Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])(C)(C)C>ClCCl>[NH2:31][C:22]1[C:21]2[N:20]=[C:19]([CH2:32][O:33][N:34]=[C:35]([CH3:37])[CH3:36])[N:18]([CH2:17][CH2:16][CH2:15][NH2:14])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 243.6 %

Procedure:
Trifluoroacetic acid (7 mL) was added to a suspension of tert-butyl[3-(4-amino-2-isopropylideneaminoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (4.12 g) in dichloromethane (70 mL). The reaction became homogeneous and was stirred at ambient temperature for 2.5 hours. More trifluoroacetic acid (10 mL) was added and the reaction was stirred for another hour. The reaction mixture was concentrated under reduced pressure and placed under high vacuum overnight to provide 7.68 g of propan-2-one O-{[4-amino-1-(3-aminopropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime a white solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[N:6][CH:7]=1.O=[CH:27][C:28]([OH:30])=[O:29].FC(F)(F)C(O)=O>CN(C=O)C>[CH3:14][C:12]1[CH:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][CH2:27][C:28]([OH:30])=[O:29])[CH:7]=[N:6][CH:5]=2)[CH:9]=[C:10]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:11]=1
Reactant: O=CC(=O)O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(N)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(NCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[3-(5-aminopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (20.0 mg, 0.058 mmol), oxoacetic acid (4.29 mg, 0.058 mmol) in DMF (0.579 mL, 0.1 M), and trifluoroacetic acid (8.92 μL, 0.116 mmol). was stirred for 1 hour at room temperature. Si-cyanoborohydride (123 mg, 0.116 mmol, 0.94 g/mmol) was added to the reaction mixture and stir for 12 hours at room temperature. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by reverse phase liquid chromatography (5:95 to 95:5, acetonitrile:water+0.1% v/v formic acid) afforded N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]glycine as the formic acid salt. MS APCI calc'd for C19H17F3N5O2 [M+H]+ 404. found 404. 1H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 2H), 3.91 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:20]=[CH:21][CH:22]=1>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:16][C:17]1[CH:18]=[C:19]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:20]=[CH:21][CH:22]=1)=[O:11]
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: O=C(O)Cc1ccccc1I
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccccc1I)Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Yield: 23.2 %

Procedure:
2-Iodophenylacetic acid (39 mg, 0.15 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 53, (1), the title compound (13 mg, yield 23%) was obtained as pale brown powder in the same manner as that of Example 1, (4).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][CH:33]([OH:47])[CH2:34][C:35]([C:38]1[C:46]2[O:45][CH2:44][CH2:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36].[OH-].[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][C:33](=[O:47])[CH2:34][C:35]([C:38]1[C:46]2[O:45][CH2:44][CH2:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(CC(O)Cc1ccc(C#N)cc1Cl)c1cccc2c1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(CC(=O)Cc1ccc(C#N)cc1Cl)c1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of Dess-Martin periodinane (661 mg) in CH2Cl2 (5 mL) was added 1-(2-chloro-4-cyanophenyl)-4-(2,3-dihydrobenzofur-7-yl)-4-methyl-2-pentanol (460 mg) in CH2Cl2 (1 mL) at 0° C. The mixture was warmed to room temperature and stirred for 1 hour. NaOH (1 M, 10 mL) was added. The organic phase was separated and the aqueous layer was extracted with 30 mL of CH2Cl2. The combined organic phases were dried over magnesium sulfate. The solvent was removed to yield 405 mg of 1-(2-chloro-4-cyanophenyl)-4-(2,3-dihydrobenzofur-7-yl)-4-methyl-2-pentanone as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH2:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][NH:10][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(C)c1NN
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)NNc1c(C)cccc1C

Procedure:
18 g of 2,6-dimethylphenyl-hydrazine and 14 g of triethylamine were dissolved in 150 ml of ethyl ether. Keeping the temperature at 0° C., 12.5 g of methyl chloroformate were added dropwise to the solution. Precipitation of the chlorohydrate of triethylamine was observed.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[O:28])[CH3:27])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[CH3:29][Mg]Br>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])([CH3:29])[CH3:27])(=[O:18])=[O:19])=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 1.25 h
Yield: 78.6 %

Procedure:
A stirred THF (1 mL) solution of 1-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)phenyl]ethanone (Example 141; 65 mg, 0.17 mmol) was treated with methyl magnesium bromide (3 N in Et2O; 0.17 mL, 0.51 mmol) at ambient temperature. After 75 minutes, the mixture was partitioned between water (20 mL) and EtOAc (20 mL). The phases were separated and the organic phase dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant 35% EtOAc/isohexane). The material thus obtained was washed with hexane to afford the title compound as a white solid (53 mg). δH (500 MHz, d6 DMSO): 8.25 (1H, d, J 8.1), 7.71–7.64 (8H, m), 7.53 (1H, t, J 6.1), 7.40 (1H, d, J 16.4), 7.30–7.22 (3H, m), 4.98 (1H, s), 1.56 (6H, s). m/z (ES+) 419 [(M+Na)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:59][O:60][C:61]([NH:63][C@@H:64]([CH:68]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:65](O)=[O:66])=[O:62]>C(Cl)Cl>[CH3:59][O:60][C:61](=[O:62])[NH:63][C@H:64]([C:65](=[O:66])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH:68]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(C#N)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(C#N)cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
(S)—N-(5-Amino-1-hydroxymethyl-pentyl)-4-cyano-N-isobutyl-benzenesulfonamide (6) obtained in the previous reaction was dissolved in 50 mL CH2Cl2. BOP (1.2 eq), and triethylamine (5 eq) were added. After 10 minutes, (S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (1 eq) was added and the mixture was stirred at RT for 3 hours. LCMS indicated a complete reaction. The reaction mixture was washed with sat. NaHCO3. The aqueous phase was washed again with 100 mL CH2Cl2. The combined organic layers where dried with MgSO4, filtered over dicalite and evaporated to dryness. The residue was purified by column chromatography with CH2Cl2-MeOH(NH3) (97:3). The appropriate fraction was evaporated to dryness. (1.31 g, 84% yield over 2 steps)
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH:2]([CH3:3])[CH3:1])[N:16]=1
Reactant: CC(C)O
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of propan-2-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-50% EtOAc/hexanes gradient elution to yield the title compound (2.94 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=8.2 Hz, 1H), 7.73 (br. s., 1H), 7.03 (d, J=7.8 Hz, 1H), 5.84 (br. s., 1H), 5.64-5.47 (m, 1H), 1.45 (d, J=6.3 Hz, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:49])[CH2:14][C@@:15]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[O:34])[C@H:19]([CH3:20])[CH2:18][N:17]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:16]1)(C)(C)C>ClCCl>[Cl:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:22]=1[CH2:21][N:17]1[CH2:18][C@@H:19]([CH3:20])[C@@:15]([CH2:14][C:13]([OH:49])=[O:12])([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]2)[CH2:16]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 143.8 %

Procedure:
Trifluoroacetic acid (8 mL) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3c (320 mg, 0.518 mmol) in dichloromethane (dehydrated) (8 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (elution solvent: water/methanol) to give a mixture containing the title compound (344 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[OH:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[C:1]1([S:7]([C:10]2[C:11](=[O:21])[C:12]3[C:17]([C:18](=[O:20])[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(O)c2ccccc2c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C1C=C(S(=O)(=O)c2ccccc2)C(=O)c2ccccc21

Procedure:
10 g of compound (4) prepared above was suspended in 150 ml of acetone, and manganese dioxide was added thereto in an excess amount, followed by refluxing for 3 hours. Inorganic matter was removed by hot filtration, and the solvent was distilled off to obtain compound (5) as crystals. Yield: 4.5 g (45%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].Cl.C(OCC)C>CC(O)C>[ClH:1].[N+:18]([C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: NC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(N)=O)n2)cc(OC)c1OC
Temperature: 90 °C
Yield: 35.3 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzamide (52 mg, 0.178 mmol) and 3,4,5-trimethoxyaniline (34 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 18 hours. After the reaction was cooled to room temperature cold diethyl ether was added to precipitate out the product. The precipitate was filtered and washed with cold diethyl ether, then dried under vacuum to give 2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)benzamide hydrochloride (30 mg, 35%) as a dark brown solid. 1H NMR (DMSO-d6/D2O): δ 9.07 (s, 1H), 8.26 (m, 1 H), 7.69 (d, 1 H), 7.34 (t, 1 H), 7.19 (t, 1 H), 6.92 (s, 2 H), 3.77 (s, 3 H), 3.59 (s, 6 H). MS m/z 440 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[CH3:15][O:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[N:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([CH:17]([O:16][CH3:15])[CH3:18])=[CH:20][CH:21]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: COC(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(C)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg, 0.14 mmol), 4-(1-methoxyethyl)phenylboronic acid (27.4 mg, 0.152 mmol) and 2N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N2, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N2. The reaction mixture was heated to 100° C. for 48 hours, cooled to room temperature and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 7.0 min, HOLD at 0% H2O/100% MeCN to 8.5 min. Flow: 25 mL/min) to afford the title compound (4.9 mg, 11% yield). MS (ES+) 331.1 (M+H)+. Retention time=2.71 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]([CH3:43])[CH3:44])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C(C)C)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K22) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (197 mg, 47%).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:4](=[O:6])[CH3:5])[CH3:2].[CH3:27][O:28][C:29](=[O:49])[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH:32]=1>>[CH3:27][O:28][C:29](=[O:49])[CH2:30][C:31]1[CH:32]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]=2[CH2:7][N:3]([C:4](=[O:6])[CH3:5])[CH2:1][CH3:2])[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: N-ethyl-N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-acetamide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([OH:11])[CH2:10][CH2:9][CH2:8]1.F[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[C:15]([NH2:28])[N:14]=1.COCCOC>ClCCl>[CH:7]1([O:11][C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[C:15]([NH2:28])[N:14]=2)[CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1nc(OC2CCC2)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium t-butoxide (3.31 g, 34.2 mmol) was added portionwise to cyclobutanol (10 ml) at room temperature. The mixture became very thick and was heated to 50° C. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added followed by 1,2-dimethoxyethane (3 ml) and the mixture stirred at 50° C. for 90 mins. and then cooled and partitioned between ethyl acetate (50 ml) and water (50 ml). A precipitate that failed to dissolve in either phase was removed by filtration. The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated to give a cream foam. This material was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (110 g) using a 0-100% ethyl acetate in cyclohexane gradient followed by a 0-20% methanol (+1% triethylamine) gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white solid (0.655 g).
Reaction SMILES: [Na].[C:2]([NH2:6])(=[O:5])[CH2:3][SH:4].[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11]Br)[CH3:8]>C(O)C>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][S:4][CH2:3][C:2]([NH2:6])=[O:5])[CH3:8]
Reactant: NC(=O)CS
Reactant: CCOC(CBr)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(CSCC(N)=O)OCC

Procedure:
Sodium (0.878 g) was dissolved in absolute ethanol (150 ml) under an inert atmosphere. Thioglycolamide (3.47 g) (prepared as described by Sokol and Ritter, J.A.C.S. 70 3517 (1948)) was added and, when practically all the amide had dissolved, bromoacetaldehyde diethyl acetal (11.5 ml) was added. The mixture was heated at 60°-65° C. for 7 hours, cooled and filtered, and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and brine (50 ml), the layers separated and the brine extracted with ethyl acetate (50 ml). The combined ethyl acetate extracts were dried over Na2SO4 and evaporated under reduced pressure to yield an oil. Chromatography on silica (50 g), eluting with ethyl acetate/petrol, provided the title compound (6 g) as an oil. νmax (CHCl3) 3500, 3400 and 1690 cm-1 ; δ(CDCl3) 1.20 (6H, t, J 7 Hz, --CH2CH3 ), 2.80 (2H, d, J 5 Hz, >CHCH2S--), 3.25 (2H, s, --SCH2CO--), 3.58 (4H, 2q J 7 Hz, --OCH2CH3), 4.62 (1H, t, J 5 Hz, --CHCH2S--), 7.00 (2H, s, --CONH2); Found 207.0951 (M+) C8H17NO3S requires 207.0929.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([F:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[F:22][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C2(F)CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate (compound 26.3, 1 g, 3.11 mmol, 1.00 equiv, 95%) in dichloromethane (20 mL) was added dropwise TFA (3.75 g, 32.89 mmol, 10.57 equiv). After stirring for 1 h at 25° C., the mixture was concentrated under reduced pressure to yield 0.5 g of the title compound as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1C=NC(C2C=CC=CC=2)=CC=1[I:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([I:34])=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCCCC2)nc1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Product: CC(C)(C)OC(=O)Nc1cnc(N2CCCCC2)cc1I

Procedure:
The title product was prepared from (3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)carbamic acid tert-butyl ester in the same manner as described in the preparation of (4-iodo-6-phenylpyridin-3-yl)carbamic acid tert-butyl ester.