Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:17])[C:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=1>>[C:12]([O:11][C:10](=[O:16])[NH:9][CH2:8][C:5]1[C:4]([F:17])=[CH:3][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=2[C:27]([F:28])([F:29])[F:30])=[CH:7][N:6]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)cc1F
Product: COc1ccc(Nc2cnc(CNC(=O)OC(C)(C)C)c(F)c2)c(C(F)(F)F)c1
Yield: 26 %

Procedure:
Analogously to Example 1a), tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate (0.55 mmol) was reacted with 4-methoxy-2-trifluoromethyl-aniline. The crude product was purified by chromatography (column: Varian Pursuit XRS C18; 10 μM; 41.4×250 mm, gradient: acetonitrile/water/CF3COOH: 10/90/0.1→100/0/0.1). The product was thus obtained in a yield of 26% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH2:24][OH:25])[N:9]=2)[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(Cl)Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]=[O:25])[N:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of N-(7-(5-fluoro-2-methylphenyl)-5-(hydroxymethyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (80 mg, 0.2 mmol) and Dess-Martin periodinane (120 mg, 0.27 mmol) and methylene chloride (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (65 mg, 80%), which was used in the next step without further purification.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=C[CH:9]=1.C([C:23](=[O:28])C(=NO)C)C.C(=O)C1C=CC=C(OC)C=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:28][CH3:23])[CH:15]=2)[O:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCC(=O)C(C)=NO
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: COc1cccc(C=O)c1
Product: CCc1oc(-c2cccc(OC)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, 1-ethyl-1,2-propanedione-2-oxime and m-anisaldehyde gave 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:32]=[CH:31][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]CC4C=CC=CC=4)=[O:22])=[O:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.NO.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[CH:31][CH:32]=3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccn2cc(-c3ccc(C(=O)NCCC(=O)OCc4ccccc4)cc3)nc12
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CO
Product: N#Cc1cccn2cc(-c3ccc(C(=O)NCCC(=O)O)cc3)nc12

Procedure:
0.55 g of benzyl 3-[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionate [obtainable by reacting 4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzoic acid with benzyl 3-aminopropionate as in Example 32] is boiled in 30 ml of methanol with 0.27 g of hydroxylamine hydrochloride in the presence of 0.72 g of K2CO3 for 4 h. After cooling, the precipitate is filtered off with suction and washed successively with water and methanol. 3-[4-(8-cyanoimidazo[1,2-a]pyridin-2-yl)benzamido]propionic acid, m.p. 212°-215°, is obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][C:24]([O:26]C)=[O:25])[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Methanol (100 ml) and sodium hydroxide solution (1 N, 22 mmol) were added to 2-t-butoxycarbonyl-9-methoxycarbonylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (7.42 g, 21.5 mmol) and stirred at room temperature for 2 hours, the solvent was removed by evaporation under a reduced pressure, the thus obtained oily material was dissolved in ethyl acetate (100 ml) and then the ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The resulting residue was precipitated by adding diisopropyl ether (30 ml), thereby obtaining 5.29 g (16.0 mmol, 74.4% in yield) of 2-t-butoxycarbonyl-9-carboxymethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]([O:6][CH3:7])=[O:5].O[C:11](=[C:14]1C(=O)OC(C)(C)[O:16][C:15]1=O)[CH2:12][CH3:13]>>[CH2:8]([C:2]1[NH:1][C:11]([CH2:12][CH3:13])=[CH:14][C:15](=[O:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:9]
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CCC(N)=CC(=O)OC
Product: CCc1cc(=O)c(C(=O)OC)c(CC)[nH]1
Temperature: 120 °C
Yield: 44 %

Procedure:
A mixture of methyl 3-amino-2-pentenoate (7.3 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (23.0 g) was heated at 120° C. for 2 hours. The residue was cooled to ambient temperature, triturated with ether and the solid collected by filtration to give methyl 2,6-diethyl-1,4-dihydro-4-oxopyridine-3-carboxylate (5.2 g) as a pale yellow solid, m.p. 124°-127° C.; NMR (d6 -DMSO): 1.2(t,6H), 2.3-2.6(m,4H), 3.7(s,3H), 6.3(s,1H); mass spectrum (chemical ionisation, ammonia): 210 (M+H)+.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CCCC[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCC[C@@H](O)C(=O)O
Temperature: 0 °C

Procedure:
To a cooled (0° C.), stirred solution of D-norleucine (500 mg, 3.81 mmol) in 10 mL of 1N aqueous sulfuric acid was added sodium nitrite (421 mg, 6.10 mmol) in 3 mL of water dropwise over a 20-minute period. The reaction mixture was allowed to slowly warm to room temperature over a 16-hour period. The mixture then was extracted with EtOAc (2×25 mL), dried (Na2SO4), and concentrated to yield 200 mg (40%) of a white waxy solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13]Br)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].C1COCC1>CC(C)=O>[C:1]1([S:7]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:22]2[CH2:21][CH2:20][N:19]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a round-bottom flask were added 2-[(Phenylsulfonyl)methyl]benzyl bromide (4{29}, 1.0 g, 3.08 mmol, 1.0 equiv.), 10 (1.06 g, 6.16 mmol, 2.0 equiv.), K2CO3 (1.70 g, 12.32 mmol, 4.0 equiv.), and 3:2 THF:acetone (15 mL). The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone. The filtrate was concentrated and purified by silica gel column chromatography (gradient, 25-50% EtOAc/hexanes) to afford 6{29} (920.1 mg, 72%) as an off-white solid. 1H-NMR (500 MHz, CDCl3): δ 7.64 (dd, 2H, J=0.5, 8.0 Hz), 7.60-7.57 (m, 1H), 7.44 (t, 2H, J=8.0 Hz), 7.21 (t, 1H, J=8.0 Hz), 7.12 (d, 2H, J=7.5 Hz), 6.98 (d, 1H, J=7.5 Hz), 4.81 (s, 2H), 4.14 (q, 2H, J=7.0), 3.31 (s, 2H), 3.15 (s, 2H), 2.50 (br s, 4H), 2.36 (br s, 4H), 1.22 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.1, 138.6, 138.1, 133.6, 132.4, 131.0, 128.8, 128.5, 128.4, 127.9, 127.3, 61.1, 60.4, 59.2, 58.9, 52.8, 52.6, 14.1.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:9][CH2:10]Cl)[C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([N:19]1[CH2:10][CH2:9][N:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:3][CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N(CCCl)CCCl
Solvent: CCO
Product: CC(C)(C)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 2000 g of bis-(2-chloroethyl)-tert-butylamine in 500 cc of ethanol and a solution of 1095 g of benzylamine in 750 cc of ethanol are simultaneously added dropwise to 1000 cc of boiling ethanol. After the addition is complete, the reaction mixture is heated to the boil for 1 hour. The mixture is subsequently concentrated in a vacuum and the residue is dissolved in dilute hydrochloric acid. The acid solution is washed with ether and is subsequently rendered alkaline with a concentrated, aqueous sodium hydroxide solution. The liberated base is extracted with ether and the ether residue is distilled. 1-benzyl-4-tert-butyl piperazine has a B.P. of 160°-162° at 12 mm of Hg.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13](=O)[NH:14][C:15]3[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=3[NH2:21])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(O)(C)C.[OH-].[K+].O>C1(C)C=CC=CC=1>[O:25]=[C:18]1[N:19]([CH2:22][CH2:23][CH3:24])[C:20]2[N:21]=[C:13]([C:8]34[CH2:11][CH2:12][C:5]([C:3]([OH:2])=[O:4])([CH2:10][CH2:9]3)[CH2:6][CH2:7]4)[NH:14][C:15]=2[C:16](=[O:29])[N:17]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(N)c(NC(=O)C23CCC(C(=O)OC)(CC2)CC3)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 17.5 °C

Procedure:
4-(6-Amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (VII, Example 83b, 0.760 kg) and isopropanol (3.62 l) are combined. The mixture is stirred under nitrogen and potassium hydroxide (2 M, 3.62 l) is added. The contents are heated at reflux for 3 hr (test for reaction completion by NMR). The mixture is then allowed to cool to 10 to 25° C. Water (8.48 l) is added followed by toluene (0.95 l) and the contents are stirred vigorously for 5 to 15 minutes. The layers are separated. Extraction with toluene (0.95 l) is performed two additional times. The aqueous phase is then cooled to between 0 and 10° C. and acidified with concentrated hydrochloric acid (0.562 l). The mixture is stirred at between 0 and 10° C. for 60 minutes. Solid product is collected by filtration and dried under reduced pressure at 50 to 60° C. to give the title compound.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[CH2:21][CH2:20][C:13]2([O:17][C:16](=O)[O:15][C:14]2=[CH2:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:3]([N:10]1[CH2:21][CH2:20][C:13]2([O:17][C:16](=[O:15])[N:2]([CH3:1])[C:14]2=[CH2:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=C1N(C)C(=O)OC12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of 1.6 g of methylamine in 35 ml of xylene prepared at 0° C. is flown to the solution of 13.0 g of 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane in 30 ml of xylene under stirring. The reaction is exothermic, thus the temperature of the reaction mixture increases up to 55° to 60° C. Thereafter, the heterogeneous reaction mixture is heated to a temperature of 100° to 102° C., maintained at the same temperature for 10 minutes, then 0.2 g of p-toluenesulfonic acid monohydrate is added to the solution and the reaction mixture is boiled while the water formed in the reaction is azeotropically distilled out. After termination of the reaction the mixture is cooled down to room temperature, washed with 5% by weight aqueous sodium hydroxide solution and after separation the xylene phase is washed to neutral with water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from a mixture of ethanol and diisopropyl ether under clarifying by activated carbon to obtain the title compound in 96.7% yield, m.p.: 96°-97° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn(Cc2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccn(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A solution of methyl 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylate (2.4 g, 9.2 mmol, 1.0 eq) in MeOH (25 mL) was treated with 5N aqueous sodium hydroxide (4.6 mL, 24 mmol, 2.6 eq) at room temperature and the reaction mixture was stirred for 15 h. The reaction mixture was then concentrated in vacuo, diluted with water and the solution was extracted with ethyl acetate, discarding the organic fraction. The aqueous fraction was cooled to 0° C. and was acidified with concentrated HCl. The resulting solid was filtered, washed with water and the solid dried in vacuo to afford the product (1.6 g, 70%), which was used without further purification. 1H NMR (DMSO-d6)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[C:18](=COS(C)(=O)=O)[C:17](=[O:25])[N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][N:13]1[CH2:32][C:33]([N:35]([CH:44]([CH3:46])[CH3:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:34].[CH3:47][N:48]([CH:50]=[O:51])[CH3:49]>>[O:11]=[C:12]1[C:18](=[CH:47][N:48]2[C:49]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:16][C:50]2=[O:51])[C:17](=[O:25])[N:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:15]=[CH:14][N:13]1[CH2:32][C:33]([N:35]([CH:44]([CH3:46])[CH3:45])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:34]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COS(C)(=O)=O)C2=O)C(C)C)cc1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=Cn3c(=O)[nH]c4ccccc43)C2=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzoximidazole (10.4 mg) in anhydrous DMF (1.5 mL) under argon was cooled to 0-5° C. Sodium bis(trimethylsilyl)amide (0.6 M in toluene, 129 μL) was added via micropipette followed by 2-[2,4-dioxo-3-(methanesulfonyloxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide [containing approximately 40% of 2-[2,4-dioxo-3-methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide](12s, 20mg). The reaction was allowed to warm to ambient temperature and stir overnight. Addition sodium bis(trimethylsilyl)amide (0.6 M in toluene, 129 μL) was added via micropipette. After approximately 10 min., the reaction mixture was quenched with several drops of glacial acetic acid and evaporated in vacuo. The residue was partitioned between ethyl acetate and aqueous 1N NaHSO4. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μM) eluting with 5% methanol in CH2Cl2. The product band was removed, eluted with 4:1 CH2Cl2/methanol, filtered and evaporated in vacuo. The residue was lyophilized from CH3CN/H2O to provide 2-[2,4-dioxo-3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (10 mg) as a white lyophilate. 1H NMR (400 MHz, CDCI3) 0.99 (m, 6H), 3.62 (d, J=16 Hz, 1H), 3.79 (s, 3H), 4.10 (d, J=16 Hz, 1H), 4.23 (t, J=6 Hz, 1H), 4.50 (m, 2H), 4.90 (m, 1H), 5.86 (d, J=6 Hz, 1H), 5.91 (d, J=6 Hz, 1H), 6.99 (m, 7H), 7.26 (m, 3H), 7.33 (m, 2H), 7.46 (d, J=8 Hz, 1H), 7.54 (s, 1H).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:22]1[O:33][C:32]2[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:32]3[O:33][CH2:22][O:23][C:24]=3[CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc3c(c2)OCO3)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 3,4-methylenedioxyphenethyl bromide (0.247 g--see Preparation 16), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 3 hours. The mixture was allowed to cool to room temperature, water (6 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield 0.27 g.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1.ON1C2C=CC=CC=2N=N1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](O)=[O:38].Cl>CN(C)C=O.CCOC(C)=O.C(N(CC)CC)C>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([N:9]2[C:13]3=[C:14]4[CH:20]=[CH:19][NH:18][C:15]4=[N:16][CH:17]=[C:12]3[NH:11][C:10]2=[O:21])[CH2:4]1)=[O:38]
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1[C@@H]1CCCNC1
Reactant: O=C(O)c1cccs1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cccs1)N1CCC[C@@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 9 h
Yield: 71.9 %

Procedure:
To a suspension of 1-[(3R)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one dihydrochloride (30 mg) and 1-hydroxybenzotriazole (18.4 mg) in N,N-dimethylformamide (0.72 mL) was added triethylamine (0.028 mL), 2-thiophenecarboxylic acid (15.1 mg), and WSCD.HCl (70 mg, 0.365 mmol). After stirring for 9 hours at ambient temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, water (×3), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 1-[(3R)-1-(2-thienylcarbonyl)-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (24.0 mg) as a white crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)(=O)=O.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CI>O1CCOCC1>[CH3:21][S:2][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13]3[N:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[C:9]=2[CH:20]=1
Reactant: O=C1Nc2cccnc2Nc2ccc(S(=O)(=O)Cl)cc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CI
Product: CSc1ccc2c(c1)C(=O)Nc1cccnc1N2

Procedure:
Intermediate 7, freshly prepared from 6 (0.5 g, 2.4 mmol) , was reduced with triphenylphosphine (2.8 g, 11.0 mmol) in dioxane (20 mL) for 2 h at 90° C. See Oae, S.; Togo, H., Bull. Chem. Soc. Jpn., 1983, 56, 3802, which is specifically incorporated by reference herein. The crude 8-thio-derivative was quenched (10 min, 25° C.) with excess methyl iodide (0.5 mL, 8.0 mmol) and crystallized from toluene to yield 50 mg (8% from 6) of 8 as a waxy solid: 1H NMR (CDCl3) δ 2.40 (s, 3 H, CH3), 6.25 (br s, 1 H, NH), 6.66 (d, J=8.3, 1 H), 6.86 (dd, J=7.7, 4.4 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 7.24 (dd, J= 8.3, 2.3 Hz, 1 H), 7.79 (d, 13 J=2.3 Hz, 1 H), 7.91 (d, J=4.5 Hz, 1 H); MS (CI/NH3) m/e 258 (MH+, base), 243,211, 113.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH2:10][O:11][C:12]([CH3:14])=[O:13].[CH:15]1([C:20](=[O:33])[CH2:21][CH2:22][NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([C:20]([OH:33])([CH2:21][CH2:22][NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH2:14][C:12]([O:11][CH2:10][CH3:9])=[O:13])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(C)=O
Reactant: O=C(CCc1ccco1)NCCC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCNC(=O)CCc1ccco1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of LDA (1.0 M, 1.1 mL, 1.1 mmol) cooled to −78° C. was added EtOAc (0.1 mL, 1.1 mmol). After stirring for 30 minutes, a solution of N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide (100 mg, 0.38 mmol; described in Step 2 of example H(4)) dissolved in 3 mL THF was added. The reaction was stirred for 2 hours and then allowed to warm to −40° C. The reaction was quenched with 10 mL saturated NH4Cl, and the layers were separated. The aqueous layer was extracted with 3×10 mL CH2Cl2, and the organic layers were combined. After concentrating the organic layers by rotary evaporation, the product was purified by flash chromatography (86 mg, 64% yield). MS (ESI): 350 (M−H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:18][C:19](=[O:21])[OH:20])[CH:10]=[CH:11][C:12]=2[O:13][C:14]([F:17])([F:16])[F:15])=[CH:5][CH:4]=[N:3]1.CN(C=O)C>C(OCC)(=O)C>[C:7]([O:21][C:19](=[O:20])[NH:18][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([F:16])([F:17])[F:15])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:8])([CH3:12])[CH3:6]
Reactant: Cn1nccc1-c1cc(NC(=O)O)ccc1OC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)OC(C)(C)C)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tart-butyl ester (65 mg, 0.18 mmol) in DMF (1.5 mL) N-bromosuccinimide (35.6 mg, 0.2 mmol) was added at 0° C. then reaction mixture stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily residue that was subjected to a purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert-butyl ester as a white solid in 89.2% yield. LCMS m/z (%)=436 (M+H 79Br, 100), 438 (M+H 81Br, 98). 1H NMR (400 MHz, CD3OD) δ: 7.79 (d, J=8.90 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.43 (d, J=8.94 Hz, 1H), 3.73 (s, 3H), 1.55 (s, 9H).