Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]=[CH:10]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Agent: [Pt]
Solvent: CCO
Product: Nc1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 242.6 %

Procedure:
A 500 mL Parr hydrogenator bottle was charged with 1-benzyl-5-nitroindazole (30.4 g, 120 mmol), absolute ethanol (240 mL) and 5% platinum on carbon (1.5 g, 50% wet). The bottle was placed on a Parr hydrogenation apparatus, the bottle pressurized with hydrogen to 50 psi and the bottle shook until the uptake of hydrogen ceased. The contents of the bottle were then transferred to a 1 L round bottomed flask, warmed to approximately 60° C. under nitrogen and rapidly filtered through a celite pad. The filter cake was washed with ethanol (100 mL). Water (250 mL) was then added to the filtrate and the resulting suspension stirred for 4 hours in an ice bath. The resulting solids were isolated by filtration, and the solids dried on the pump for 1 h. Three additional reduction runs were carried out under identical conditions. The four separate batches of material were then combined to give 87.4 g of crude material, which was re-crystallized from ethyl acetate (900 mL). Filtration and drying under reduced pressure (1 mmHg) afforded 65.0 g (59%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][C@H:13]([OH:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](CCOCc2ccccc2)C1
Temperature: -78 °C

Procedure:
In a 100 mL flask with 3-(benzyloxyethyl)cyclobutanone (2.5 g, 12.2 mmol) inside, dry THF 30 mL was added under argon to give a light yellow solution. This was cooled to −78° C., after a while, L-selectride (1.0 M in THF, 14.7 mL, 14.6 mmol) was added drop by drop and this was allowed to warm up to room temperature, after which the reaction was quenched with saturated NaHCO3. Then the mixture was cooled to 0° C. and 30% H2O2 was added drop by drop, followed by the addition of H2O and EtOAc. The organic phase was separated, washed with H2O twice and brine once, dried over MgSO4 and solvent evaporation gave the crude product, which was purified by silica gel flash chromatography (Hexane:EtOAc=3:1) to give a colorless oil (2.0 g, 79.4%, Rf=0.2 (Hexane:EtOAc=3:1)). 1H NMR (CDCl3, 300 MHz): δ 1.40-1.60 (m, 2H), 1.60-1.90 (m, 3H), 2.05-2.21 (bs, 1H), 2.38-2.50 (m, 2H), 3.32-3.44 (t, J=, 2H), 4.52 (s, 2H), 7.20-7.40 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 22.90, 37.08, 37.85, 39.91, 64.14, 68.78, 73.04, 127.62, 127.68, 128.45, 138.59. MS (FAB): expected for C13H18O2 (M+H)+ 207.28. Found 207.13801.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20].Cl.[OH-].[K+]>N1C=CC=CC=1.O>[CH2:19]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[CH:9][N:10]=2)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCNC(=O)Nc1ccc2ncc(-c3ccc(O)cc3)nc2n1
Temperature: 75 °C

Procedure:
0.50 g of 4-(6-aminopyrido[2,3-b]pyrazin-3-yl)phenol (2.10 mmol) were initially charged in 5.0 ml of pyridine. 183 μl of ethyl isocyanate (2.31 mmol) were added dropwise at room temperature and the mixture was heated to 70-80° C. for 2 h. Thereafter, another 183 μl of ethyl isocyanate were added and the mixture was heated to 70-80° C. for a further 2 h. Once the reaction had ended, the reaction mixture was added to ice-water and neutralized with 1N hydrochloric acid. The precipitated product was filtered off with suction and dried. The product which had been filtered was partly dissolved in ethanol and admixed with 52 mg of potassium hydroxide (0.93 mmol), dissolved in water. The mixture was heated to 40° C. for approx. 1 h. Thereafter, the reaction solution was neutralized with 1N hydrochloric acid and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CN
Reactant: N#Cc1ccc(F)cc1
Product: CNc1ccc(C#N)cc1

Procedure:
According to a similar manner to that in Reference Example 1, the title compound was synthesized from 4-fluorobenzonitrile and 40% aqueous methylamine solution.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([OH:16])=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1
Reactant: OC1=Cc2ccccc2C=Cc2cc(Cl)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
To a solution of 2-chloro-5-hydroxy-dibenzo[a,e]cyclooctene (1.5 g) in dry dichloromethane (60 ml) was added pyridinium dichromate (5 g) and crushed 4 A molecular sieves (2.5 g). After stirring at room temperature for 14 h, diethyl ether (150 ml) was added and the reaction mixture was filtered through a plug of celite. The solvent was removed in vacuo and the residue purified by chromatography on flash silica with 5% ethyl acetate in hexane as eluent to give. as a colourless oil, the title compound (1.4 g). δ (360 MHz, CDCl3) 4.04 (2H. s, CH2), 6.93 (1H, d, J =12.9 Hz, CHA =CHB), 7.10 (1H. d, J=12.9 Hz, CHA =CHB), 7.22-7.42 (6H, m, ArH), 8.17 (1H. d, J =8.4 Hz, ClC=CH--CH=C--C=O). m/e 256 and 254 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:13][N:12]=[C:11]([OH:14])[CH:10]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:14][C:11]1[CH:10]=[C:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:13][N:12]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1cc(-c2c(Cl)cccc2Cl)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2c(Cl)cccc2Cl)on1
Yield: 63.7 %

Procedure:
5-(2,6-Dichlorophenyl)-3-hydroxyisoxazole (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.23 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.31 g, 65%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (Aldrich; 2.296 g), piperazine (5.45 g), and water is heated at 100° C. for 16 h. After cooling, the mixture is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (8/92) with about 0.5% ammonium hydroxide present, to give 2.20 g of 1-(5-trifluoromethylpyridin-2-yl)piperazine; mp 45-47° C.; IR (mineral oil) 1127, 1323, 1319, 1118, 1614 cm-1 ; 1H NMR (CDCl3) δ 2.98, 3.62, 6.63, 7.62, 8.40.
Reaction SMILES: [I:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17](O)[CH3:18].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[CH:6][C:2]=2[I:1])[CH3:18])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(S)cc1C
Reactant: CC(O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1I
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)CCc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2I)cc1C
Reaction time: 8 h

Procedure:
To a solution of 1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanol (1.52 g, 3.96 mmole) and 3-(4-Mercapto-2-methyl-phenyl)-propionic acid methyl ester (0.769 g, 3.96 mmole) in toluene (20 mL) at room temperature, is added tributylphosphine (1.98 mL, 7.92 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (1.99 g, 7.92 mmole) in toluene (20 mL). The reaction is stirred overnight, and then diluted with hexane (100 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as yellow solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32]Cl)([CH3:4])([CH3:3])[CH3:2].[C-:34]#[N:35].[Na+].O>CCO>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])[CH:11]=2)[N:6]1[CH2:31][CH2:32][C:34]#[N:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2N1CCC#N
Temperature: 110 °C
Yield: 48 %

Procedure:
N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and KI (cat) in EtOH (0.6 mL) and water (0.3 mL) were combined and heated at 110° C. for 30 min in the microwave. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing N-(2-tert-butyl-1-(2-cyanoethyl)indolin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (24 mg, 48%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:13]([NH2:15])=[O:14])=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[C:5]([C:13]([NH2:15])=[O:14])=[CH:6][C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH:12]=1
Reactant: NC(=O)c1cc2scnc2cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2scnc2cc1N

Procedure:
A solution of 5-nitrobenzothiazole-6-carboxamide (0.30 g, 1.34 mmol) in MeOH/EtOAc (1:1, 25 mL) is hydrogenated over 5% Pd/C at 60 psi for 1 h to give 5-aminobenzothiazole-6-carboxamide. This is immediately dissolved in triethyl orthoformate (30 mL) and the mixture is heated under gentle reflux for 18 h. An equal volume of petroleum ether is added to the cooled solution, precipitating thiazolo[5,4-g]quinazol-4(3H)-one (0.17 g, 57%) as a tan powder. 1H NMR (DMSO) δ12.30 (1H, brs), 9.67 (1H, s). 9.00 (1H, s), 8.31 (1H, s), 8.14 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:41][NH:42][CH3:43]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](=[O:18])[N:42]([CH3:43])[CH3:41])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CNC
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)CCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 23 %

Procedure:
To a solution of 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid, Compound 24, (0.06 g, 0.15 mmol) in dichloromethane (1 mL) was added EDC (0.057 g, 0.3 mmol), HOBT (0.0020 g, 0.015 mmol) and dimethyl amine (0.15 mL, 2 M solution in THF, 0.30 mmol). The mixture was stirred at room temp for 6 h then concentrated and the crude product purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (0.0147 g, 23% yield). HRMS (M+H) calcd for C19H24N3Cl2O4: 428.11440. found: 428.1143.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1.[CH3:28][Mg]Br.C(OCC)C>O1CCCC1.[NH4+].[Cl-]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])([CH3:28])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(N)nc(C)n2)cc1F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ncc(Nc2ncc(C(C)(C)O)nc2-c2cc(N)nc(C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of 1-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)ethanone (11 mg, 0.030 mmol) and methylmagnesium bromide, 3.0 M solution in diethyl ether (10.65 μL, 0.089 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (1 mL) was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic extracts were washed with saturated NaCl 5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give 2-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)propan-2-ol (8.5 mg, 0.022 mmol, 74.1% yield). 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 6H) 2.66 (s, 3H) 3.66 (s, 1H) 4.03 (s, 3H) 5.01 (s, 2H) 7.45 (s, 1H) 8.11 (d, J=1.90 Hz, 1H) 8.22 (dd, J=12.13, 2.05Hz, 1H) 8.39 (s, 1H) 12.66 (s, 1H). m/z (ESI, +ve ion) 386.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:44]=1[CH2:45]O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:45][C:44]2[CH:47]=[C:48]([F:51])[CH:49]=[CH:50][C:43]=2[F:42])=[CH:4][CH:3]=1
Reactant: OCc1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.5 %

Procedure:
At 0° C., 4-chlorobenzenethiol (5.45 g, 38.2 mmol), triphenylphosphine (11.1 g, 41.6 mmol) and diisopropyl azodicarboxylate (8.16 ml, 41.6 mmol) were sequentially added to a tetrahydrofuran (150 ml) solution of 2,5-difluorobenzyl alcohol (5.00 g, 34.7 mmol). The reaction mixture was stirred at room temperature for 4 days, followed by concentration. The residue thus obtained was purified by silica gel column chromatography (1% ethyl acetate-hexane) to give 2-[(4-chlorophenyl)thiomethyl]-1,4-difluorobenzene (2.68 g, 29%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:8]=1[C:9]#[N:10]>>[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:4][CH2:3][C@H:2]([NH2:1])[CH3:5])[C:8]=1[C:9]#[N:10]
Reactant: N#Cc1c(N)cccc1F
Reactant: C[C@@H](N)CO
Product: C[C@@H](N)COc1cccc(N)c1C#N

Procedure:
Prepared as in Example 24d from (R)-2-aminopropan-1-ol and 2-amino-6-fluoro-benzonitrile as brown solid (81%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.5 Hz, 3H), 3.08 (m, 1H), 3.71 (d, J=6.1 Hz, 2H), 5.95 (s, 2H), 6.15 (d, J=8.3 Hz, 1H), 6.2 (d, J=8.3 Hz, 1H), 7.13 (t, J=8.3 Hz, 1H). MS 192 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=C(O)c1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromobenzoic acid. MS (ESI): mass calcd. for C17H12FN3O2, 309.09; m/z found, 310.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.87 (m, 1H), 7.76 (d, J=7.5, 1H), 7.60 (m, 1H), 7.50 (d, J=7.2, 1H), 7.44 (d, J=8.2, 1H), 7.25 (d, J=5.1, 1H), 7.22 (s, 1H), 6.70 (s, 2H).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30].C(N(CC)CC)C>O1CCCC1>[C:7]([NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][C:25]1=[O:30])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 45.3 %

Procedure:
Add triphenylmethyl chloride (35.11 g, 126.0 mmol) to a suspension of 3-amino-piperidin-2-one dihydrochloride (21.42 g, 114.5 mmol) in tetrahydrofuran (250 mL), follow by dropwise addition of triethylamine (55.9 mL, 400.8 mmol). Stir the reaction at room temperature under nitrogen overnight. Filter the mixture, wash with tetrahydrofuran, concentrate the filtrate to a yellow oil, and partition the material between 20% isopropanol/chloroform and water. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1.25% methanol/chloroform) which gives 18.50 g of the title compound as a white foam, 45% yield. 1H NMR: consistent with structure. MS (ion spray) 113 (M+−1).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:16]=2[N:15]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:17]4[NH:18][C:14]([CH3:13])=[N:15][C:16]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Agent: N
Product: Cc1nc2cc(C(=O)NC3C4CC5CC3CN(C5)C4)ccc2[nH]1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to methods A and C; yield 84 mg, 0.21 mmol (58%): 1H NMR (300 MHz, methanol-d4) δ 1.99 (d, J=13 Hz, 2 H), 2.30-2.46 (m, 3H), 2.51 (s, 2H), 2.90 (s, 3H), 3.59 (s, 2H), 3.69 (s, 4H), 4.45 (s, 1 H), 7.82 (dd, J=9, 1 Hz, 1H), 8.07 (dd, J=8, 1 Hz, 1H), 8.25 (dd, J=1, 1 Hz, 1H), 8.50 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+; Anal. C18H22N4O.2HCl.1.0H2O: C, H, N.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:18][CH2:19][CH3:20])[N:16]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)ccc2F)n1
Temperature: 150 °C
Yield: 42.2 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 2,5-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.029 g (42% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[NH:17][C:18](=[O:35])[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1>>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:13]2[S:12][CH:16]=[CH:15][N:14]=2)=[O:35])=[CH:24][C:23]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc2c(C)noc2c1
Yield: 7.5 %

Procedure:
Example 8 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-(thiazol-2-yl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 18, 17 mg) followed by purification via mass directed autoprep to give the title compound as an oil (1.3 mg).