Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C#N)cc1F
Reaction time: 3 h
Yield: 75 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. found 240.2 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH:42]=[CH:41][CH:40]=[CH:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:8]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([NH:29][C:30]([C:32]2[CH:33]=[N:34][C:35]([N:38]3[CH:42]=[CH:41][CH:40]=[CH:39]3)=[CH:36][CH:37]=2)=[O:31])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccc(-n2cccc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc(-n2cccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
1.0 mL of trifluoroacetic acid was added to 1.0 mL of methylene chloride solution containing 20 mg of tert-butyl 4-phenethyl-2-(6-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate and stirred at room temperature for 1 hour and 30 minutes. Tine solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 17 mg of 4-phenethyl-2-(6-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoic acid as white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:35][N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][NH:40][CH2:39]1.O(C(C)C)C(C)C>CCOC(C)=O>[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1
Reactant: CN(C)C1CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
DIPEA (0.182 mL, 1.043 mmol) was added to 6-chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 70 mg, 0.174 mmol), N,N-dimethylazetidin-3-amine (60.1 mg, 0.348 mmol) and iPr2O (1 mL) in a vial, which was sealed and the RM was stirred at 110° C. for 5 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The aq. phase was extracted with DCM (2×20 mL) and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title compound as white crystals. HPLC (Condition 7) tR=5.627 min, UPLC-MS (Condition 3) tR=0.75 min, m/z=447.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.01 (s, 6H) 2.90-3.05 (m, 1H) 3.49-3.62 (m, 2H) 3.70-3.87 (m, 2H) 6.36-6.51 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.80-7.92 (m, J=8.60 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.69-8.79 (m, J=2.30 Hz, 1H) 10.24 (s, 1H) 12.90-13.21 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:24]3[C:16](=[CH:17][N:18]=[C:19]4[C:23]=3[CH:22]=[CH:21][N:20]4[S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:15]=[N:14]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[C:28]1([S:25]([N:20]2[CH:21]=[CH:22][C:23]3[C:19]2=[N:18][CH:17]=[C:16]2[C:24]=3[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]3)[N:14]=[N:15]2)(=[O:26])=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
A mixture of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester (1.00 g, 2.07 mmol) and trifluoroacetic acid (4 mL) was stirred at ambient temperature for 90 minutes. The mixture was purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol) to afford 600 mg (76%) of racemic trans 3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine as an off white foam. LCMS (Method B, ESI): RT=2.40 min, m+H=383.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A stirred suspension of 6-(N-(4-amino-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropyl-N-methylbenzofuran-3-carboxamide (0.421 g, 0.773 mmol) in 25 mL of acetonitrile was treated with 25 mL of 48% aqueous HBr and the resulting suspension cooled in an ice water bath. To the mixture was added a solution of sodium nitrite (0.056 g, 0.812 mmol) in 2 mL of water. After stirring at 0° C. for 30 minutes an additional 14 mg portion of sodium nitrite in 1 mL of water was added. After stirring at 0° C. for another 30 minutes, the mixture was treated with CuBr (0.130 g, 0.906 mmol) in four portions over 5 minutes. The mixture was warmed to 60° C. for 30 minutes and then cooled to RT. The mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite. The EtOAc solution was washed with 5% aqueous sodium bisulfite (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient from hexane to 3:7 hexane/EtOAc) followed by recrystallization from hexane/EtOAc to give the title compound (0.212 g, 45%) as a white solid. LCMS (m/z, ES+)=609 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29].[C:32]1([O:38][CH2:39][CH:40]2[O:42][CH2:41]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[OH:42][CH:40]([CH2:39][O:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:41][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:18]([CH3:27])=[C:17]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccccc1
Yield: 51.5 %

Procedure:
In 1,300 ml of methanol were dissolved 13 g of dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 4.5 g of glycidyl phenyl ether, and the solution thus formed was refluxed under heating for 16 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform-methanol (96:4 v/v). Crude crystals were recrystallized from ethanol to give 9 g of dimethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[N:16]=1>CN(C)C=O>[S:29]1[CH:30]=[CH:31][C:27]([CH2:26][O:25][C:17]2[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=[C:15]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[CH:28]1
Reactant: FC(F)(F)c1cc(Cl)nc(OCc2ccsc2)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2cc(C(F)(F)F)cc(OCc3ccsc3)n2)c1

Procedure:
To a mixture prepared by adding to meta-trifluoromethylphenol (1.1 g, 0.0034×2.0 mol) successively dimethylformamide and sodium hydride (0.20 g, (ca.60% in mineral oil), 0.0034×1.5 mol), 2-chloro-6-(3-thienylmethyloxy)-4-trifluoromethylpyridine (1.0 g, 0.0034 mol) was added, and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([O:30]C)=[C:25]([CH3:32])[CH:24]=2)([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:6]1=[O:33].Cl.N1C=CC=CC=1.Cl>[Cu].C(OCC)(=O)C>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:24]=[C:25]([CH3:32])[C:26]([OH:30])=[C:27]([CH3:29])[CH:28]=2)([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:6]1=[O:33]
Reactant: COc1c(C)cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1C
Agent: [Cu]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C2(c3ccc([N+](=O)[O-])cc3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Temperature: 190 °C
Yield: 40.1 %

Procedure:
Evaporate 1-(2-chloro-benzyl)-3-(4-methoxy-3,5-dimethyl-phenyl)-3-(4-nitro-phenyl)-1,3-dihydro-indol-2-one (62 mg, 0.12 mmol) into a vial and add pyridine hydrochloride (300-500 mg). Suspend the vial, by means of a copper wire, in an oil bath heated to 180-200° C. so that the entire vial, except the cap, is immersed in the bath. When the pyridine hydrochloride melts, stir to effect a homogeneous solution. Heat for 1.5 h and then allow to cool. Treat the resulting solid with 1N HCl solution and ethyl acetate until all solids are dissolved and transferred to a separatory funnel. Extract the aqueous portion with ethyl acetate (2×). Combine the organic portions and wash with brine, then dry (MgSO4), filter and concentrate in vacuo to give a yellow gum. Purify by flash chromatography (gradient of 10% EtOAc/hexanes to 33% EtOAc/hexanes) followed by trituration in diethyl ether and drying under house vacuum to obtain 24 mg (40%) of the title compound as a pale yellow solid. MS (ES): m/z=499 (M+1), 497 (M−1); 1H NMR(DMSO-d6): δ8.43 (s, 1H), 8.24 (d, J=9 Hz, 2H), 7.57-7.43 (m, 4H), 7.37-7.23 (m, 3H), 7.15 (t, J=8 Hz, 1H), 7.01 (m, 2H), 6.76 (s, 2H), 5.11 (s, 2H), 2.12 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccccc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and phenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4 (s, 1H), 8.4 (s, 1H), 8.2 (m, 1H), 8.05 (d, 1H, J=7.2 Hz), 7.9 (m, 2H), 7.8 (m, 2H), 7.4-7.7 (m, 7H), 7.0 (d, 1H, J=10.1Hz), 4.3 (m, 2H), 3.6 (s, 4H), 2.9 (m, 2H), 2.6 (m, 4H).
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][CH:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[CH:4]([CH2:31][C:30](=[O:32])[CH2:29][CH2:28][CH:27]([CH3:33])[CH3:26])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:13])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CC(=O)CCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
An oily suspension (50% by weight; 0.5 g) of sodium hydride is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1.6 g) in anhydrous dimethylformamide (20 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. A solution of 5-methyl-2-hexanone (1.2 g) in anhydrous dimethylformamide (5 cc) is then added and stirring is continued for 5 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (200 cc) and extracted with dichloromethane (3×100 cc). The organic phases are combined, washed with distilled water (5×20 cc) and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is purified by chromatography on silica gel (15 g) contained in a column 1.5 cm in diameter [eluent: dichloromethane/methanol (99:1 by volume)]. Elution is first performed with 30 cc of solvent: the corresponding eluate is discarded; elution is then performed with 100 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is recrystallized in ethyl acetate; 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (1.3 g), m.p. 150° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[C:16]3[O:23][CH2:22][CH:21]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:20][C:17]3=[N:18][CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.B.C1COCC1>C1COCC1>[CH2:25]([NH:24][CH:21]1[CH2:22][O:23][C:16]2[C:17](=[N:18][CH:19]=[C:14]([NH:13][S:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:15]=2)[CH2:20]1)[CH2:26][CH3:27]
Reactant: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Agent: B
Solvent: C1CCOC1
Product: CCCNC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a solution of N-[7-(4-trifluoromethoxy-benzenesulfonylamino)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl]-propionamide (93 mg, 0.20 mmol) in THF (20 ml) was added dropwise 1M BH3.THF (2.08 ml, 2.08 mmol) and the mixture was stirred at room temperature for 12 h. It was then quenched by adding carefully 1N aqueous HCl (8 ml) and then the resulting solution was heated at reflux for 4 h. The solution was cooled to room temperature, the aqueous mixture was adjusted to pH˜8 with 2 N NaOH solution and diluted with CH2Cl2. Separation of the layers, drying (Na2SO4) of the organic phase and evaporation in vacuo provided the crude material, which was purified by flash column chromatography (CH2Cl2:methanol, 97:3) to give the title compound (70 mg, 78%) as a white amorphous solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)(C)(C)C>>[C:1]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: O=C(c1ccccc1)N1CCNCC1

Procedure:
This was similarly prepared from benzoic acid (5.02 g) and 1-(tert-butoxycarbonyl)piperazine (7.66 g) and the title compound was isolated as a white solid (7.7 g, 82%). LCMS: Rt 0.51 min; m/z 191 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][O:11][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](COC1CCCCO1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl N-(tert-butoxycarbonyl)-L-serinate (prepared according to the reported procedure: Bioorg. Med. Chem. 2007, 15, 2860-2867, 10.0 g, 64.27 mmol) in dichloromethane (100 mL), p-toluenesulfonic acid (0.24 g, 1.28 mmol) and 3,4-dihydro-1H-pyran (8.8 mL, 96.67 mmol) were added and the mixture was stirred at the room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2×50 mL), brine solution (50 mL) and dried over sodium sulfate. Removal of solvent under vacuum and also high vacuum to remove excess 3,4-dihydro-1H-pyran. The residue was dissolved in ethyl acetate (10 mL) and pet. ether (100 mL) was added over it was stirred for 10 minutes. The solid obtained was filtered and washed with pet. ether (50 mL). Yield: 12.0 g (78%). 1H NMR (400 MHz, DMSO-d6) δ: 1.33-1.34 (m, 1H), 1.39 (s, 9H), 1.41-1.68 (m, 6H), 3.41-3.45 (m, 1H), 3.55-3.59 (m, 1H), 3.61 (s, 3H), 3.81-3.84 (m, 1H), 4.23-4.28 (m, 1H), 4.58 (br s, 1H), 7.15 (d, 1H).
Reaction SMILES: [Si](O[C@@:9]1([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[S:32][CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)[N:35]=4)=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:16]=2)[N:10]1C([O-])=O)(C(C)(C)C)(C)C.Cl.C[OH:58]>>[OH:58][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C@@H:9]1[NH:10][C@H:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[S:32][CH:33]=[C:34]([C:36]5[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:45])[F:44])=[CH:40][CH:41]=5)[N:35]=4)=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CO
Reactant: CC(C)(C)[Si](C)(C)O[C@@]1(Cc2ccccc2)CCC(Cc2ccc(NS(=O)(=O)c3ccc(-c4nc(-c5ccc(C(F)(F)F)cc5)cs4)cc3)cc2)N1C(=O)[O-]
Agent: Cl
Product: O=S(=O)(Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 16 mg (0.02 mmol) of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl-5-(4-{[(4-{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}phenyl)sulfonyl]amino}benzyl)pyrrolidine-1-carboxylate (from Step A) in 0.25 mL methanol was added 0.25 mL conc. HCl and the reaction mixture stirred at room temperature for 30 min. Azeotrop with toluene (2×) to remove water. The residue was taken up in acetonitrile/water/MeOH (9:1:1) and purified on the Gilson HPLC eluting with a 0-50% gradient of acetonitrile/water with 0.05% TFA buffer. The fractions containing the product were combined, frozen, and lyophilized to give a white foam (7.3 mg, 61%). m/z (ES) 650 (MH)+. 1HNMR (500 MHz, CD3OD) δ: 8.22 (br d, J=7.8 Hz, 2H), 8.15-8.10 (m, 3H), 7.86 (d, J=7.8 Hz, 2H), 7.72 (d, J=7.8 Hz, 2H), 7.38-7.30 (m, 4H), 7.16 (br d, J=7.8 Hz, 2H), 7.09 (br d, J=7.8 Hz, 2H), 4.56 (d, J=8.1 Hz, 1H), 3.54-3.45 (m, 2H), 2.93 (dd, J=6.4, 13.0 Hz, 1H), 2.82 (dd, J=7.7, 13.0 Hz, 1H), 1.90-1.82 (m, 1H), 1.68-1.53 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O.N>O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:23])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reaction time: 0.5 h
Yield: 463.4 %

Procedure:
214 g ( =1.0 mole) of 2,4-dihydroxybenzophenone were added to a mixture of 500 ml of 2 N sodium hydroxide solution and 150 ml of water at room temperature and stirring was carried out until everything had dissolved (20 minutes). Thereafter, 31.6 ml (=0.33 mole) of dimethyl sulfate were added and stirring was continued for 0.5 hour, after which a further 31.6 ml (=0.33 mole) of dimethyl sulfate were added while stirring. After 0.5 hour, a further 31.6 ml (=0.33 mole) of dimethyl sulfate were added while stirring and, after 0.5 hour, 50 ml of 2 N sodium hydroxide solution and 9.5 ml of dimethyl sulfate were added. The mixture was stirred for 1 hour at room temperature, 30 ml of concentrated ammonia solution were added and stirring was then continued for a further 0.5 hour. The precipitate which had separated out was filtered off under suction and washed with a little water to give 349 g (202.4 g of dry product=89% of theory) of moist 2-hydroxy-4-methoxybenzophenone, which contains 1.07% of 2,4-dimethoxybenzophenone. The moist filtration residue was recrystallized from 1,170 ml of methanol with the addition of 5 g of active carbon. After filtration under suction and drying under reduced pressure from a water pump at 50° C., 171 g (=75% of theory) of pure 2-hydroxy-4-methoxybenzophenone of melting point 62°-63° C. were obtained. According to gas chromatography, the product did not contain any dimethoxy derivative.