Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccn1
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2ccccn2)c1
Yield: 91.4 %

Procedure:
To a 1 L 3-neck round-bottom flask was added 2-bromopyridine (12.07 mL, 127 mmol), (3-methoxyphenyl)boronic acid (24.04 g, 158 mmol), potassium phosphate tribasic monohydrate (87 g, 380 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (S-phos) (2.079 g, 5.06 mmol), 450 mL toluene, and 45 mL water. Nitrogen was bubbled directly into the mixture. Pd2(dba)3 (1.159 g, 1.266 mmol) was added and the reaction mixture heated to reflux overnight under nitrogen. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The crude material was purified by column chromatography eluting with 20% ethyl acetate to afford a yellow liquid (21.5 g, 92%).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=2[S:4][CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Reactant: CSc1ncnc2c(Br)csc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1ncnc2c(-c3ccc(S(C)(=O)=O)cc3F)csc12
Temperature: 100 °C

Procedure:
7-bromo-4-methylsulfanylthieno[3,2-d]pyrimidine (270 mg, 1.03 mmol) was added to 1,4-dioxane (10 mL), and 2-(2-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 eq), tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.06 eq), 2N aqueous sodium carbonate (3.1 mL, 3 eq) were sequentially added thereto while stirring. The reaction mixture was degassed with Ar(g), heated to 100° C., and stirred at 100° C. for 4 hours. After completion of the reaction using sodium bicarbonate, the reaction mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, dried, and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound as a yellowish solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(OC)(=O)C=C.C=CC(Cl)=C.Cl.[Cl:17][C:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH:19]=1.ClC1CC(C(OC)=O)CCC=1>C(Cl)Cl>[Cl:17][CH:18]1[CH2:19][CH2:20][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:22][CH2:23]1
Reactant: COC(=O)C1CC=C(Cl)CC1
Agent: C=CC(=C)Cl
Agent: COC(=O)C1CCC=C(Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: C=CC(=O)OC
Product: COC(=O)C1CCC(Cl)CC1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
A mixture of 200 parts of anhydrous aluminum chloride in 2000 parts of methylene chloride was maintained under an atmosphere of nitroge while 129 parts of methyl acrylate was added over a period of about 0.5 hours. With the addition of the methyl acrylate, the temperature of the mixture rose exothermically to about 34° C. The mixture was cooled to about 22° C. and 132.8 parts of freshly prepared chloroprene was added slowly, with stirring over a period of about 1.5 hours. During the addition, the temperature rose slowly to reflux condition (about 40° C.). The reaction mixture was then maintained under a nitrogen atmosphere, with stirring, for about 16 hours at ambient conditions. The crude reaction product was then treated with 10% HCl, and washed with methylene chloride and distilled to yield an essentially pure mixture of 1-chloro-4-carbomethoxy cyclohexene (92%) and its isomer 1-chloro-5-carbomethoxy cyclohexene (8%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]([CH3:47])=[N:42]2)=[O:36].CN(C=O)C>[NH4+].[Cl-]>[CH2:1]([O:8][CH2:9][CH:10]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:11](=[O:18])[CH:12]([CH2:34][C:35]([C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]([CH3:47])=[N:42]2)=[O:36])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12)C(=O)C(COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50-mL round-bottomed flask was added (R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (608) (1.21 g, 3.31 mmol), K2CO3 (1.04 g, 7.52 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (1.01 g, 3.01 mmol), and DMF (8 mL). The reaction was stirred at RT for 4 h. The reaction mixture was diluted with sat. NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic extract was washed with water (10 mL), dried over Na2SO4, and concentrated. Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (468a) was obtained as a light yellow oil and used without further purification. m/z (ESI, +ve) 621.3 (M+H)+. To a 15-mL glass tube was added ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (468a), crude from previous step, NH4OAc (0.93 g, 12.0 mmol), EtOH (10 mL), and AcOH (3 mL). The tube was sealed and heated at 60° C. for 2 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (20 mL) and water (10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10-30% EtOAc in hexanes to give ethyl 2-(2-(benzyloxy)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (468b) (0.97 g, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (br. s., 1H), 7.73 (dd, J=1.27, 7.53 Hz, 1H), 7.62 (dd, J=1.37, 8.02 Hz, 1H), 7.55 (d, J=2.35 Hz, 1H), 7.36 (t, J=7.73 Hz, 1H), 7.21-7.31 (m, 5H), 7.09 (br. d, J=10.17 Hz, 1H), 5.67-5.80 (m, 1H), 4.37-4.59 (m, 2H), 4.15-4.25 (m, 2H), 3.51-3.67 (m, 2H), 2.46 (s, 3H), 1.56 (s, 9H), 1.39 (s, 9H), 1.29 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 602.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:39][CH:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>CCOC(C)=O>[CH:40]([S:42]([N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1)(=[O:44])=[O:43])([CH3:41])[CH3:39]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)N1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.5 %

Procedure:
2-(3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 7.1 mg, 0.016 mmol) was suspended in DCM (90 μL, 0.018 mmol) and cooled in an ice bath. To this was added triethylamine (7.5 μL, 0.054 mmol) followed by propane-2-sulfonyl chloride (2.7 mg, 0.019 mmol). The reaction mixture was allowed to warm to ambient temperature. After 15 hours, the reaction mixture was diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to afford 2-(1-(isopropylsulfonyl)-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (4.8 mg, 0.010 mmol, 58% yield) as a light yellow oil. MS (apci) m/z=466.6 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:5]([C:7]1[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=1[C:9]([O:11]CC1C=CC=CC=1)=O)=[O:6].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C>[CH3:27][O:28][C:29](=[O:30])[NH:31][C:32]1[NH:26][C:25]2[CH:24]=[CH:23][C:4]([C:5](=[O:6])[C:7]3[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=3[C:9]([CH2:5][C:4]3[CH:23]=[CH:24][CH:25]=[CH:2][CH:3]=3)=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)Cc3ccccc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of benzyl 2-(3,4-diaminobenzoyl)benzoate (25 g, 72 mmole) and 1,3-bis(methoxy carbonyl)-2-methyl-2-thiopseudourea (19.3 g, 94 mmole) in acetic acid (100 ml) was heated to 75° C. for 45 minutes. The solution was cooled to room temperature and concentrated in-vacuo. The resultant oil was diluted in ethyl acetate (300 mL) and washed with 1N sodium hydroxide (200 mL), water (2×200 mL), dried over sodium sulfate, filtered and concentrated in-vacuo. The resultant solid was re-crystallized using ethyl ether and ethyl acetate (2:1). The solid was isolated by vacuum filtration and washed ethyl ether to afford [5-(2-benzylcarbanoyl-benzoyl)-1H-benzoimidazol-2-yl]-carbamic acid methyl ester, 21.4 g, 49.8 mmol, (69%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.04 (br s, 1H), 7.77-7.68 (m, 3H), 7.52-7.41 (m, 3H), 7.28-7.10 (m, 5H), 5.05 (s, 2H), 3.76 (s, 3H); MS (EI) for C24H20N4O4: 430 (MH+)
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=[O:9])[CH2:3][CH2:2]1.[CH3:21][Mg]Br>C(OCC)C>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:7]=2[CH:8]([OH:9])[CH3:21])[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Solvent: CCOCC
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)O
Reaction time: 0.5 h

Procedure:
2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.0 g) is dissolved in diethylether (50 ml) and thereto is added a 2M methyl magnesium bromide in diethylether (7.35 ml) under nitrogen flow at −70° C. The mixture is stirred at the same temperature for 30 minutes, and the reaction solution is quenched with a saturated aqueous ammonium chloride solution and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethanol (5.43 g). MS (m/z): 302 [M+H]+
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[C:34]([O:36][CH:37]([CH3:39])[CH3:38])[CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:31]1[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH3:38])[CH3:39])=[CH:35][C:30]=1[F:29])[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g) and 2-fluoro-4-isopropoxyphenylboronic acid (0.34 g) in 1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.35 g, 59%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:18]
Reactant: Cn1c(=O)c2c(Cl)nccc2n(C)c1=O
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2c(NN)nccc2n(C)c1=O
Yield: 93.1 %

Procedure:
0.69 g of Compound 17 and 0.31 g of hydrazine hydrate were added to 20 ml of methanol and the solution was heated under reflux for 24 hr. The solvent was distilled off to give 0.63 g of 5-hydrazino-1,3-dimethylpyrido[4,3-d]pyrimidine-2,4-dione (Compound 18).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)(=O)=O>CN(C=O)C>[O:33]1[CH2:34][CH2:35][C@@H:31]([N:12]2[C:13]3=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]3[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:11]2)[CH2:32]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Reactant: CS(=O)(=O)O[C@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc([N+](=O)[O-])cc1)nn2[C@@H]1CCOC1
Reaction time: 3 h

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (S)-tetrahydrofuran-3-yl methanesulfonate (0.389 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 3 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford 1-((R)-tetrahydrofuran-3-yl)-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. ESI-MS m/z [M+H]+ found 327.6, calculated 327.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:3][CH2:2]1.[CH3:25][CH2:26][N:27](C(C)C)C(C)C.BrCC#N>CC#N>[C:26]([CH2:25][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=2)[CH2:3][CH2:2]1)#[N:27]
Reactant: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: N#CCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 50 °C

Procedure:
N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (3.54 g, 10.0 mmol) was dissolved in CH3CN (100 mL). DIPEA (1.94 g, 15.0 mmol) and bromoacetonitrile (1.32 g, 11.0 mmol) were added. The reaction mixture was heated at 50° C. overnight. The solvent was removed in vacuo. Saturated NaHCO3 (40 mL) was added and the mixture was extracted with CH2Cl2 (4×30 mL). The combined organic solution was dried over anhydrous Na2SO4 and passed through a silica gel plug. The desired compound was eluted off with EtOAc. The product was further purified by crystallization from EtOAc/petroleum ether as a white solid (3.62 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[F-].[K+].[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:13]([F:17])([F:16])[F:12])=[C:4]([F:9])[CH:3]=1
Reactant: FC(F)(F)CI
Reactant: Oc1ccc(Cl)cc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 4-Chloro-2-fluoro-phenol (521, 5.0 g, 0.034 mol) in methanol (50.0 mL) was added potassium fluoride (2.2 g, 0.038 mol). The solvent was removed. The resulting salt was added to N,N-dimethylformaldehyde (25 mL), followed by adding 1,1,1-trifluoro-2-iodo-ethane (8.60 g, 40.9 mmol). The reaction was stirred at 50° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give colorless oil (522, 2.0 g, 26%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(Br)cc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Oc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of lithium hydroxide (3.5 g, 0.042 mmol) in tetrahydrofuran, menthol and water (120 mL, 3:1:1) was added methyl 2-(4-bromophenyl)-2-phenoxyacetate (6.8 g, 0.021 mol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quench with 10% hydrochloric acid (aqueous, 5 mL), extracted with dichloromethane and menthol (10:1), the combine organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to give 2-(4-bromophenyl)-2-phenoxyacetic acid (6 g, 80%). 1H NMR (300 MHz, DMSO-d6): δ 7.68-7.65 (m, 5H), 7.52-7.49 (m, 2H), 6.88-6.86 (m, 2H), 5.35-5.31 (m, 1H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[O:36])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from TFA de-protection of 3-[2-(5-fluoro-3-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester, as prepared in the previous step, using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]1(C)[CH:6]=[C:5](C)[CH:4]=[C:3](C)[C:2]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C(O)(=O)C1C=CC=CC=1>>[C:2]1([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:1]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(-c2nc3ccccc3[nH]2)c(C)c1
Agent: O=C(O)c1ccccc1
Product: c1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 88 %

Procedure:
2-Phenylbenzimidazole was synthesized in a similar way to 2-mesityl-benzimidazole, except using benzoic acid instead of 2,4,6-trimethylbenzoic acid. Molar amounts of carboxylic acid and diamine used were as previously described to provide an off-white powder in 88% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
59 mg (0.33 mol) 4-fluoro-1H-indol-7-carboxylic acid, 101 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 120 mg (81%) product as a colorless viscous oil. MS (ISP) 497.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>O>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(CC(=O)OC(C)(C)C)c(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-benzyloxy-4-ethoxycarbonyl-6-methyl-1-tert-butyloxycarbonylmethyl-2-pyridinone from step 2 above (1.1 g, 2.8 mmol) in 1:1 THF:H2O (20 mL) was added aqueous LiOH (3.0 mL of a 1.1 N solution, 3.3 mmol) and the resulting solution was stirred at ambient temperature for 18 h. Aqueous HCl was added (3 mL of a 1 N solution, 3 mmol) and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted four times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo to give the title compound as an amorphous solid (0.91 g; HPLC RT=15.98 min, method B).