Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH3:10])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[CH:13][C:12](=[O:23])[N:11]2[CH:9]([CH3:10])[CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:3][CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 43 %

Procedure:
1-[2-(4-aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example 69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing 0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][C@H:11]([CH2:13][S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:10][C:9]1=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-:35].[Na+].Cl>CO.O>[OH:35][C@@H:11]([CH2:13][S:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C@@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9]([OH:10])=[O:34]
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.72 g (7.88 mmol) of the product of Example 17 in 100 mL of methanol (1:1) at room temperature was added 16.7 mL of 1.0N NaOH solution. The reaction was stirred at room temperature for 1 h and then diluted with 100 mL of H2O and carefully acidified to pH 6 with 5% HCl solution. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue, 3.72 g (100%) of the crude hydroxy-acid was used in the next step (Example 25) without further purification. Electrospray Mass Spec: 489.4 (M-H)-.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl[CH:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:31](=[O:32])[CH3:33])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(C(C)=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 43.8 %

Procedure:
6.6 g (0.02 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 80° C. with 4.5 g of methyl 2-chloroacetoacetate and 4.2 g of triethylamine in 100 ml of dimethylformamide for 3 hours. The solution is then concentrated in vacuo, the residue is stirred with 50 ml of water and the resulting solid product is washed with methanol and water and recrystallized from glycol monomethyl ether. 3.9 g (44% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-[2-oxo-1-(methoxycarbonyl)-1-propyl]-1-piperazinyl}-3-quinolinecarboxylic acid of decomposition point 224° to 228° C. are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:23][S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:40](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.[N:53]1(OC(N(C)C)=[N+](C)C)[C:57]2[N:58]=[CH:59][CH:60]=[CH:61]C=2N=N1>O1CCCC1.N1CCCN=C1N>[C:1]([O:5][C:6](=[O:7])[C@@H:8]([NH:23][S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:25])=[O:26])[CH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18](=[O:19])[NH:40][C:57]2[NH:53][CH2:61][CH2:60][CH2:59][N:58]=2)=[CH:12][CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1cccc2ccccc12
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1=NCCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
61 mg of 4-{4-[(2S)-2-tert-butoxycarbonyl-2-(naphthalene-1-sulfonylamino)-ethyl]-phenoxy}-butyric acid were dissolved in tetrahydrofuran and 14 mg of 1,4,5,6-tetrahydropyrimidin-2-ylamine, 0.103 ml of diisopropylethylamine and 49.7 mg of 7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were added. The reaction mixture was stirred overnight, and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on reversed-phase (C-18) silica gel eluting with a gradient of 10-90% acetonitrile in water. Yield 31 mg. MS (FAB+): m/e=595.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2CC(=C)C[CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:24]CC1.[C:28]([OH:32])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:30][C:28]([OH:32])([CH2:31][OH:24])[CH2:29][CH:11]3[O:16][C:17](=[O:19])[CH:18]=[C:10]23)=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1CC2OC(=O)C=C2N(Cc2ccc(Cl)nc2)C1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=C1C=C2C(CC(O)(CO)CN2Cc2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.86 g (6.72 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-6-methylene-5,6,7,7a-tetrahydrofuro-[3,2-b]pyridin-2(4H)-one (cf. I-5) are dissolved in 20 ml of tetrahydrofuran, and 5.06 ml (0.40 mmol) of a 2.5% strength solution of osmium tetroxide in tert-butanol and 1.28 g (10.08 mmol) of N-methylmorpholine N-oxide are added successively at 0° C. After 3 hours of stirring at room temperature, the mixture is substantially concentrated under reduced pressure, the residue is taken up in water and the mixture is extracted repeatedly with ethyl acetate. Concentration of the organic phase under reduced pressure gives 1.8 g of crude product (mixture of diastereomers). 200 mg of the crude product (taken into account for the determination of the yield) are purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (95:5 to 90:10). This gives both possible diastereomers of 4-[(6-chloropyridin-3-yl)methyl]-6-hydroxy-6-hydroxymethyl-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one: (a) 41 mg (18% of theory) of diastereomer A and (b) 104 mg (47% of theory) of diastereomer B.
Reaction SMILES: C12OC1CCN(C(OCC1C=CC=CC=1)=O)C2.[NH2:18][CH:19]1[CH:24]([OH:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:20]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH:38]1[OH:53].[CH3:54][C:55]([O:58][C:59](O[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:60])([CH3:57])[CH3:56].C(N(CC)CC)C>[OH-].[NH4+].C(O)C.ClCCl>[C:55]([O:58][C:59]([NH:18][CH:19]1[CH:24]([OH:25])[CH2:23][CH2:22][N:21]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:20]1)=[O:60])([CH3:57])([CH3:56])[CH3:54].[C:65]([O:64][C:62]([NH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[O:44])[CH2:39][CH:38]1[OH:53])=[O:63])([CH3:66])([CH3:67])[CH3:68]
Reactant: NC1CN(C(=O)OCc2ccccc2)CCC1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1O
Agent: O=C(OCc1ccccc1)N1CCC2OC2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (+/−) benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) in saturated ammonium hydroxide aqueous solution and ethanol (1:1, 0.05 M solution) in a sealed steel bomb was heated to 70° C. for 5 h. After all volatile materials were removed by N2 gas stream, ethyl acetate and water were added for work-up. The crude regioisomeric mixture, (+/−) benzyl 3-amino-4-hydroxypiperidine-1-carboxylate and (+/−) benzyl 4-amino-3-hydroxypiperidine-1-carboxylate was reacted with Boc2O (1.0 equiv.) and triethylamine (1.0 equiv.) in dichloromethane (0.1 M solution). After stirred for 2 h at room temperature, the reaction mixture was extracted with dichloromethane. The polar (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate and nonpolar (+/−)-benzyl 4-(tert-butoxycarbonylamino)-3-hydroxypiperidine-1-carboxylate were obtained by flash column chromatography (20% to 40% EtOAc in hexanes, 28% and 51% each). LCMS (m/z): 351.1 (MH+), Rt=0.81 min, LCMS (m/z): 351.1 (MH+), Rt=0.83 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8]2)[CH2:3]1.C1CC=CCC=1>CO.[Pd]>[NH:10]1[CH2:11][CH2:12][CH:7]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CC[C@H](O)C2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: O[C@H]1CCN(C2CCNCC2)C1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
Phenylmethyl 4-[(3S)-3-hydroxy-1-pyrrolidinyl]-1-piperidinecarboxylate (1.33 g, 4.37 mmol) was dissolved in methanol (11.65 ml) and 1,4-cyclohexadiene (2.91 ml) was added. The mixture was flushed with nitrogen and palladium on carbon (10%) (0.023 g, 0.218 mmol) was added. The reaction mixture was heated in an 80° C. oil bath at reflux for 1 h. The mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated to afford (3S)-1-(4-piperidinyl)-3-pyrrolidinol (0.670 g, 81% yield). MS (m/z) 171.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A −78° C. solution of 2-bromo-5-fluorotoluene (12.0 g, 63.5 mmol) in dry THF (60 mL) is treated with a 1.6 M hexanes solution of n-butyl lithium (59.5 mL, 95.3 mmol) and then stirred for 15 minutes at −78° C. under N2. The mixture is then treated with DMF (27.8 g, 0.381 mol) and warmed to rt. The reaction is acidified with 1 N HCl, diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 5/1 to 3/1 to hexanes/ethyl acetate to afford 6.24 g (71%) of the title compound. Rf=0.49 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH2:3][OH:4].Cl[O-].[Na+]>C(O)(=O)C>[OH:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:22])[CH2:19][OH:20]
Reactant: CC(C)(CO)CCCCCCC(O)CCCCCCC(C)(C)CO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC(C)(CO)CCCCCCC(=O)CCCCCCC(C)(C)CO
Yield: 34.5 %

Procedure:
To a solution of 211i (2.42 g, 7.02 mmol) in acetic acid (10 mL) was added dropwise sodium hypochlorite solution (1.76 mL, ca. 3.5 mmol) at 18° C. Additional sodium hypochlorite solution (3×1.0 mL, ca. 6.0 mmol) was added after 20, 40, and 60 min under monitoring by TLC. The reaction was quenched with 2-propanol (4 mL) and diluted with deionized water (100 mL). The reaction mixture was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated NaHCO3 solution (3×60 mL), water (60 mL) and brine (60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification of the crude product (2.38 g) by column chromatography (silica gel, ethyl acetate/hexanes=1/1) gave 214i (0.83 g, 35%) as a colorless wax. 1H NMR (CDCl3): δ (ppm): 3.33 (s, 4H), 2.41 (t, J=7.4, 4H), 1.85 (br, 2H), 1.62-1.45 (m, 4H), 1.35-1.18 (m, 16H), 0.87 (s, 12H). 13C NMR (CDCl3): δ(ppm): 212.09, 72.10, 42.99, 38.75, 35.20, 30.48, 29.42, 24.05, 23.99, 23.82. HRMS (LSIMS, gly): Calcd for C21H43O3 (MH+): 343.3212. found: 343.3208. HPLC: 96.4% pure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(S(C)(=O)=O)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
To a round bottom flask was added 6-(3-(2,4-difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.105 g, 0.256 mmol, Example #Q.1.1.1), DCM (5 mL) and DIPEA (0.054 mL, 0.31 mmol). Then methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The reaction mixture was stirred at ambient temperature for about 10 min. The reaction mixture was purified directly by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 9:1) to give the title compound (0.120 g, 96%): LC/MS (Table 1, Method g) Rt=2.28 min; MS m/z: 488.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]([F:18])([F:17])[CH:13](OC)[OH:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:13]([OH:14])[C:12]([F:18])([F:17])[F:11])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(O)C(F)(F)F
Reactant: NC(=O)c1ccc(Br)cc1
Product: O=C(NC(O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 100 °C

Procedure:
was prepared by use of 2,2,-trifluoro-1-methoxy-ethanol in place of chloral in the general method set forth above with the following procedural changes: A mixture of 4-bromobenzamide (0.78 g, 3.9 mmol) and 2,2,2-trifluoro-1-methoxy-ethanol (0.51 mL, 4.3 mmol) was heated at 100° C. for 18 hours. The mixture was evaporated and the residue was diluted with chloroform and concentrated onto silica gel. The product was purified on a SiO2 MPLC column with 1% MeOH:CH2Cl2 to yield the intermediate 4-bromo-N-(2,2,2-trifluoro-1-hydroxyethyl)benzamide, which was used in the general method set forth above to prepare Compound 13.
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].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:29])=[CH:26][CH:25]=1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)cc4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-chlorobenzoyl chloride (0.53 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.80 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.97 min (97.05%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.92-2.15 (m, 1H, CHH), 2.54-2.71 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.5, 12.8 Hz, 1H, CH), 7.53-7.63 (m, 2H, Ar), 7.74-7.87 (m, 2H, Ar), 7.87-8.03 (m, 3H, Ar), 9.31 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.67, 48.99, 122.01, 123.55, 128.50, 129.21, 129.84, 131.62, 132.64, 133.47, 136.30, 147.38, 165.40, 166.96, 167.10, 169.80, 172.72; LCMS: MH=426/428; Anal Calcd for C21H16N3O5Cl: C, 58.98; H, 3.82; N, 9.83. Found: C, 58.67; H, 3.67; N, 9.53.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH2:10][CH2:11][CH:12]=2)[N:7]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH2:10][CH2:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: N#Cc1c(C2=CCCO2)nc(N)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1C1=CCCO1

Procedure:
From 2-amino-4-(4,5-dihydro-furan-2-yl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, 2-picolyl chloride hydrochloride and caesium carbonate in DMF. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[OH:30][C@:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)no1
Yield: 58 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (14.3 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](Cl)=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10]1>N1C=CC=CC=1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:16]=1
Reactant: Nc1cnccc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cnccc2Cl)cc1OC1CCCC1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL) is heated at 80° C. for 7 hours and then it is allowed to stand overnight. The reaction mixture is evaporated, to give a brown oil, which is subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1 g), m.p. 130-132° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CCOC(C)=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:27]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1cc(F)ccc1I
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: CC(=O)N(C)C
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 62.4 %

Procedure:
To a stirred solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (440 mg, 1.70 mmol), 5-fluoro-2-iodobenzoic acid (543 mg, 2.04 mmol), and DIPEA (438 mg, 3.40 mmol) in anhydrous DMA (10 mL) was added HATU (971 mg, 2.55 mmol) at rt under nitrogen and the reaction stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 70% EtOAc/hexanes) to afford the title compound as a yellow oil (537 mg, 62%). ESI MS (M+H) 507.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:16](=[O:19])[CH2:17][CH3:18])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH2:1][CH3:2])=[C:4]1[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)c1[nH]c2cc(C(=O)OC)ccc2c1CC
Reactant: Clc1ccccc1CBr
Product: CCC(=O)c1c(CC)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl

Procedure:
Methyl 1-(2-chlorobenzyl)-3-ethyl-2-propionylindole-6-carboxylate (66 mg) was prepared from methyl 3-ethyl-2-propionylindole-6-carboxylate (88 mg) and 2-chlorobenzyl bromide (0.051 ml) in a similar manner to that of Example 1.