Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([Cl:12])=[O:11])[CH2:3]2.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10]([CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[O:11])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (4.76 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride is added at 0° C. to a solution of 900 mg (5.24 mmol) of 4-bromoaniline and 1.85 g (14.28 mmol) of N,N-diisopropylethylamine in about 10 ml of dry DMF. The mixture is stirred at room temperature overnight. Purification by preparative HPLC is followed by chromatography again on silica gel (mobile phase: dichloromethane/methanol/triethylamine 80:20:2). The product is dissolved in methanol and mixed with 1N HCl in methanol. Finally, the solvent is removed. 0.63 g (31% of theory) of the title compound is obtained. The raw material is employed directly in the next synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.Cl.C(OCC)(=[O:20])C>C1(C)C=CC=CC=1.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([CH3:12])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)=O)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 790 mg (2.90 mmol) of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (from Example 80, Step A) in 5.0 mL of toluene was combined with water (2.0 mL), iron powder (730 mg, 13.45 mmol), and ferric chloride (14.2 mg, 0.088 mmol) in a 25-mL three-neck round bottom flask fitted with a mechanical stirrer and reflux condenser. With vigorous agitation, the suspension was heated at 80° C., and 1.3 mL of conc. HCl was added over a period of 2 h via syringe. After the addition was completed, the heating and stirring were continued for an additional 30 min. After the reaction had cooled to RT, ethyl acetate (50 mL) was added to the solid was removed by filtration. The filtrate was washed with 20 mL of saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was filtered again and the filtrate was extracted with 2×40 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of brine. Drying over sodium sulfate and concentration afforded a red oil which was purified by flash column chromatography, eluting with 30% dichloromethane in hexane followed by dichloromethane, to give 411 mg of the title compound as a yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([C:15](=O)[CH2:16][Br:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][Br:17])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(C(=O)CBr)cc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(CCBr)cc1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of ethyl 2-[2-bromo-4-(2-bromoacetyl)phenoxy]acetate (2.12 g) in trifluoroacetic acid (4.29 ml) was added triethylsilane (2.67 ml), and the mixture was stirred for 1 hour at 50° C. After concentration of the reaction mixture under reduced pressure, purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) gave ethyl 2-[2-bromo-4-(2-bromoethyl)phenoxy]acetate (1.84 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 16 h

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (50 mg 0.13 mmol) in dioxane (3 mL) at room temperature (20° C.) was added ethyl isocyanate (20 uL 0.26 mmol). The reaction mixture was stirred for 16 h. The solvent was removed in vacuo and the solid residue triturated with ether. The solid was collected by filtration and dried in vacuo to afford (32 mg 55%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(-c3cccc(F)c3F)noc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(-c3cccc(F)c3F)noc2c1Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 12 g of 7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-benzisoxazole in 120 ml of DMF, 6.36 g of K2CO3 is added followed by 7.83 g of BrCH2CO2C2H5. The reaction is warmed at 60° C. for two hours and then allowed to stand for 18 hours. To the mixture 200 ml of water and 15 ml of 50% NaOH are added. The mixture is warmed at 90° C. for 90 minutes, poured into water and acidified. The product is extracted into ethylacetate which is dried over Na2SO4 and evaporated to give {[7-chloro-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 183°-187° C.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH2:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:8]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CC1
Product: CCCCCCC(=O)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 12.2 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.530 g, 5.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.03 mmol) were reacted to provide 0.148 g (15.4% yield) of the title compound (13) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 112.6-113.2° C. 1H NMR (CDCl3, 400 MHz): δ=6.79 (q, 1H), 5.81 (s, 0.2H), 5.4 (s, 0.8H), 2.3 (m, 2H), 1.64 (m, 4H), 1.51 (d, 3H), 1.32 (m, 8H), 0.98 (t, 3H). MS (ESI) m/z 324.05 (M+Na)+; 300.04 (M−H)−.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[S:16][C:17]([C:20]([CH3:41])([CH3:40])[CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18][N:19]=1)(C)(C)C>C(Cl)Cl>[C:36]([Si:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:22][CH2:21][C:20]([C:17]1[S:16][C:15]([NH2:14])=[N:19][N:18]=1)([CH3:41])[CH3:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1nnc(C(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.4 %

Procedure:
A 10% solution of TFA in DCM (720 mL) is added at 0° C. to a solution of {5-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-1,3,4-thiadiazol-2-yl}-carbamic acid tert-butyl ester (12.0 g, 23.4 mmol) in DCM (800 mL). The reaction mixture is stirred at room temperature for 14 h. The solvent is removed under reduced pressure and the crude purified by column chromatography to afford 8.8 g of 5-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-1,3,4-thiadiazol-2-ylamine as a viscous liquid. Yield: 91%; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (9H, s), 1.30 (6H, s), 3.60 (2H, s), 7.30-7.50 (6H, m), 7.50-7.70 (4H, m), 9.00 (2H, s); m/z 412 [M+H].
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:29]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cncc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cncc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (1.65 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.38 mmol) and 1,1′-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(5-morpholin-4-yl-pyridin-3-yl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (256 mg, 40%) as a white solid: LC/MS m/e calcd for C24H30N4O4S (M+H)+: 471.6, observed: 471.1.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.[OH-].[Li+].C(O)(=O)C>O1CCCC1>[C:6]([CH2:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)COC(=O)c1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)COC(=O)c1ccc(O)cc1
Temperature: 55 °C

Procedure:
To a solution of 4-hydroxy-benzoic acid tert-butoxycarbonylmethyl ester 15 (18 grams, 71.42 mmol) in tetrahydrofuran (100 mL) is added 10% lithium hydroxide solution (35 mL). The mixture is heated at 50-60° C. for 1 hour. The reaction mass is cooled to room temperature, and the pH is adjusted to 4 with dilute acetic acid. The organic phase is separated and distilled to give crude 16, which can be purified in appropriate solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2)[CH3:22]
Reactant: CC=O
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 50.5 h
Yield: 25.5 %

Procedure:
A mixture of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol), acetaldehyde (10.0 mg, 0.227 mmol), and sodium triacetoxyborohydride (52.1 mg, 0.246 mmol) was stirred at room temperature for 50.5 h. The reaction was then partitioned between EtOAc and H2O. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the solid chromatographed (CHCl3/MeOH, 97.5:2.5) to afford the title compound (14.1 mg, 25%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[C:24](O)(=[O:28])[CH:25]([CH3:27])[OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:24](=[O:28])[C@@H:25]([OH:26])[CH3:27])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: CC(O)C(=O)O
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[2,3-d]pyrimidine (600 mg) was reacted with lactic acid via General Procedure B to give (S)-1-(4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH2:19][C@H:18]([S:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][CH2:19][C@H:18]([S@@:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[O:37])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](Sc3ccccn3)C2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H]([S@](=O)c3ccccn3)C2)cc1
Yield: 80 %

Procedure:
A solution of 378 (15 mg, 0.04 mmol) and mCPBA (6 mg, 0.04 mmol) in DCM (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by flash chromatography using the gradient EtOAc to 5% MeOH in DCM as an eluent, to afford the title compound (13 mg, 80% yield). 1H NMR (CDCl3) δ 1H NMR (CDCl3) δ 8.63 (m, 1H), 8.58 (m, 1H), 7.6-8.0 (m, 10H), 7.40 (m, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.85 (m, 3H), 6.58 (d, J=8.8 Hz, 2H), 6.50 (d, J=11.1 Hz, 2H), 3.7-4.0 (m, 6H), 3.2-3.5 (m, 4H), 2.4-2.8 (m, 3H), 2.95 (m, 1H). LRMS: (calc) 406.1; (found) 407.1 (M+H1).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:29])([F:28])[CH2:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:21][C:22]([F:29])([F:28])[CH2:23][S:24]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2([CH3:13])[CH:11]3[CH:9]2[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12]3)[CH:15]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.10 g, 0.37 mmol) in pyridine (8 ml) cooled at 0° C. was treated with 2,2,2-trifluoroethanesulphonyl chloride (0.08 g, 0.44 mmol). The reaction mixture was allowed to warm to room temperature and then stirred for 16 h. The reaction mixture was concentrated in vacuo and the residue was poured into saturated aqueous sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (Na2SO4) and then concentrated in vacuo. The crude residue was purified by preparative HPLC (condition 7) to give a yellow solid, (15 mg, 10%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([CH3:19])([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[C:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:33][CH:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH2:24]2)[C:10]1=[O:18])([CH3:8])[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(Cn1c(=O)n(C(C)(C)C(=O)OC(C)(C)C)c3ccccc31)CN2C
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a mixture of 2-methyl-2-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (130 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (250 mg, 0.73 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired 2-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-2methyl-propionic acid tert-butyl ester (138 mg, 68%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]([NH2:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.CN(C)N1C=CC=CC1.[CH2:35]([O:42][C:43]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:44]=1[S:52](Cl)(=[O:54])=[O:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH:16][S:52]([C:44]1[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:43]=1[O:42][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:53])=[O:54])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Reactant: CCOC(OCC)C(N)CC(=O)OC(C)(C)C
Agent: CCN1CCOCC1
Agent: CN(C)N1C=CC=CC1
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of 7.69 g (31 mmol) 3-amino-4,4-diethoxy-butyric acid tert-butyl ester, 4.2 mL (33 mmol) N-ethylmorpholine, 0.37 g (3 mmol) N N-dimethylaminopyridine was stirred in 75 mL dichloromethane and cooled to 0° C. in an ice/water bath. 10.1 g (31 mmol) of % 2-benzyloxy-4-nitro-benzenesulfonyl chloride was added in one portion and the resulting mixture was stirred at room temperature 18 h. TLC analysis indicated complete reaction. The reaction mixture was transferred to a separatory funnel and washed with water and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a pale yellow oil. The oil was purified over silica eluting with 1:1 ethyl acetate:hexanes to give 11.7 g (21.7 mmol, 70%) (S)-3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a pale yellow oil. MS (APCI) m/z 538.1 (M−1).
Reaction SMILES: C([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][C:18]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[C:19]([F:23])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[CH2:15][NH:14][CH2:22]2
Reactant: Fc1cc2c(cc1C1CCOCC1)CN(C(c1ccccc1)c1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: Fc1cc2c(cc1C1CCOCC1)CNC2
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred solution 0.12 mmol 2-benzhydryl-5-fluoro-6-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole in 4 ml methanol was added 4 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to yield the title compound as a yellow solid (100% yield). MS (m/e): 222.1 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C1(CN)CCCCC1.[O:12]=[C:13]1[C:21]2([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]2=3)[CH2:30][CH2:29][O:28]4)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1[CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:1]([NH:3][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([CH2:33][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]3=4)[CH2:30][CH2:29][O:28]5)[C:13]2=[O:12])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: CCNC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using ethylamine (2 M solution in tetrahydrofuran) to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (57%) as a colorless solid: mp 190-191° C.; 1H NMR (300 MHz, CDCl3) δ7.79-7.71 (m, 2H), 7.44-7.36 (m, 2H), 7.24-7.15 (m, 2H), 7.08-6.99 (m, 1H), 6.77-6.70 (m, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 6.14-6.04 (m, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H), 3.54-3.43 (m, 2H), 3.09-2.90 (m, 2H), 1.28-1.21 (m, 3H); 13C NMR (75 MHz, CDCl3) δ178.0, 166.8, 161.9, 161.3, 141.8, 139.1, 134.4, 132.6, 128.7, 127.5 (2C), 124.0, 123.6, 120.0, 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 34.9, 29.0, 14.8; MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (101 mg, 91%), MS (ISP) m/z=443.5 [(M+H)+], mp 263° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and tetrahydropyran-4-yl-carboxylic acid.