Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[N:35]([CH:41]1[CH2:46][CH2:45][C:44](=[O:47])[NH:43][C:42]1=[O:48])[C:34]2=[O:49].CCOC(C)=O>CN(C)C=O>[O:48]=[C:42]1[CH:41]([N:35]2[C:34](=[O:49])[C:33]3[C:37](=[CH:38][CH:39]=[C:31]([CH2:30][NH:29][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=4)=[O:11])[CH:32]=3)[C:36]2=[O:40])[CH2:46][CH2:45][C:44](=[O:47])[NH:43]1
Reactant: CSc1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A stirred mixture or 5-methylsulfanyl-pyridine-2-carboxylic acid (0.34 g, 2.00 mmol) and CDI (0.34 g, 2.10 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 90% EtOAc). The product fractions were combined and concentrated to give 5-methylsulfanyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.55 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 2.89 min (98.58%); mp: 185-187° C.; 1H NMR (DMSO-d6) δ 1.83-2.18 (m, 1H), 2.52-2.68 (m, 5H), 2.78-3.02 (m, 1H), 4.64 (d, J=6.4 Hz, 2H), 5.14 (dd, J=5.4, 12.9 Hz, 1H), 7.76-7.91 (m, 4H), 7.92-8.00 (m, 1H), 8.53 (d, J=1.9 Hz, 1H), 9.52 (t, J=6.3 Hz, 1H), 11.11 (s, 1H); 13C NMR (DMSO-d6) δ 13.93, 21.99, 30.93, 42.36, 48.99, 122.08, 123.51, 129.78, 131.56, 133.56, 133.83, 139.66, 145.03, 145.90, 147.57, 164.11, 166.99, 167.13, 169.80, 172.72; LCMS: MH=439; Anal Calcd for C21H18N4O5S: C, 57.53; H, 4.14; N, 12.78. Found: C, 57.17; H, 4.04; N, 12.54.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=3)[C:9](=[O:19])[NH:8]2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=1)[NH:8][C:9]2=[O:19]
Reactant: O=c1[nH]n(Cc2ccc(F)cc2)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of 1-(4-fluoro-benzyl)-5-nitro-1,2-dihydro-indazol-3-one (0.81 g) in MeOH (100 mL) was added Pd/C(10%) catalyst (0.1 g) and the reaction mixture was stirred for three hours at 40° C. under a hydrogen atmosphere using a balloon. After this time the reaction mixture was filtered through Celite® which was washed with more EtOAc. The combined organic solution was evaporated in vacuo for afford the desired 5-amino-1-(4-fluoro-benzyl)-1,2-dihydro-indazol-3-one (0.617 g) which was taken into the next reaction without further purification. MS (ESI+): 258.3 ([M+H]+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[I-:40].[Na+].O>CC(=O)CC>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@H:15]2[C@H:16]([OH:21])[C@@H:17]([OH:20])[C@H:18]([OH:19])[C@@H:13]([CH2:12][I:40])[O:14]2)=[CH:23][C:24]=1[CH2:29][C:30]1[S:31][C:32]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=[CH:33][N:34]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](CI)[C@H]1O
Yield: 48.3 %

Procedure:
The solution of toluenesulfonate 90 (100 mg, 0.17 mmol) and sodium iodide (38 mg 0.25 mmol) in 2-butanone (1.7 mL) was stirred at 80° C. for 2 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the titled compound 95 (45 mg, 48%) as a solid. MH+547
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:34]([F:33])([F:43])[F:44])=[O:24])[CH2:19][CH2:18]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1

Procedure:
A solution of trans-4-(4-(methylamino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid as TFA salt (18.4 mg, 0.04 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (10.5 mg, 0.06 mmol, 1.5 equivalents) and DMAP (1.3 mg, 0.26 equivalents) in dichloromethane (1 ml) was cooled with stirring in an ice bath. EDCl (12.7 mg, 0.066 mmol, 1.65 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed to give the crude product, which was further purified by RP-HPLC (Luna 5μ, C8(2), 100×21 mm, 5-40% CH3CN/H2O, 0.1% TFA, 25 min) to give the final product (5.33 mg, 21.5%). MS (ES+): m/e 507.21 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=[O:6])[CH2:3]1>Cl>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: CCOC(=O)C1CCCN(C)C1
Agent: Cl
Product: CN1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
(±)-Ethyl N-methylnipecotate (5.0 g) was dissolved in 5M hydrochloric acid (100 ml) and stirred at room temperature for 16 h. The solution was then evaporated at reduced pressure and the residue re-evaporated from toluene (×2). Trituration gave the hydrochloride salt of (±)-N-methylnipecotic acid as a white solid (3.91 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@H:32]1[CH2:41][C:40]2[C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:34][CH2:33]1>CN(C)C=O>[C:51]([O:50][C:48]([N:45]1[CH2:46][CH2:47][N:42]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[CH2:41][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33][CH2:34]3)[CH2:43][CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.59 g, 2.8 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformamide (30 mL) was added 1,1′-carbonyldiimidazole (0.48 g, 3.0 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of tert-butyl (R)-4-(7-amino-5,6,7,8-tetrahydro-1-naphthyl)piperazine-1-carboxylate (0.90 g, 2.7 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 1.5 g (84% yield) of the title compound as a dark-red viscous oil: [α]21D −45° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 520 (5, M+).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1)=[O:35]>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([C@H:36]1[CH2:37][CH2:38][C@H:39]([NH:42][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:40][CH2:41]1)=[O:35]
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.Cl>C(#N)C.O1CCOCC1>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 65 °C

Procedure:
To a solution of (R)-methyl 3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 8a, (21 g, 39 mmol) in acetonitrile (157 mL) was added 4M HCl in dioxane (174 mL). The reaction mixture was heated to 65° C. for 4 h. The solution was cooled to room temperature and the solvents were removed under reduced pressure. The mixture was flushed with acetonitrile after which dichloromethane (100 mL), sat. aqueous NaHCO3 (355 mL) and ethyl acetate (400 mL) were added. The phases were separated and the aqueous layer washed with ethyl acetate (500 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on silica gel (EtOAc/Hexanes) to provide the desired product, 9a, (12.1 g): LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=2.26 minutes (M+H) 391.05.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:14])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].Cl[S:16](F)(=[O:18])=[O:17]>>[CH3:12][C:10]1[O:11][S:16](=[O:18])(=[O:17])[NH:14][C:8](=[O:13])[CH:9]=1
Reactant: CC(=O)CC(N)=O
Reactant: O=S(=O)(F)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(=O)NS(=O)(=O)O1
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture, with a total volume of 50 ml, of 40.4 g (0.4 mol) of triethylamine and liquid SO2 was added dropwise, at -10° C., to a solution of 20.2 g (0.2 mol) of acetoacetamide and 23.7 g (0.2 mol) of chlorosulfonyl fluoride in 70 ml of liquid SO2. The mixture was stirred for 2 hours and the liquid SO2 was then distilled off, a vacuum being applied at the end. The residue was added dropwise to 400 ml of aqueous NaOH, acidified with concentrated hydrochloric acid, with ice-cooling, and extracted with ethyl acetate. After treatment of the ethyl acetate phase with animal charcoal and Na2SO4, the extract was evaporated in vacuo. 15 g (approx. 20% of theory) of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide were obtained.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C.O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(O)CCl
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(O)COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 36.7 %

Procedure:
A solution of 8.15 g (0.075 mol) of 1-chloro-2-methyl-2-propanol in 20 ml of ethanol is run over the course of 25 minutes into a solution, kept at about 60° C., of 15 g (0.068 mol) of p-(p-chlorophenoxy)phenol and of 3 g (0.075 mol) of sodium hydroxide pellets in 20 ml of water and 20 ml of ethanol. The mixture is heated to the reflux temperature for 2 hours and the ethanol is driven off under reduced pressure. The residue is extracted with diethyl ether and after drying and evaporation of the solvent gives 7.3 g of a yellow oil. This oil is purified by crystallisation from a mixture of cyclohexane and petroleum ether (1:2 by volume) followed by washing with 2 N NaOH. 4 g of a white powder which is insoluble in water are obtained.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]([CH3:7])=[CH2:6].[CH3:8][CH:9]([CH2:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:10]>>[CH:9]([CH:11]([CH2:2][CH:3]=[CH:4][C:5]([CH3:7])=[CH2:6])[C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:10])[CH3:8]
Reactant: C=C(C)C=CCCl
Reactant: CC(C)CC(=O)CC(C)C
Product: C=C(C)C=CCC(C(=O)CC(C)C)C(C)C

Procedure:
According to the procedure described in Example 1, from 1-chloro-4-methyl-2,4-pentadiene and 2,6-dimethyl-heptan-4-one there is obtained the above ketone; b.p.=72° C./0.3 mm Hg; nD20 =1.4728. Odour: linalool-like with a musk note, very natural.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)[CH2:6][C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]1([CH2:4][C:5]2[N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[N:14]=[N:15][C:6]=2[C:7]([OH:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CC1CC1
Agent: CC[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CC2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 101.7 %

Procedure:
Ethyl 4-cyclopropyl-3-oxobutyrate (1.20 g, 7.05 mmol, 1.2 eq.) obtained in Example 96a) and 4-azido-N-ethylbenzamide (1.20 g, 5.88 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (556 mg, 7.35 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 80° C. for 2.5 hr. 2% Aqueous sodium carbonate solution (40 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with water (20 ml) and washed twice with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid, and stood still at 5° C. The precipitate was collected by filtration, washed with cold water and dried to give the title compound as a pale-brown powder (1.88 g, 5.98 mmol, 101.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>CO.N1CCCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:16][C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(F)c1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cccc(F)c1
Temperature: 75 °C

Procedure:
6-Chloro-1,3-dihydro-indol-2-one (Aldrich, 7.5 g, 44.92 mmol) was treated with 3-fluoro-benzaldehyde (Aldrich, 5.57 g, 44.92 mmol) in methanol (50 mL) and piperdine (0.2 mL). The mixture was heated at 75° C. overnight and then cooled to room temperature. The solid was filtered and dried to give a yellow solid. 8.8 g.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>Br.C(O)(=O)C>[Br:21][CH:9]([C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: BrBr
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.25 g. of 1-(3-benzoylpropionyl)-L-proline (Example 16) in 80 ml. of acetic acid is added 5 drops of 30% hydrogen bromide in acetic acid followed by 4.80 g. of bromine in 20 ml. of acetic acid. The mixture is stirred at room temperature for 18 hours, evaporated to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed with water and saline, dried over magnesium sulfate and evaporated to dryness giving the desired product as 10.3 g. of a white glass.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[C:5](=[O:12])[N:4]1[C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:28][C@@H:29]([C:31]1[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(O)(C)C>[C:23]([O:28][C@@H:29]([C:31]1[N:32]=[C:33]([N:8]2[CH2:9][CH2:10][C:11]3[N:3]([CH3:2])[N:4]([C:13]4[CH:22]=[N:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[C:5](=[O:12])[C:6]=3[CH2:7]2)[CH:34]=[CH:35][N:36]=1)[CH3:30])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 1-methyl-2-quinoxalin-2-yl-1,2,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one hydrochloride (prepared according to the method of Example 75, Step C, 175 mg, 0.55 mmol) and (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 126 mg, 0.55 mmol) in isopropanol (6 mL) was added triethylamine (230 μL, 1.66 mmol). This mixture was heated to reflux overnight, cooled to room temperature, and evaporated. The residue was diluted, with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5% methanol/chloroform) to give 248 mg (95%) of the title compound of Example 75, Step D as a yellow oil. 1H NMR (CDCl3, 250 MHz) δ 9.70 (s, 1H), 8.29 (d, 1H), 8.15 (dd, 1H), 8.03 (m, 1H), 7.82-7.70 (c, 2H), 6.48 (d, 1H) 5.72 (q, 1H), 4.36 (s, 2H), 4.35-4.15 (c, 2H), 3.42 (s, 3H), 2.77-2.82 (c, 2H), 2.43 (t, 2H), 1.79-1.60 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 474 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][CH3:37])=[C:9]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:43])=[O:42]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:35][CH2:36][CH3:37])=[C:9]([C:11]2[N:12]([C:32]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:48][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 20% of 1:1 ethanol/acetonitrile in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C38H49N4O4SCl2 [(M+H)+] 727.2846, observed 727.2847.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F-].[K+].Br[CH2:17]Br>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[O:12][CH2:17][O:13][C:10]=2[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)c(O)c1Cl
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1Cl)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a heavy walled vial containing methyl 2-chloro-3,4-dihydroxybenzoate (899.8 mg, 4.4 mmol, 1 equiv.) in 13 mL DMF was added KF (1.29 g, 22.2 mmol, 5 equiv.) and the mixture was stirred at room temperature for 30 min. Dibromomethane (0.375 mL, 5.3 mmol, 1.2 equiv.) was added and the mixture was heated to 120° C. for 4 h. The mixture was cooled down to room temperature, diluted with water, and extracted with ethyl ether. The combined ether layers were washed with 1M NaOH, water, brine, dried over anhydrous Na2SO4, filtered and solvent removed under vacuum. The crude product was absorbed onto silica and purified by flash column (silicagel, hexane:ethyl acetate 8 Å to give 395.8 mg (42%) of methyl 4-chlorobenzo[d][1,3]dioxole-5-carboxylate as a colorless crystalline solid. See Tetrahedron Lett. 38: 3361-3364 (1978); U.S. Patent Appl. Publication No. 20050009867.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:11][CH:10]=2)[S:3]1.Cl.C(=O)([O-])[OH:27].[Na+]>C(O)C>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:27])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)=[N:19][CH:20]=1
Reactant: Cc1ccc(CCOc2ccc(CC3SC(=N)NC3=O)cc2)nc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Yield: 87.5 %

Procedure:
A mixture of 2-imino-5-{4-[2-(5-methyl-2-pyridyl)ethoxy]benzyl}-4-thiazolidinone (8.0 g), 2N HCl (80 ml) and ethanol (80 ml) was refluxed for 16 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate to yield crystals. The crystals were collected by filtration and recrystallized from ethanol to give 5-{4-[2-(5-methyl-2pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as colorless prisms (7.0 g, 87.5%), m.p. 192°-193° C.