Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([NH:27][C:28]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 33.4 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and t-butylisocyanate (0.31 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×100 mL), dried (MgSO4) and concentrated. The crude product was purified by prep-HPLC (35/65 CH3CN/H2O). The product fractions were combined, concentrated and dried in vacuo to give 1-tert-butyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.40 g, 84% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.89 min (97.00%); mp: 202-204° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 1.97-2.14 (m, 1H), 2.53-2.71 (m, 2H), 2.79-3.02 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 5.89 (s, 1H), 6.34 (t, J=6.0 Hz, 1H), 7.65-7.79 (m, 2H), 7.87 (d, J=7.7 Hz, 1H), 11.08 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 29.2, 30.9, 42.3, 48.9, 49.2, 121.4, 123.4, 129.5, 131.5, 133.0, 149.6, 157.3, 167.0, 167.2, 169.8, 172.7; Anal Calcd for C19H22N4O5+0.3H2O: C, 58.24; H, 5.81; N, 14.30. Found: C, 58.15; H, 5.52; N, 14.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.O.NN.Cl>C(O)COCCO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)CCCCCC(=O)O)cc1
Agent: Cl
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(CCCCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a stirring solution of 7.5 gms 9(4-methoxyphenyl)-7-ketononanoic acid in 35 ml diethylene glycol was added 5.1 ml hydrazine hydrate. The mixture was heated to 120° for 4 hrs, cooled to room temperature, connected to a water aspirator, and gently heated to 120° to remove excess water and hydrazine. The reaction mixture was cooled to 70°, 7.2 gm KOH was added, and the mixture was heated up to 220° C. where it was kept for 5 hr, then cooled. The cooled reaction mass was dissolved in 120 ml hot water, acidified with conc. HCl, and 3× extracted with CHCl3. The combined organic phases were dried over MgSO4, filtered, and the solvent was evaporated in vacuo. Attempts to crystallize the product failed, so it was vacuum sublimed twice, dissolved in 300 ml chloroform, filtered through silica gel, and the solvent evaporated to give 38% product, a white solid of m.p. 41°-3° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[OH-].[Na+].O.Cl>CO>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:6]=1
Reactant: COC(=O)c1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
6-Methyl-2-(4-trifluoromethyl-phenyl)nicotinic acid methyl ester (7.26 g) was dissolved in methanol (30 mL). 4M sodium hydroxide (7.2 mL) was added thereto at 0° C. under cooling. The mixture was stirred at 45° C. for 3 hours. Water (30 mL) was added to the mixture at 0° C. under cooling, followed by acidification (pH=3) with 1M hydrochloric acid (about 30 mL) to give the precipitate. The precipitate was filtered and dried to give the title compound as a colorless solid (6.5 g). 1H-NMR (δ, 300 MHz, CDCl3): 2.66 (3H, s), 7.61 (2H, d, J=8.3 Hz), 7.67 (2H, d, J=8.3 Hz), 7.27 (1H, d, J=7.9 Hz), 8.18 (1H, d, J=7.9 Hz)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (496 mg, 1.28 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2.0 mL, 4.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (321 mg, 87%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.0 Hz), 4.51 (s, 2H), 3.50 (t, 2H, J=6.0 Hz), 3.39 (br, 1H), 3.07 (d, 2H, J=12.0 Hz), 2.59 (t, 2H, J=11.6 Hz), 1.66 (d, 2H, J=12.8 Hz), 1.54 (m, 3H), 1.20 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[O:3]1.Cl.[NH:28]1[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[OH:33][CH:30]1[CH2:31][CH2:32][N:28]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:6]4[CH2:5][C:4]5([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)[O:3][C:2]4=[O:1])=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)[CH2:29]1
Reactant: O[C@@H]1CCNC1
Reactant: O=Cc1ccc(-c2ccc(CN3CC4(CCCCC4)OC3=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccc(CN3CCC(O)C3)cc2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehyde (50 mg, 0.143 mmol) was mixed with (R)-(−)-3-pyrrolidinol hydrochloride (20 mg, 0.157 mmol) in DCE (2.5 mL). Na(OAc)3BH was added as a solid at room temperature and the reaction was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous phase was extracted with DCM (3×5 mL), the combined organic phases were washed with brine (5 mL), dried over sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with DCM containing 0.5˜2% 2M ammonia in methanol to give the product as off-white solid (34 mg, 56.5%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.59 (dd, 4H), 7.38 (d, 2H), 7.29 (d, 2H), 4.42 (s, 2H), 4.37 (m, 1H), 3.69 (s, 2H), 3.13 (s, 2H), 2.87 (m, 1H), 2.67 (d, 1H), 2.58 (dd, 1H), 2.37 (m, 2H), 2.2 (m, 1H), 1.76 (m, 4H), 1.51 (m, 6H).
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]S)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][S:10][CH:13]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Product: CCOC(=O)C1=CCCCC1SCc1ccc(OC)cc1
Yield: 95.6 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (1 g) and (4-methoxyphenyl)methanethiol (893 mg) were reacted to give ethyl 6-[(4-methoxybenzyl)-sulfanyl]-1-cyclohexene-1-carboxylate (848 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[O:10][CH3:11].[C:12]([NH2:23])(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](N)=[O:16].[K]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8][N:23]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: COc1c(Br)cccc1CBr
Agent: [K]
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 51.4 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)-2-(methyloxy)benzene (41.4 g, 0.15 mol) in DMF (350 mL), Potassium Phthalamide (PhtK) (28.8 g, 0.16 mol) was added, and the mixture was heated to 90° C. over night. Then the solvent was removed under reduced pressure. The residue was dissolved in CHCl3 (300 mL), and filtered. The filtrate was washed with H2O (100 mL×2), brine (100 mL), and dried over Na2SO4. After removing the solvent, the residue was recrystallized with EtOH (200 mL). 26.7 g of the product was obtained as white solid. Yield: 52.1%. 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3 H), 4.95 (s, 2H), 6.93 (t, J=8.0 Hz, 1 H), 7.20 (d, J=0.8 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 7.72-7.87 (m, 4 H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])=[CH:11][C:10]=3[F:23])[N:7]=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=2)[CH2:3][CH2:2]1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([C:4]2[N:8]([C:9]3[C:10]([F:23])=[CH:11][C:12]([NH:16][C:17](=[O:22])[C:18](=[CH:30][N:31]([CH3:33])[CH3:32])[C:19](=[O:21])[CH3:20])=[CH:13][C:14]=3[F:15])[N:7]=[C:6]([C:24]([F:27])([F:26])[F:25])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Product: CC(=O)C(=CN(C)C)C(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-3,5-difluorophenyl)-3-oxobutanamide (1 g, 2.6 mmol) and N,N-Dimethylformamide dimethylacetal (1.7 g, 14.2 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.7 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[NH:12][C:11](=[O:22])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:47]([O:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[O:21])[NH:55][O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:17]=2)[NH:12][C:11](=[O:22])[C:10]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To an ice-cooled solution of 1-Benzyloxy-7-carboxyquinoxaline-2,3(1H,4H)-dione (422 mg, 1.35 mmol) in 10 ml of N,N-dimethylformamide was added 1-hydroxybenzotriazole (218 mg, 1.48 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol). Stirring was continued for 30 min at 0° C. and O-benzylhydroxylamine hydrochloride (237 mg, 1.49 mmol) and dry triethylamine (0.21 ml, 1.5 mmol) was added. The mixture was stirred overnight at room temperature, then cooled and filtered. The isolated solid was successively washed with water, saturated aqueous sodium hydrogen carbonate and water. Recrystallisation from ethanol gave 290 mg (51%) of the title compound. 1H-NMR (DMSO-d6): 4.95 (s, 2H, CH2), 5.19 (s, 2H, CH2), 7.2-7.8 (m, 13H, ArH), 11.8 (br.s, 1H, exchangeable), 12.3 (br.s, 1H, exchangeable).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([NH:21][C:22]([NH:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][C:11]3([S:15][C:14](=[O:16])[NH:13][C:12]3=[O:17])[C:6]=2[CH:5]=[C:4]([F:18])[CH:3]=1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(F)cc2c1OCCC21SC(=O)NC1=O
Temperature: 50 °C

Procedure:
268 mg of (±)-8-amino-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione were stirred in 2 ml of tetrahydrofuran with 100 μl of ethyl isocyanate at room temperature for 2.5 hours and the mixture was subsequently heated to 50° C. for an additional 2 hours. The liquid constituents were removed under reduced pressure, he residue was purified by chromatography on a silica gel column using hexane/ethyl acetate (1:2) for the elution, decolorized with active carbon and recrystallized from ethyl acetate/hexane. (±)-1-Ethyl-3-[6-fluoro-2,3-dihydro-2',4'-dioxospiro[4H-1-benzopyran-4,5'-thiazolidin]-8-yl]-urea was obtained in the form of colorless crystals of melting point 197°-199° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[F:33][C:31]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:32]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1C(F)(F)F
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(F)cc2C(F)(F)F)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro -pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-trifluoromethyl-4-fluorobenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (25.7 mg, 56% yield). 1HNMR (500 MHz, CDCl3) δ: 12.07 (1H, s), 7.92 (1H, t, J=5.34), 7.53–7.47 (1H, m), 7.36 (1H, s), 7.24 (2H, d, J=8.24 Hz), 7.06 (2H, dd, J=8.54, 7.33 Hz), 4.63 (2H, d, J=6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C20H12F6N3O3 (M−H): 456.0783; found: 456.0793.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24]C(=O)OC(C)(C)C)[N:8]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:9]1[N:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:12]2[C:13](=[O:16])[NH:14][CH2:15][C:11]=2[CH:10]=1
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (94 mg, 0.22 mmol) and TFA (1 mL, 12.98 mmol) in DCM (1 mL) was stirred at RT for 2 h. The mixture was subsequently concentrated. The residue was purified by preparative HPLC (01-25; 5.45 min) and basified to give the title compound as a yellow solid (10 mg, 14%). 1H NMR (500 MHz, DMSO-d6) δ ppm 122-1.61 (m, 8 H), 3.63 (s, 3 H), 4.19 (s, 2 H), 6.46 (br s, 1 H), 7.98 (s, 1 H), 8.29 (s, 1 H), 8.85 (s, 1 H). [M+H] calc'd for C17H22N6O, 327; found, 327.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccc(Br)cc2)CCCC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (20 g, 60.01 mmol) in dimethyl sulfoxide (100 mL) were added KI (0.99 g, 6.00 mmol) and NaCN (4.41 g, 90.02 mmol). The reaction mixture was then stirred at 140° C. for 5 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate (2×250 mL) and the organic layer was washed with water and brine. It was then dried over Na2SO4, and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (13.9 g, 87%) as a colorless thick liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.Cl.CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:8]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2cccc(Br)c2nc1Nc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cc(C)c(Nc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of 8-bromo-3-methyl-N-phenylquinolin-2-amine (182.0 mg, 0.581 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Inc., Wake Forest, N.C.; 0.216 mL, 0.639 mmol), and Pd(PPh3)4 (33.6 mg, 0.029 mmol) in toluene (3.0 mL) was sparged with argon and stirred under argon at 100° C. for 16 h. The mixture was then concentrated in vacuo, and the residue was taken up in THF (3.0 mL). HCl (concentrated, aq.; 0.073 mL, 0.872 mmol) was added, and the resulting mixture was stirred at 60° C. for 15 min. Et3N (0.243 mL, 1.743 mmol) was added, and the mixture was concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished 1-(3-methyl-2-(phenylamino)quinolin-8-yl)ethanone (161 mg, 0.583 mmol, 100% yield) as a yellow oil: 1H NMR (400 MHz, CD Cl3) δ ppm 7.79 (1H, s), 7.76 (1H, d, J=7.2 Hz), 7.64-7.72 (3H, m), 7.38 (2H, t, J=7.8 Hz), 7.29 (1H, t, J=7.5 Hz), 7.11 (1H, t, J=7.4 Hz), 6.52 (1H, br. s.), 2.76 (3H, s), 2.44 (3H, s). m/z (ESI, +ve) 277.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]([O:17][CH2:18][N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([NH:29]C(=O)C)=[N:23][C:24]=2[OH:28])[CH2:8][O:9]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].C1CCCCC=1>[Pd].C(O)C>[NH2:29][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[CH:27][N:19]2[CH2:18][O:17][CH:7]([CH2:8][OH:9])[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:24]([OH:28])[N:23]=1
Reactant: CCCCOCC(COCc1ccccc1)OCn1cnc2c(O)nc(NC(C)=O)nc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCCOCC(CO)OCn1cnc2c(O)nc(N)nc21
Reaction time: 36 h
Yield: 8.7 %

Procedure:
A mixture of N-[9-[[1-(butoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6-hydroxy-9H-purin-2-yl]acetamide (1.15 g, 25.9 mmol), 20% palladium on carbon (0.2 g), cyclohexene (20 ml), and ethanol (10 ml) is heated at reflux under N2. After 8 and 2O hours, additional amounts of catalyst (0.1 g) are added. After 36 hours, the solution is cooled, filtered through celite, and the filter cake is washed with DMF/ethanol. The filtrates are combined, refiltered and concentrated. The residue is mixed with aq. methyl amine (20 ml) and the mixture is heated at reflux for two hours, filtered and concentrated. The residue is recrystallized from water to give the desired product (0.7 g), mp 208°-211° C.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]1([C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1>C(O)C>[CH:8]1([C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][O:9]1
Reactant: COC(=O)C(C)(C)C1OCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)C1OCCc2ccccc21
Reaction time: 8 h

Procedure:
Sodium hydroxide (1N, 12 ml) is added dropwise over several minutes, followed by a few mls of THF (to aid in solution) to a mixture of methyl 2-(isochroman-1-yl)-2-methylpropionate (LXXI, 1.833 g, 7.8 mmol) in ethanol (12 ml). The mixture is stirred overnight at 20°-25°, then at 47° for 2 hr, followed by stirring at 20°-25° over the weekend. Additional THF and sodium hydroxide (1N, 12 ml) are added and the mixture is stirred overnight at 20°-25° and then at 40° for 7 hr, followed by overnight at 20°-25°. Ethanol is then removed under reduced pressure and the resulting solids are dissolved in water. The aqueous phase is separated and washed twice with hexane to remove any unreacted starting material and the aqueous phase is then cooled in an ice/water bath and hydrochloric acid (4N, 6 ml) is added dropwise. The mixture is extracted three times with ether and the combined organic phases are backwashed with saline, dried over magnesium sulfate, and concentrated. Recrystallization from dichloromethane/hexane gives 2-(isochroman-1-yl)-2-methylpropionic acid (LXXII), mp 110.5°-115.75°.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH-:13].[K+:14].[OH-:15].[Na+]>>[O:1]=[C:2]([O-:15])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[K+:14].[K+:14]
Reactant: [OH-]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [K+]
Agent: [Na+]
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
The oxidation of D-glucose was carried out as in Examples 1 and 2. However, potassium hydroxide was substituted for sodium hydroxide in the neutralization process to give crude D-glucaric acid dipotassium salt (151.25 g, 70.4% based on pure dipotassium D-glucarate). The salt was precipitated from methanol as described to give an off white solid (145.75 g, 67.9% based on pure dipotassium D-glucarate).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:35][CH2:34]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2F)CC1
Temperature: 20 °C
Yield: 46.2 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), triethylamine (3.5 cc) and 4-(2-fluorophenyl)piperazine (4.4 g) in toluene (150 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (15 cc), 2-{3-[4-(2-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1dioxide (4.8 g) is obtained, m.p. 112° C.