Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].C(Cl)(=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](=[O:17])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2
Yield: 97.2 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with benzoyl chloride (0.16 ml, 1.4 mmol) and DIPEA (0.32 ml, 1.8 mmol) as described in Example 36, Step A, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a white solid (330 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C.CO>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (366 mg, 1.27 mmol) in methylene chloride (10 mL) and 1 drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.76 mL, 1.53 mmol). The reaction was stirred for 30 min at 0° C., at which time, 1,1,1,3,3,3-hexamethyldisilazane (0.81 mL, 3.81 mmol) was added to the reaction mixture. The reaction was allowed to slowly warm to 25° C. and then stirred at 25° C. for 16 h. The reaction mixture was then treated with methanol (5 mL). The resulting reaction mixture was washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous layers were extracted with methylene chloride (3×10 mL). The combined organic layers were then washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (229 mg, 63%) as a white solid: mp 98.6-100.1° C.; EI-HRMS m/e calcd for C14H17Cl2NO (M+) 285.0687, found 285.0688.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][NH2:12])[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15].C(O)C>C(O)(=O)C>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][N:12]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:15])[CH2:5][CH2:6]1
Reactant: CC(=O)c1ccccn1
Reactant: NNC(=S)NCCN1CCOCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=S)NCCN1CCOCC1)c1ccccn1
Reaction time: 8 h

Procedure:
A mixture of 6.00 g (0.0294 mole) of 4-(2-morpholinoethyl)thiosemicarbazide, 3.91 g (0.0323 mole) of 2-acetylpyridine, 20 mL of 95% ethanol, and 0.4 mL of glacial acetic acid was heated under reflux for 1.25 hours. The mixture then stood overnight at room temperature. Colourless crystals were collected and recrystallised from 40 mL of 95% ethanol; yield 7.81 g (86%) of pale yellow crystals of 2-acetylpryridine 4-(2-morpholinoethyl)thiosemicarbazone, mp 167.5°-169° C.
Reaction SMILES: O[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>C(O)(=O)C>[N:12]1([CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CC(=O)O
Product: CCCC1CC(=O)N(Cn2cnc3ccccc32)C1

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of 1-(hydroxymethyl)-4-propyl-pyrrolidin-2-one a24 (2.5 mmol, 400 mg) and benzimidazole (1 eq, 2.5 mmol, 300 mg) in acetic acid (20 ml) was heated at reflux overnight. After cooling, acetic acid was removed under vacuum, and the crude product was purified by preparative chromatography on silicagel to give 1-(1H-benzimidazol-1-ylmethyl)-4-propyl-pyrrolidin-2-one 91 after recrystallization in diisopropylether (16%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29](Cl)=[O:30].[CH2:32](N(CC)CC)[CH3:33].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:33][CH2:32][CH2:28][C:29]5=[O:30])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), chloroacetyl chloride (60 mg), triethylamine (50 mg) and acetonitrile (5 ml) was stirred under ice cooling for 2 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (90 mg) as white needles (yield: 49%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:10]=[C:9]([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].ClC1C=C(C=CC=1)C(O)=[O:28].C(=O)([O-])[O-].[K+].[K+].[OH2:39]>C(O)C>[CH3:1][S:2]([C:3]1[N:10]=[C:9]([CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:20]([CH3:22])[CH3:21])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])(=[O:28])=[O:39]
Reactant: O
Reactant: CSc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Reactant: O=C(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)[Si](OCc1ccc(C#N)c(S(C)(=O)=O)n1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-(methylthio)-6-{[(triisopropylsilyl)oxy]methyl}nicotinonitrile (1.5 g, 4.5 mmol) that was obtained in Example 24 (24a) in ethanol (10 ml) was added m-chlorobenzoic acid (2.3 g, 14 mmol) at 0° C. with stirring, and after raising the reaction temperature to room temperature, the resulting mixture was stirred for 3 hours and then evaporated in vacuo. Subsequently, to a solution of the residue obtained in ether (20 ml) was added a saturated aqueous solution of potassium carbonate (10 ml) with stirring, and the resulting mixture was stirred for 1 hour. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 3:7) as the eluent to afford the title compound (1.7 g) in a yield of 100% as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1.[C:15]1([C@H:21]([NH:39][C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(OC)=O)=CC=2)C=CC=CC=1>>[C:15]1([C@H:21]([NH:39][C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([O:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:6][CH:7]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(Cc1ccc(CO)cc1)OC
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2cccc(C(=O)O)c2)c1)O[C@H]1CN2CCC1CC2
Agent: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: Cl
Product: COC(Cc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1)OC

Procedure:
The title compound was prepared as described in Example 1 Step 10 with (4-(2,2-dimethoxyethyl)phenyl)methanol and 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde and methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate hydrochloride respectively.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[CH:19]=[C:18]1[CH3:20]
Reactant: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2C(=O)CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2C(=O)CN1CCN(C)CC1

Procedure:
A solution of 303 mg (0.001 mole) of 4-chloroacetyl-1,2-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 200 mg (0.002 mole) of N-methylpiperazine in 10 ml of dry dioxane is boiled under reflux for 2 hours. 20 ml of saturated aqueous sodium bicarbonate solution are added thereto, and then the mixture is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated in vacuo. The resulting oil is chromatographed on neutral silica gel (methylene chloride/methanol). Yield: 280 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:13].N1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:32]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)CBr
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-trifluoromethyl-phenyl)-(5-chloro-2-methoxy-phenyl)-methanone (IV) (14.13 g, 42.9 mmol, 1 eq) in Dichloromethane (120 mL) at 0° C. was added pyridine (4.65 mL, 57.5 mmol, 1.34 eq), then Bromoacetyl bromide (4.98 mL, 57.2 mmol, 1.33 eq). After 3 h, the reaction was quenched with Sodium bicarbonate (aq) and extracted three times into Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C([N:13](CC)CC)C.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[NH:13][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][CH:28]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1NC(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
L-Proline methyl ester hydrochloride (7.2 g, 43.8 mmol) was dissolved in 100 mL of anhydrous DMF at 0° C. To this solution was added triethylamine (4.2 g, 43.8 mmol). After vigorous stirring for 1 hour, the solid triethylamine hydrochloride was removed by filtration. To the filtrate was added 4-benzyloxybenzoic acid (10.0 g, 43.8 mmol) followed by DCC (9.9 g, 48.2 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solid DCU was then removed by filtration, and the filtrate distributed between H2O/ethyl acetate (300 mL ea.). The organic was washed several times with 200 mL portions of H2O to remove DMF. The organic was dried (Na2SO4), and concentrated in vacuo to a solid residue that was chromatographed (SiO2, 15-100% ethyl acetate/hexanes). Isolation provided 5.3 g (35%) of N-(4-benzyloxybenzamido)-L-proline methyl ester as a white solid. MS.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9](N)[CH2:8]2)([O-:4])=[O:3].C=O.[BH3-][C:18]#[N:19].[Na+].[C:21](O)(=O)C>ClCCCl>[CH3:21][N:19]([CH3:18])[CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[CH2:10]1
Reactant: [BH3-]C#N
Reactant: NC1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Yield: 50.4 %

Procedure:
(5-Nitro-2,3-dihydro-1H-inden-2-yl)amine hydrochloride (5.52 g, 26 mmol), paraformaldehyde (4.1 g, 128 mmol), NaCNBH3 (8.1 g, 128 mmol), and acetic acid (7.4 mL, 128 mmol) were combined in 1,2-dichloroethane (200 mL) and the suspension was heated to reflux for 15 h. The reaction was cooled and quenched with saturated aqueous NaHCO3. The organic layer was separated, washed with brine dried with MgSO4 and concentrated to an oil. The crude material was purified by silica gel flash column chromatography (0-100% (90% DCM/9% MeOH/1% NH4OH)/DCM) and yielded 2.7 g (52%) of a yellow oil that crystallized while stored on the bench top. 1H NMR (400 MHz, CDCl3) δ 8.07 (m, 2H), 7.36 (d, J=8.1 Hz, 1H), 4.13 (m, 1H), 3.34 (m, 4H), 2.74 (s, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[N:26]=[CH:27][C:28]([C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[CH:29][N:30]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: COc1ccc(-c2cnc(N3CCC(N(C(=O)c4ccc(-c5cnco5)cc4)C4CC4)CC3)nc2)cc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-(4-methoxy-phenyl)-pyrimidine following a procedure analogous to that described in Example 19. LC (method 9): tR=2.33 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:4]=[CH:3]1.[Li]CCCC.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][N:36]=1)[CH:32]=[O:33]>C1COCC1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]([C:3]2[N:2]([CH3:1])[CH:6]=[C:5]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=4)[N:8]=3)[N:4]=2)[OH:33])[CH:34]=[CH:35][N:36]=1
Reactant: O=Cc1ccnc(Cl)c1
Reactant: Cn1cnc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1C(O)c1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a solution of 5-(1-methyl-1H-imidazol-4-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (500 mg, 1.61 mmol) in THF (10 mL) at −78° C., n-BuLi (2.0 mL, 3.2 mmol, 1.6 M) was added slowly. After stirred at −78° C. for 30 min, 2-chloroisonicotinaldehyde (454 mg, 3.22 mmol) in THF (5 mL) was dropwise added. The mixture was gradually warmed to 0° C., and stirred for 1 h. After quenched by water (20 mL), the mixture was extracted by EA (2×20 mL). The combined organic phases were washed by water (2×30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by prep-TLC (EtOAc:Petroleum ether=1:1) to give (2-chloropyridin-4-yl)(1-methyl-4-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-imidazol-2-yl)methanol as a yellow solid (230 mg, 31.7%). MS (ES+) C19H13ClF3N5O3 requires: 451, found: 452 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[N:4]=1.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:2][C:3]1[N:7]([CH2:8][C:9]([N:26]2[CH2:27][C@H:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][C@H:25]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[N:4]=1
Reactant: Nc1nc(C(F)(F)F)nn1CC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: Nc1nc(C(F)(F)F)nn1CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 51 %

Procedure:
Proceeding as in Example 1, but substituting 2-(5-amino-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 11, (2S,4R)-1-(2-(5-amino-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (100.1 mg, 51%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.90 (s, 1H), 7.37-7.14 (m, 7H), 7.02-6.81 (m, 6H), 5.43 (s, 2H), 4.82 (d, 1H), 4.73 (d, 1H), 4.65 (d, 1H), 3.71 (t, 1H), 3.24 (t, 1H), 3.02-2.90 (m, 1H), 2.80 (dd, 1H), 2.65 (dd, 1H), 2.38 (dd, 1H), 1.99 (br s, 2H), 1.81-1.71 (m, 1H). MS (EI) for C29H27F4N6O3 found 583 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:26]([NH2:27])=[CH:25][NH:24][N:23]=2)=[O:21])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[C:26]([NH:27][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[CH:25][NH:24][N:23]=2)=[O:21])=[CH:17][CH:18]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1C(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
2-Methoxy-benzoic acid (38 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol), and HOBt (37 mg, 0.27 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. The residue was purified by preparative LC/MS and, after evaporation of product-containing fractions, yielded the product as a pinkish solid (12 mg, 15%). (LC/MS: Rt 4.00, [M+H]+ 354.67).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:26][CH2:25][C@@H:24]([NH:27]C(=O)OC(C)(C)C)[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](N)C5)n4)n[nH]c3cn2)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a stirred solution of tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate (60.0 mg, 0.12 mmol) in anhydrous DCM (5.0 mL) and methanol (2.5 mL) was added 4M HCl in 1,4-Dioxane (4.0 mL). The reaction mixture was stirred at 60° C. under N2 for 18 h. Volatile solvent was evaporated in vacuo. The crude was redissolved in DMSO (1 mL) and was purified by reverse phase HPLC to give 189 as a white solid (25.5 mg, 58.4%). 1H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.81-3.64 (m, 4H), 3.63-3.52 (m, 2H), 2.17 (dt, J=12.3, 6.5 Hz, 2H), 1.88-1.75 (m, 2H). LC/MS: m/z 361.1 [M+1]
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][C:22]#N)=[CH:3]1.[OH-:24].[K+].C[OH:27]>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH2:21][C:22]([OH:27])=[O:24])=[CH:3]1
Reactant: [OH-]
Reactant: Cn1cc(CC#N)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: CO
Agent: [K+]
Solvent: O
Product: Cn1cc(CC(=O)O)c2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Yield: 25 %

Procedure:
The mixture of [1-methyl-5-(4-trifluoromethyl-phenyl)-1H-indol-3-yl]-acetonitrile (0.230 g, 0.732 mmol), potassium hydroxide (2.16 g, 38.5 mmol), methanol (5 mL) and water (5 mL) was heated at refluxed for 24 hours. The reaction mixture was cooled to room temperature and concentrated. Water was added and the mixture was acidified with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification of the residue by HPLC using 4% methanol in methylene chloride as the mobile phase afforded the title compound as a light brown solid (0.0598 g, 25%), mp 167-168° C. Mass spectrum (+APCI, [M+H]+) m/z 334. 1HNMR (400 MHz, DMSO-d6): δ 12.1-12.4 (br s, 1H), 7.9 (d, 3H, J=7.8 Hz), 7.8 (d, 2H, J=8.1 Hz), 7.55 (d, 2H, J=1.2 Hz), 7.3 (s, 1H), 3.8 (s, 3H) and 3.7 ppm (s, 2H). Elemental Analysis for C18H14F3NO2: Calculated: C, 64.86; H, 4.23; N, 4.20. Found: C, 64.88; H, 4.17; N, 4.03.