Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>CCN(C(C)C)C(C)C>[CH:10]1([NH:14][C:6]2[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Cl)c(NC2CCC2)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,4,5-trichloro-pyrimidine (0.5 M in DMSO) cyclobutyl amine (0.5 M in DMSO, 160 μL) and DIEA (neat, 30 μL) were added to an 8-ml reaction vial. The vial was capped and the contents shaken at 25° C. for 22 h. The reaction mixture was concentrated in Genevac to provide 4-cyclobutylamino-2,5-dichloro-pyrimidine. The solid was treated with C16 (0.5 M in DMSO, 160 μL), concentrated in Genevac, and the resultant residue treated with EtOAc (160 ul). The vial was capped and the contents shaken at 75° C. for 22.5 hours. The reaction mixture was then concentrated in Genevac. The resultant crude product was dissolved in DMSO and purified by HPLC to provide 418 (11.9 mg, 35%). APCI LCMS: Retention time: 3.00 min (Method A), Observed mass: 419.99 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:11]([O-])(=O)=O.[K+].ClCCl>Cl.O>[Cl:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
73 g (0.52 mol) of 3-nitrophenol are dissolved in 2 liters-of 6N hydrochloric acid while heating. The mixture is cooled in an ice bath to 28°-30° C. 32 g (0.26 mol) of potassium chlorate in 500 ml of water are added over 1.5 hours and then, at the end of the addition, the mixture is left stirring for 30 minutes at 28°-30° C. The mixture is cooled to 15° C. and 1 liter of dichloromethane is added. The layers are separated and the organic phase is washed with water. The organic phase is dried and evaporated. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/methanol (80/20) mixture. Recrystallization is carried out from toluene. 29 g of product are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1S[CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(C=O)[O:25]C=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[O:25][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Reactant: O=Cc1ccco1
Product: COC(=O)/C(=C/c1ccco1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that 2-furylcarboxaldehyde (288 mg) was used as the aldehyde component to afforded the desired product (530 mg). 1H NMR (300 MHz, CDCl3) δ 3.788 (s, 3H), 5.17 (s, 2H), 6.29 (m, 1H), 6.46 (m, 1H), 6.73 (br., 1H), 6.94 (s, 1H), 7.37 (m, 6H). LC/MS: 2.27 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl>O1CCCC1.CCCCCC>[CH3:24][Si:25]([CH3:28])([CH3:27])[O:22][C:21]([O:23][Si:25]([CH3:28])([CH3:27])[CH3:24])=[CH:20][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)OC(=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A cooled (0°-5° C.) solution of 41.4 g (0.41 mol) of diisopropylamine in 300 ml of tetrahydrofuran was treated slowly with butyllithium in hexane (250 ml of a 1.6 M solution, 0.4 mol). A solution of 34.12 g (0.2 mol) of p-chlorophenylacetic acid in 200 ml of tetrahydrofuran was added dropwise and the reaction mixture was stirred 30 minutes at 0° C. Trimethylchlorosilane (100 g) was added and the mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The contents of the flask were filtered under nitrogen and the filtrate was evaporated under reduced pressure. The residue was dissolved in 80 ml of diethyl ether; the solution was filtered and the filtrate was evaporated. The resultant residue was distilled in a Vigreux column, maintaining the pot temperature below 130° C. to prevent decomposition of the product. The product β,β-bis(trimethylsiloxy)p-chlorostyrene, 32.56 g (52% yield), was obtained as a colorless liquid, bp 110° C. (0.1 mm); 1H NMR (CDCl3) δ7.0-7.4 (m, 4H), δ4.52 (s, 1H); δ0.22 (s) and δ0.26 (s) together 18H. The moisture sensitive product was stored under nitrogen.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CO>[Pd].O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)Nc1nc2ccc([N+](=O)[O-])cc2[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc2cc(N)ccc2[nH]1
Yield: 35.4 %

Procedure:
A mixture of 13.3 g (47.8 mmol) of (5-nitro-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester and (6-nitro-1H-benzimidazol-2-yl)-carbamic acid tert-butyl ester, 100 ml of methanol, 100 ml of tetrahydrofuran and 1 g of 10% Pd/C catalyst is hydrogenated. After completion of the reaction, the catalyst is filtered off, washed with tetrahydrofuran and the filtrate is concentrated. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and chloroform:methanol=10:1 as eluent to yield 4.72 g (40.4%) of (6-amino-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester (Rf. 0.5), Melting Point: 159° C. (diethyl ether) and 4.2 g (36.0%) of (5-amino-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester (Rf. 0.4) Melting Point: 168° C. (diethyl ether)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:34])=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(l), starting from tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(3-oxo-3-phenyl-propyl)-phenyl]-piperidine-1-carboxylate by cleavage of the BOC group using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-3-[4-(3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-1-phenyl-propan-1-one trifluoroacetate as a white powder; MS: 450 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:32](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Si:32]([O:23][CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10][C:11]1=[O:26])[CH2:24][CH3:25])([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 44.7 g (114 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 185, Step B) and 19.4 g (285 mmol) of imidazole in DMF (350 mL) was added 39.4 mL (154 mmol) of tert-butyldiphenylsilyl chloride. The colorless solution was stirred at room temperature for 17 h. The reaction was partitioned between water and ethyl ether (3×), and then the combined organic layers were washed with saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 60% EtOAc/hexanes, gradient elution) provided the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH3:34].C(#N)C>C(OCC)(=O)C>[CH2:33]([S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:26][C:7]=2[N:8]=1)[CH3:34]
Reactant: CCI
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (383 mg), 1M aqueous sodium hydrogen carbonate solution (1.0 ml), iodoethane (0.4 ml) and acetonitrile (10 ml) was stirred at 100° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (80 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (375 mg).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[NH:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][C:11]=1[C:12]#[N:13].CCOCC.C(O)(=O)C>CCCCCC>[Cl:6][C:7]1[NH:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[C:10]([Cl:4])[C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)[nH]c1Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: N#Cc1c(Cl)[nH]c(-c2ccc(Cl)c(Cl)c2)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (1.8 g) is added dropwise to a 0° C. mixture of 2-chloro-5-(3,4-dichlorophenyl)pyrrole-3-carbonitrile, ether (30 mL) and acetic acid (30 mL). After stirring for 2 hours at 0° C., the reaction mixture is poured into an ice-water slurry. The cold mixture is diluted with hexane and the solids are collected and dried to give the title compound as a beige solid (mp >200° C.) which is identified by 13C NMR spectral analysis.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][OH:9])[CH2:4][CH2:3]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:27][C:28]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31]>>[F:27][C:28]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:29]=1[C:30]([O:32][C:5]1([N:8]=[O:9])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:31]
Reactant: CN1CCC(=NO)CC1
Reactant: O=C(O)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1CCC(N=O)(OC(=O)c2ccc(F)cc2F)CC1

Procedure:
1-Methyl-4-nitrosopiperidin-4-yl 2,4-difluorobenzoate was prepared from 1-methyl-piperidin-4-one oxime, lead tetraacetate and 2,4-difluorobenzoic acid using conditions of General Method 3. 1H NMR (400 MHz, chloroform-d) δ 7.59 (2H, dd, 7.5, 2.3 Hz), 7.09 (1H, tt, 8.6, 2.4 Hz), 2.98 (2H, dt, 11.7, 3.6 Hz), 2.32-2.50 (7H, m), 2.04 (2H, dd, 14.2, 2.7 Hz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=O.[NH2:21][C@H:22]1[CH2:27][C:26]2[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:29][CH:30]=[CH:31][C:25]=2[O:24][CH2:23]1>CN(C)C=O>[CH3:38][N:35]1[CH2:36][CH2:37][N:32]([C:28]2[C:26]3[CH2:27][C@H:22]([NH:21][C:18]([C:14]4[NH:13][CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:23][O:24][C:25]=3[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: O=C(O)c1ccc[nH]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc[nH]2)CO3)CC1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1,1′-carbonyldiimidazole (360 mg, 1.85 mmol) and pyrrole-2-carboxylic acid (225 mg, 2.03 mmol) in anhydrous N,N-dimethylformamide (8 mL) was stirred at 75° C. for 45 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (457 mg, 1.85 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred for 7 days at room temperature under nitrogen. The solvent was removed in vacuo, and the residue was extracted with diethyl ether (50 mL) and water (20 mL). The aqueous layer was extracted with another portion of diethyl ether (50 mL). The combined ethereal layers were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 90:10+0.5% conc. NH3) yielding the title compound as an oil. Evaporation with diethyl ether afforded 300 mg (48% yield) of the title compound as a white powder: mp sinters >96° C.; [α]21D−82.8° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 340 (10, M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>CN(C=O)C>[Cl:8][C:6]1[C:5]([I:16])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccn1
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a solution of 2-amino-4-chloropyridine (150 g, 0.78 mol) in DMF (1.5 L) was added NIS (341 g, 1.52 mol) and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo to 300 mL volume. The resultant residue was poured into 10% aqueous sodium thiosulfate solution (1.2 L), stirred for 15 min and the precipitate formed collected by filtration, washed with water then dried at 35° C. in vacuo to give the title compound as a pale brown solid (185 g, 62%). 1H NMR 400 MHz (CDCl3) δ: 8.33 (1 H, s), 6.68 (1 H, s), 4.52 (2 H, s).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:11])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a solution of 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL) were added 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 232 mg, 1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285 mmol), and DIEA (367.7 mg, 2.85 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification via SiO2 column chromatography (dichloromethane/methanol=95/5) afforded 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile as a white solid (193 mg, 44% yield). m/z (ES+) 440 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=5.4 Hz. 2H), 7.56-7.30 (m, 4H), 1 proton obscured by methanol solvent peak, 4.10-3.98 (m, 1H), 3.64 (t, J=10.7 Hz, 1H), 3.33-3.21 (m, 1H), 3.00 (t, J=8.9 Hz, 2H), 2.58 (s, 3H), 2.48 and 2.38 (2 singlets, amide rotamers, ArCH3, 3H), 2.28-1.92 (m, 6H), 1.92-1.55 (m, 4H). 1H NMR (400 MHz, DMSO-d6): δ 13.66 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.62-7.34 (m, 4H), 4.78-4.63 (m, 1H), 4.31 (br s, 1H), 3.45 (br s, 1H), 3.15 (app t, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H), 2.44-1.80 (m, 12H), 1.80-1.37 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([O:11]C)[O:9]C)[CH:3]=1.O[Li].O.[CH2:16]1[CH2:20]OC[CH2:17]1.CO>O>[NH:5]1[C:6]2[C:7](=[CH:2][CH:17]=[CH:16][CH:20]=2)[CH:3]=[C:4]1[C:8]([OH:9])=[O:11]
Reactant: C1CCOC1
Reactant: COC(OC)c1cc(Cl)ccn1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of the above ether (770 mg, 2.1 mmol) in THF/MeOH (25 mL/10 mL) was added LiOH.H2O (218.1 mg, 2.50 eq) dissolved in 3 mL of water. The clear reaction solution was stirred at room temperature for 5 h, then concentrated in vacuo. The residual aqueous solution was diluted with water (15 mL), and extracted with ether. The organic layer was disgarded. The aqueous layer was acidified to pH 5 with 1.4 N HCl (˜2.5 mL). A large amount of white precipitates were extracted with 200 mL of EtOAc and washed with brine. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give the desired indole-2-carboxylic acid intermediate (644 mg, 90.5%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([Cl:32])=[O:31])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[ClH:32].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[C:12]([NH:18][C:30]([CH:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[CH2:34][CH2:33]2)=[O:31])[CH:13]=1
Reactant: COc1ccc(NC(=O)c2ccc(F)cc2N)cc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: COc1ccc(NC(=O)c2ccc(F)cc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 77.6 %

Procedure:
Using the procedure described in Example 138, N-(4-methoxyphenyl)-2-amino-4-fluorobenzamide (1.8 mmol) and N-(4-pyridyl)isonipecotoyl chloride (3.6 mmol), purifying with RPHPLC Method A, yielded 677 mg (78%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
2-Amino-4,6-dichloropyrimidine (15 g, 91 mmol) was treated with 1-methylpiperazine (10.1 g, 100 mmol), treated with Et3N (90 mL, 0.64 mol), treated with EtOH (185 mL), heated to 80° C. over night, cooled, concentrated and partitioned between CH2Cl2 (100 mL) and 1 M NaOH (125 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and crystallized from EtOAc to provide 14.9 g (71%) of the title compound. 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.45 (m, 4H), 3.60 (m, 4H), 4.82 (s, 2H), 5.96 (s, 1H); MS (DCl—NH3) m/z 228 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].C[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[I-].[K+].[ClH:24].[CH2:25](O)C>C(N(CC)CC)C>[ClH:24].[CH3:25][CH:19]1[CH2:18][CH2:17][N:16]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)=[O:4])[CH2:21][CH2:20]1
Reactant: CCO
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CN1CCCCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC1CCN(CC(=O)c2ccc3ccccc3c2)CC1

Procedure:
2.5 g of 2-bromo-2'-acetonaphthone, 1 g of methylpiperdine, 0.1 g of potassium iodide, and 3.1 g of triethylamine were added to 100 ml of ethanol. The mixture was refluxed for 20 min. The solvent was distilled off, and dichloromethane was added to the residue. The mixture was washed with water and dried. The dichloromethane was distilled off, and the residue was purified by column chromatography (silica gel) to prepare an oleaginous and oily intended compound. The compound was converted into a hydrochloride by an oridinary method and then recrystallized to prepare 1.87 g of an intended hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=O.[CH3:17][CH:18]1[C:22](=[O:23])[NH:21][C:20]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:19]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][C:18]2([CH3:15])[C:22](=[O:23])[NH:21][C:20]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:19]2)[CH2:11][CH2:10]1
Reactant: CC1N=C(c2cccnc2)NC1=O
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Product: COc1ccccc1N1CCN(CC2(C)N=C(c3cccnc3)NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine (1.65 g) and 37-40% aqueous formaldehyde solution (0.39 ml) was stirred at ambient temperature under nitrogen for 10 minutes, then a suspension of 4-methyl-2-(3-pyridyl)-2-imidazolin-5-one (1.5 g) in industrial methylated spirit (75 ml) was added in one portion. The mixture was stirred and heated under reflux for 52 hours, then the solvent was removed in vacuo. The residue was triturated with a 49:49:2 mixture of ether, ethyl acetate and propan-2-ol, and the resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at ambient temperature to give 4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as an off-white solid (1.55 g), m.p. 159-162° C.