H, Ar), 7.58 (d, J=10 Hz, 1H, Ar), 8.26 (d, J=10 Hz, 1H, Ar), 8.84 (s, 1H), 10.46 (s, 1H), 10.57 (s, 1H); 13C NMR (DMSO-d6): δ 8.4, 8.5, 15.2, 15.9, 35.4, 46.2, 52.2, 55.9, 64.3, 74.6, 112.4, 112.7, 119.7, 119.8, 121.5, 131.7, 132.9, 136.4, 140.2, 148.4, 149.1, 166.3, 167.6, 172.4; Anal. Calcd. for C26H28ClN3O7+0.5H2O: C, 58.01; H, 5.48; N, 8.46; Found: C, 57.97; H, 5.29; N, 8.53, H2O, 1.5.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:1][CH2:2][C@@H:3]1[CH2:4][CH2:5][C:6](=[O:8])[NH:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@@H](CO)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.69 mmol) in dichloromethane (40 mL) at 0° C. was added triethylamine (1.816 mL, 13.03 mmol) followed by dropwise addition of methanesulfonyl chloride (0.812 mL, 10.42 mmol). The resulting mixture was stirred at room temperature for two hours, and then it was partitioned between water and dichloromethane (3×). The organic extracts were combined and dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give the title compound as a colorless, waxy solid (1.68 g, quantitative).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]([CH3:43])([CH3:42])[CH2:25][CH2:26][N:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:39][CH3:40])([CH2:37][CH3:38])[O:29][C:28]1=[O:41]>C(O)(C)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:21])[CH2:22][NH:23][C:24]([CH3:43])([CH3:42])[CH2:25][CH2:26][N:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]([CH2:39][CH3:40])([CH2:37][CH3:38])[O:29][C:28]2=[O:41])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c(C3CO3)cc(OCc3ccccc3)cc2[nH]1
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)c2ccccc21

Procedure:
A suspension of 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one (112 mg, 0.382 mmol) and 1-(3-amino-3-methylbutyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one (220 mg, 0.758 mmol) in isopropanol (1.0 mL) is heated in the microwave for 1 hour to 135° C. The mixture is diluted with EtOAc (10 mL) and washed with 0.5 M aqueous tartaric acid solution, whereupon half the product is precipitated. The phases are separated and the aqueous suspension is combined with MeOH until a clear solution is obtained again. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried with sodium sulfate and evaporated down in vacuo. The residue is stirred with EtOAc and the precipitate is filtered off and dried in vacuo. Yield: 152 mg (68%); HPLC-MS: Rt=14.8 min. (method A).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccnc(N)c1
Agent: Cl
Product: CCCC(=O)Nc1cc(C(=O)OC)ccn1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (1.94 g, a white solid) from methyl 2-aminoisonicotinate hydrochloride (2.00 g, 10.6 mmol) and butyryl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][C:21]([S:24][CH3:25])=[CH:22][N:23]=2)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>C(Cl)(Cl)Cl>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][C:21]([S:24]([CH3:25])=[O:1])=[CH:22][N:23]=2)=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CSc1cnc(NC(=O)c2ccc(OC(C)=O)cc2)s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(C(=O)Nc2ncc(S(C)=O)s2)cc1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (I), 515 (0.841 g, 2.73 mmol) gives crude 7. The crude product is stirred with chloroform (50 mL) and the suspension is filtered. The pad is washed once with chloroform and air dried to give pure 7 (0.35 g) as a white solid.