Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:31]=[O:32]>>[C:6]1([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH:31]=[O:32])[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cc(-c3ccccc3)n(-c3ccccc3)n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
32 grams phosphorus oxychloride were added dropwise at 0°-5° C. to 75 grams dimethylformamide. The mixture was thereafter stirred for 1 hours at room temperature. Thereafter, 25 grams 1,3,5-triphenyl-pyrazol were added to the mixture, which was then stirred for 8 hours at 80° C. The reaction mixture, was evaporated and water added to the residue. The pH of the aqueous mixture was adjusted to 8-10. The precipitate was separated and crystallized from ethanol. 22 grams 1,3,5-triphenyl-pyrazol-4-aldehyde, melting at 159°-160° C., were obtained, representing a yield of 80%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[OH2:12]>C(#N)C>[OH:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4]
Reactant: O
Reactant: Cc1cccc(C(=O)CBr)c1
Solvent: CC#N
Product: Cc1cccc(C(=O)CO)c1

Procedure:
A solution of 2-bromo-1-(3-methylphenyl)ethanone (1 g) in acetonitrile (2.5 mL) and water (13 mL) is treated under microwave irradiation (125° C., 50 min) The same experiment is repeated three times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:13][CH2:12][NH:11][C@@H:10]2[C:14](OC)=[O:15])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:13][CH2:12][NH:11][C@@H:10]2[CH2:14][OH:15])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H]1NCC[C@H]1c1ccc(C(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Product: OC[C@H]1NCC[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 15.2 %

Procedure:
To a stirred mixture of (2S,3S)-methyl 3-(4-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate (0.33 g, 1.21 mmol) in THF (5.0 mL) was added BH3-THF (12 mL, 12 mmol) at 0° C. The mixture was heated at reflux for 4 hours. The mixture was cooled to 0° C., the reaction carefully quenched with MeOH, and the mixture was evaporated in vacuo. The residue was diluted with saturated aqueous NaHCO3, water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography (ISCO Combiflash system, eluting with a gradient from pure DCM to 5% MeOH in DCM) to provide ((2S,3S)-3-(4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol as a white solid (45 mg, 15%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O-:9])=[CH2:2].[K+].[OH-].[K+].C1(C)C=CC=CC=1.Br[CH:21]([CH3:29])[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:24]1([C:22](=[O:23])[CH:21]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[CH2:2])[CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C=Cc1ccccc1[O-]
Reactant: CC(Br)C(=O)N1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1OC(C)C(=O)N1CCCC1
Temperature: 45 °C
Yield: 71.2 %

Procedure:
To a solution of 6.35 g (40.1 mmol) potassium 2-vinylphenolate in 110 mL of water (pH adjusted to 14 by addition of KOH) under argon was added 150 mL of toluene, 0.65 g (2.0 mmol) of tetrabutylammonium bromide and 11.54 g (50.16 mmol) of 2-bromo-1-pyrrolidin-1-yl-propan-1-one. The two-phase mixture was stirred vigorously over night at 45° C. After this time the organic phase was removed, washed with water, 4 M sodium hydroxide aqueous solution, 1 M hydrochloric acid solution and water, dried (Na2SO4), and evaporated to dryness. Crystallization of the residue from warm heptane (200 mL) afforded the title compound as a white powder (7.0 g, 70.5% yield): MP 85-86° C., MS: 246.1496 (M+H)+, 268.1317 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[N:15][CH:16]=1)[NH2:6])#[N:2].[Br:18]Br>C(O)(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([Cl:17])[CH:14]=[N:15][CH:16]=2)=[C:3]([C:1]#[N:2])[C:4]=1[Br:18]
Reactant: BrBr
Reactant: N#Cc1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: CC(=O)O
Product: N#Cc1c(Oc2cncc(Cl)c2)ccc(N)c1Br
Yield: 37 %

Procedure:
3-Cyano-4-(3-chloro-5-pyridyloxy)aniline (see Example 2) was combined with bromine in acetic acid in a manner similar to that described in Example 40 to produce 5-(4-amino-2-cyano-3-bromophenoxy)-3-chloropyridine (37%) after chromatography.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24])#[CH:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28])#[CH:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: C#Cc1cc(N)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 71.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 204 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 211 mg of 3-ethynyl-4-fluoroaniline, and 195 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.126 ml of pyridine and 3 ml of N,N-dimethylformamide. 200 mg of N-(3-ethynyl-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]1[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:5]1
Reactant: COc1cc(Br)c(C=O)cc1OC
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)c(C2OCC(C)(C)CO2)cc1OC
Temperature: 25 °C
Yield: 104.8 %

Procedure:
3.6 g of 2-bromo-4,5-dimethoxybenzaldehyde and 3.22 g of 2,2-dimethyl-1,3-propanediol were dissolved in 200 ml of toluene and boiled at reflux in the presence of 0.8 g of p-toluenesulphonic acid for 3 hrs. Then, the reaction mixture was left to cool to room temperature and was washed with NaHCO3 solution, water and saturated NaCl solution. Subsequently, the solvent was removed in a vacuum and there were obtained 5.1 g of 2-(2-bromo-4,5-dimethoxy-phenyl)-5,5-dimethyl-[1,3]dioxan as yellow-green needles.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:18]C1C=CN=CC=1C1N=CN(CN2C(=O)C3C(=CC=CC=3)C2=O)C=1.NN>C(O)C>[Cl:18][C:4]1[CH:3]=[CH:2][N:7]=[CH:6][C:5]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)N1Cn1cnc(-c2cnccc2Cl)c1
Reactant: NCCCCc1nc(-c2ccc(Cl)nc2)c[nH]1
Agent: NN
Solvent: CCO
Product: NCCCCc1nc(-c2cnccc2Cl)c[nH]1
Temperature: 65 °C
Yield: 94 %

Procedure:
4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(4-chloro-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (2.82 g, 7.42 mmoles) in ethanol (75 ml) was added hydrazine (0.58 ml, 18.6 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (200 ml) and was washed with 1M NaOH (250 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (1.74 g, 94%). MH+(251)
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)#[CH:2].[CH3:11][CH2:12][CH2:13][CH2:14][SnH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:9][N:6]1[CH2:7][CH2:8][C:3](/[CH:1]=[CH:2]/[Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH3:11])([OH:10])[CH2:4][CH2:5]1
Reactant: C#CC1(O)CCN(C)CC1
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](/C=C/C1(O)CCN(C)CC1)(CCCC)CCCC

Procedure:
1-Methyl-4-((E)-2-tributylstannanyl-vinyl)-piperidin-4ol is prepared in analogy to the procedure described in example 9 from 4-ethynyl-1-methyl-piperidin-4-ol and Bu3SnH.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:10]([CH3:11])[C:9]([C:8]1[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=[N:6][CH:7]=1)=[O:12]
Reactant: CCC(=O)c1cncnc1CC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ncncc1C(=O)C(C)Br
Yield: 88.2 %

Procedure:
49.2 g (0.30 mol) of 1-(4-ethylpyrimidin-5-yl)propan-1-one was dissolved in 500 ml of carbon tetrachloride, and 53 g (0.30 mol) of N-bromosuccinimide and 0.3 g of azoisobutyronitrile were added, followed by refluxing for 2 hours. After cooling, crystals were removed by filtration, and the filtrate was concentrated and the obtained oily product was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:2) to obtain 64.3 g (yield: 89%) of 2-bromo-1-(4-ethylpyrimidin-5-yl)-propan-1-one as yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.C(O)(=[O:19])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:19])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: CC(=O)O
Agent: CC(=O)OO
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 88.5 %

Procedure:
To a stirred solution of 16.67 g (77.8 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (naproxen aldehyde) in ethyl acetate (78 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 4.67 g (77.8 mmol) of glacial acetic acid and 8.33 g (77.8 mmol) of 2,6-dimethylpyridine (2,6-lutidine). To this solution was then added slowly dropwise 8.87 g (116.7 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 1 hour). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 3.5 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (300 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL). The ethyl acetate layer was further washed with two portions of water (110 mL each), and the combined water washes were back-extracted with ethyl acetate (100 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 110 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #4 Whatman filter. The white solid thus obtained was dried in a vacuum oven overnight at 45° C. (25 mm Hg), giving 15.85 g (88.5%) of naproxen. HPLC analysis of this material (Chiracel OD-H column) indicated an `S` acid content of 99.2%, the same as the starting aldehyde as measured following KMnO4 oxidation.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]#[N:52])[CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:49]=3[N:48]=[CH:47][CH:46]=[CH:45]4)[CH:35]=2)=[C:28]([C:51]2[NH:52][N:7]=[N:6][N:5]=2)[CH:27]=1
Reactant: N#Cc1cc(Cl)ccc1NC(=O)c1cccc(-c2cccc3cccnc23)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1-c1nnn[nH]1)c1cccc(-c2cccc3cccnc23)c1
Temperature: 100 °C
Reaction time: 66 h
Yield: 54 %

Procedure:
240 mg (2.08 mmol) of trimethylsilyl azide and 25.9 mg (0.10 mmol) of dibutyl tin oxide were added to a toluene (50 mL) solution comprising 400 mg (1.04 mmol) of N-(4-chloro-2-cyanophenyl)-3-(quinolin-8-yl)benzamide, and the mixture was stirred at 100° C. for 66 hours. The reaction mixture was condensed, and ethyl acetate was added thereto. Solids were collected by filtration. The obtained solids were recrystallized using DMF/IPE. The resulting solids were suspended in H2O, and stirred at 80° C. for 6 hours. Thereafter, diluted hydrochloric acid was added, and solids were collected by filtration and dried, thereby giving 242 mg of the target N-[4-chloro-2-(1H-tetrazol-5-yl)phenyl]-3-(quinolin-8-yl)benzamide (yield: 54%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.O.[Fe]>[NH2:13][C:3]1[C:4]([CH3:12])=[C:5]([CH:10]=[CH:11][C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(N)c(N)c1C
Yield: 97.8 %

Procedure:
To a solution of methyl 4-amino-2-methyl-3-nitrobenzoate (1.10 g, 5.22 mmol) in tetrahydrofuran (75 mL) and water (25 mL) was added ammonium formate (6.6 g, 104 mmol) and iron powder (2.92 g, 52.2 mmol). This mixture was refluxed for 12 hours then filtered and the filter cake rinsed with ethyl acetate. The filtrate layers were separated and the organic layer was dried (magnesium sulfate), filtered and concentrated to give 0.92 g (98% yield) of crude methyl 3,4-diamino-2-methylbenzoate, which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 7.05 (d; 1H), 6.40 (d, 1H), 3.69 (s, 3H), 2.29 (s, 3H). MS (EI) for C9H12N2O2: 181 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:14][CH3:15])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11](=[S:13])[NH2:12])[NH:7][CH:8]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=1)=O>C(O)C.O1CCOCC1>[F:28][C:23]1[CH:22]=[C:21]([C:19]2[N:12]=[C:11]([CH2:10][CH2:9][C:6]3[NH:5][C:4]([CH2:3][C:2]([CH3:16])([CH3:1])[CH2:14][CH3:15])=[CH:8][N:7]=3)[S:13][CH:18]=2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CCC(C)(C)Cc1c[nH]c(CCC(N)=S)n1
Reactant: O=C(CBr)c1ccc(F)c(F)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CCC(C)(C)Cc1cnc(CCc2nc(-c3ccc(F)c(F)c3)cs2)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(2,2-Dimethylbutyl)-1H -imidazol-2-yl]propanethioamide (58 mg, 0.24 mmol) in ethanol (1 mL) was added to 2-bromo-1-(3,4-difluorophenyl)ethanone (56 mg, 0.24 mmol) in anhydrous 1,4-dioxane (4 mL). After stirring at rt overnight, the reaction mixture was concentrated to give a residue, which was purified by reverse phase HPLC (KR100-5C18 100×21.2 mm column; 10-100% MeCN/H2O over 12 min) to afford the title compound. LC-MS: m/e 376 (M+H).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:21][O:22][C:23]1[N:28]=[C:27](C=CC#N)[CH:26]=[CH:25][CH:24]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:20]([C:26]3[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:16]=[C:14]([NH2:13])[N:12]2[N:13]=1
Reactant: COc1cccc(C=CC#N)n1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: COc1ccc(-c2cc(N)n3nc(-c4ccco4)nc3c2)cn1

Procedure:
The title compound, MS m/e (%): 307 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(6-methoxy-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[C:43](=[O:45])[CH3:44])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was weighed 26.8 mg (52 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The vial was charged with 0.5 mL of THF, followed by 15 μL (185 μmol) of pyridine, and 7 μL (98 μmol) of acetyl chloride. After stirring for 30 minutes at ambient temperature, LC/MS analysis of the reaction showed complete conversion to product. The reaction was quenched by addition of a small amount of water. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 1-((2R)-2-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidin-1-yl)ethanone was isolated as a white powder, yield 20.2 mg (70%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.61 (m, 1H), 7.56-7.42 (m, 4H), 7.38-7.34 (m, 0.6H), 7.30-7.26 (m, 0.4H), 7.20-7.16 (m, 2.4H), 7.05-7.04 (m, 0.6H), 5.34-5.31 (m, 0.4H), 5.08-5.05 (m, 0.6H), 3.78-3.67 (m, 1H), 3.63-3.49 (m, 1H), 3.09 (s, 1.8H), 3.08 (s, 1.2H), 2.52-2.46 (m, 0.4H), 2.36-2.26 (m, 1.6H), 2.14 (s, 1.8H), 2.12 (s, 1.2H), 2.08-1.95 (m, 2H); MS (ES): 554.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:18][OH:19].CN1CCOCC1.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:18][O:19][Si:28]([CH3:30])([CH3:29])[CH3:27]
Reactant: C[Si](C)(C)Cl
Reactant: CCOc1ccc(Cc2ccc(CO)c(Br)c2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(Cc2ccc(CO[Si](C)(C)C)c(Br)c2)cc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
To a cooled solution (−10° C.) of (2-bromo-4-(4-ethoxybenzyl)phenyl)methanol (0.137 g, 0.43 mmol) and N-methylmorpholine (0.1 mL, 0.9 mmol) in 2 mL of THF under N2, was added dropwise trimethylsilyl chloride. One hour later, the reaction was allowed to stir at 35° C. for 5 h and then stirred at 20° C. overnight. After dilution with AcOEt, the mixture was cooled to 0° C. prior to cautiously adding H2O at a rate such that the temperature did not exceed 10° C. The organic layer was separated and washed with aqueous KH2PO4, H2O, and brine. The volatiles were removed using a rotary evaporator to yield the title compound, which was used in the next step without further purification.
Reaction SMILES: O[C:2]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5](C(=O)C)[CH2:4][CH2:3]1.[OH-].[Na+]>Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C2(O)CCN(C(C)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C2=CCNCC2)cc1
Yield: 23.7 %

Procedure:
1-(4-Hydroxy-4-[4-methoxyphenyl]piperidin-1-yl )ethanone (14.75 g, 59 mmol) was dissolved in hydrochloric acid (250 mg, 6M) and refluxed for 12 hours. The reaction mixture was cooled in ice and basified with sodium hydroxide solution (155 ml, 10M), then extracted with dichloromethane (2×500 ml). The extractions were combined, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% methanol in dichloromethane, containing 1% aqueous ammonia. Concentration of the appropriate fractions gave 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (2.65 g, 24%) as a tan solid; δH (DMSO-d6) 2.3 (2H, m, tetrahydropyridinyl CH2), 2.9 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.4 (2H, d, J 3.4 Hz, tetrahydropyridinyl CH2), 3.7 (3H, s, ArOCH3), 6.1 (1H, m, CH=CR), 6.9 (2H, d, J 9.6 Hz, ArH), 7.3 (2H, d, J 9.6 Hz, ArH), and 9.6 (1H, br s, NH).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1[F:8].[CH3:32]B(O)O.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[F:8][C:7]1[N:6]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)[CH:4]=[CH:3][C:2]=1[CH3:32]
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Cl)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1F
Temperature: 150 °C
Yield: 84.3 %

Procedure:
A microwave reaction vial was charged with 3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (387.1 mg, 0.8489 mmol), methyl boronic acid (254.1 mg, 4.245 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (69.3 mg, 0.085 mmol), 1.00 M of Potassium acetate in Water (1.27 mL, 1.27 mmol), 1.00 M of Sodium carbonate in Water (1.27 mL, 1.27 mmol), and Acetonitrile (10 mL). The reaction mixture was heated under microwave at 150° C. for 5 minutes. Added another 5 equivalences of Methyl boronic acid and continue heated under microwave at 150° C. for 3 minutes. The same procedure was repeated one more times. The mixture was concentrated, and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford 3-(6-fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (311.7 mg, 84%).