Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]([CH3:8])([CH3:7])[CH3:6])=[O:4].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.O>CN(C)C=O>[CH3:6][C:5]([CH3:8])([CH3:7])[C:3](=[O:4])[CH2:2][C:10]1[NH:9][CH:13]=[CH:12][N:11]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Cc1ncc[nH]1
Reaction time: 1 h

Procedure:
Bromomethyl-t-butyl ketone (17.9 g) (ref. J. Amer. Chem. Soc , 70, 2886 (1948)) was added to a solution of imidazole (34.1 g) in 34 ml of dimethylformamide. After stirring for 1 hour, 600 ml of water was added and the aqueous mixture extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate, concentrated, and the resulting oil chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to give 3,3-dimethylbutan-2-on-1-yl imidazole.
Reaction SMILES: C([Li])CCC.C1([B:12]([OH:14])[OH:13])C=CC=CC=1.[C:15]12([OH:26])[CH2:23][CH:19]([C:20]1([CH3:22])[CH3:21])[CH2:18][CH2:17][C:16]2([OH:25])[CH3:24].BrCCl>C1COCC1>[C:15]1([CH2:23][B:12]([OH:14])[OH:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:15]12([OH:26])[CH2:23][CH:19]([C:20]1([CH3:22])[CH3:21])[CH2:18][CH2:17][C:16]2([OH:25])[CH3:24]
Reactant: OB(O)c1ccccc1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: ClCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)Cc1ccccc1
Reaction time: 8 h

Procedure:
n-Butyllithium (2.5 M soln in hexane, 4.66 mL, 11.64 mmol) was added dropwise to a stirred solution of (+)-pinanediol benzeneboronate 12a (Morandi, F. et al., J. Am. Chem. Soc. 2003, 125, 685-695) (2.48 g, 9.70 mmol) and bromochloromethane (0.95 mL, 14.55 mmol) in THF (25 mL) at −80° C. under argon atmosphere. The mixture was allowed to reach room temperature overnight. Then the solution was partitioned between light petroleum (80 mL) and water (25 mL), the organic phase was washed with saturated ammonium chloride (20 mL) and the combined aqueous phases were extracted with petroleum ether (2×40 mL). The organic phases were dried, filtered and concentrated and the crude residue was purified by gradient chromatography (light petroleum to light petroleum/ethyl ether 95:5), affording 13a as a colorless oil (2.33 g, 89% yield). [α]D+14.2 (c 2.0, CHCl3). 1H-NMR (200 MHz, CDCl3): δ 0.87 (3H, s, pinanyl CH3), 1.10 (1H, d, J 10.8, pinanyl Hendo), 1.30 (3H, s, pinanyl CH3), 1.41 (3H, s, pinanyl CH3), 1.62-2.39 (5H, m, pinanyl protons), 2.37 (2H, s, BCH2), 4.30 (1H, dd, J 8.8, 1.9, CHOB), 7.10-7.31 (5H, m, HAr). 13C-NMR (50 MHz, CDCl3): δ 19.3 (CB), 24.0, 26.4, 27.1, 28.6, 35.5, 38.1, 39.5, 51.3, 78.0, 85.8, 124.8, 128.3, 128.9, 138.8. EI-MS: m/z 217 (M++1, 2%), 270 (M+, 81%), 269 (M+−1, 21%), 255 (32), 229 (24), 214 (32), 201 (88), 200 (33), 187 (30), 179 (28), 174 (100), 135 (58), 134 (38), 119 (32), 118 (26), 117 (28), 109 (24), 93 (44), 91 (74), 83 (75), 82 (32), 81 (34), 79 (24), 77 (26), 67 (66), 65 (27), 55 (47), 53 (29). Anal. Calcd. for C17H23BO2: C, 75.57; H, 8.58. Found: C, 75.39; H, 8.44.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[Br-:10].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[Br:10][C:5]1[C:6]([NH2:9])=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: [Br-]
Reactant: CSc1ncc(N)cn1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CSc1ncc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
A stirred solution of 2.0 g (14.2 mmol) of 2-methylsulfanylpyrimidin-5-ylamine in 50 mL of dichloromethane and 10 mL of methanol was cooled in an ice bath. 6.08 g (15.6 mmol) of benzyltrimethylammonium tribromide was added in portions over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 3 minutes. The mixture was quenched with saturated aqueous sodium bicarbonate solution until the pH was 8. The organic layer separated and was removed. The aqueous layer was extracted with two 200 mL portions of ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was absorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes to afford 150 mg (5%) 4-bromo-2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2=[C:7]([CH:11]=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1
Reactant: CC1(C)Cc2c(CO)cccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)Cc2c(C=O)cccc2O1
Yield: 122.8 %

Procedure:
2,2-Dimethyl-2,3-dihydro-benzofuran-4-methanol (7.35 g, 41 mmol) was oxidized using DMSO, oxalyl chloride, and triethyl amine similar to the above procedures to give the product as a clear oil (8.87 g, 100%).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.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.C(O)C>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.30 g, Example 33), 4-bromophenylsulfonic acid amide (0.26 g), ethanol (6 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 90° C. for 6 hours. After work-up, the residue was purified by column chromatography on silica gel eluting with 5:95 methanol:ethyl acetate to give the title compound as a solid (0.04 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@H:26]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: C[C@@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (R)-1-phenylethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 316.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.37 (d, J=5.1 Hz, 1H); 7.83 (d, J=8.0 Hz, 1H); 7.3-7.5 (m, 8H); 6.77 (d, J=5.3 Hz, 1H); 6.03 (br s, 1H); 5.22 (br s, 1H); 1.65 (d, J=7.0 Hz, 3H).
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2OC)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[NH:12]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([B:24]([OH:29])[OH:25])=[CH:16][CH:15]=1)=[O:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
n-Butyl lithium (1.6 M in hexane solution, 5.7 ml, 9.05 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.0 g, 3.62 mmol) in tetrahydrofuran (27 mL) at −78° C. After 30 minutes, triisopropyl borate (1.25 mL, 5.43 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 6 hours. Hydrochloric acid (2.5N, 27 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was re-crystallized from ethyl acetate/heptane to give 4-(anilinocarbonyl)phenylboronic acid (0.354 g, 40%). 1H NMR (DMSO-d6) δ 7.10 (m, 1H), 7.35 (m, 2H), 7.80 (m, 4H), 7.92 (m, 2H), 8.23 (s, 2H), 10.23 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=[S:14].[OH-].[K+].O>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][SH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: ClCCOCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCOCc1ccccc1
Yield: 58.1 %

Procedure:
A solution of 2-benzyloxy-1-chloroethane (Synthesis, 1990, 495.) (7.2 g, 0.043 mol) and thiourea (3.2 g; 0.043 mol) in 95% ethanol (50 ml) was refluxed for 24 hours. To the reaction mixture, potassium hydroxide (4 g, 0.061 mol) and water (40 ml) were added and they were refluxed for 5 hours. The solvent was then distilled off under reduced pressure. The residue was neutralized with a 10% aqueous solution of sulfuric acid, followed by extraction with ethyl ether. The ether solution was washed with water, dried over sodium sulfate and then distilled off under reduced pressure, whereby 2-benzyloxyethanethiol (4.2 g, yield: 59.0%) was obtained as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH3:21].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:22][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH3:21])=[O:31]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC)c1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(C)=O)c1CC

Procedure:
Prepared from product of Example 2 (5.8 g, 16.9 mmol) and MCPBA (3.43 g, of an 85% mixture with MCBA, 16.9 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (5.39 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1>C(O)(C)C>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(CCCO)cc1
Agent: Cl
Solvent: CC(C)O
Product: OCCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 16.1 %

Procedure:
Following general procedure A2, employing iso-propanol as the solvent, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 3-(4-aminophenyl)propan-1-ol (0.075 g, 0.50 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.022 g, 16%) as an off-white solid. MW=415.36. 1H NMR (DMSO-d6, 500 MHz) δ 14.00 (s, 1H), 9.74 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.62-7.57 (m, 1H), 7.32 (s, 4H), 6.98 (s, 1H), 3.43 (t, J=6.4 Hz, 2H), 3.15 (t, J=7.7 Hz, 2H), 2.91 (q, J=7.2 Hz, 2H), 2.67-2.63 (m, 2H), 2.24 (quin, J=7.5 Hz, 2H), 1.77-1.71 (m, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:14])[C:3]=1[Cl:15].[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1COCC1.CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([NH2:1])=[C:3]([Cl:15])[C:4]=1[F:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(Cl)c1F
Yield: 39.4 %

Procedure:
To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane (9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. After completion of reaction, the reaction mixture is concentrated via rotary evaporation with acetic acid in the trap. The recovered oily solid is triturated with diethyl ether to provide 1.51 g of a yellow solid. The filtrate is concentrated and triturated with diethyl ether to give an additional 0.69 g of yellow solid. A total of 2.20 g (57%) of pure desired product is recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[C:35]([C:34]1[CH:37]=[CH:38][C:31]([NH:30][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)=[CH:32][CH:33]=1)#[N:36]
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C#N)cc3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 4-aminobenzonitrile according to the procedure from Example 137C substituting 4-aminobenzonitrile for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (51.5 mg, 62%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 11.11 (s, 1 H), 10.62 (s, 1 H), 9.11 (s, 1 H), 9.00 (d, J=5.51 Hz, 1 H), 8.57-8.80 (m, 1 H), 7.97 (d, J=8.82 Hz, 2 H), 7.68-7.90 (m, J=8.82 Hz, 3 H), 7.38-7.52 (m, 2 H), 6.88-7.12 (m, 3 H), 6.45-6.71 (m, 1 H), 3.77 (s, 3 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37](=[O:38])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:14][CH:13]=1)([CH3:25])[CH3:26]
Reactant: CC(C)c1ccc(NCc2ccc(OCC(F)(F)F)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(N(Cc2ccc(OCC(F)(F)F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-isopropylphenyl){(4-(2,2,2-trifluoroethoxy)phenyl)methyl}amine (1.12 g) in toluene (15 mL) was added 2,6-diisopropylphenyl isocyanate (1.1 mL), and the mixture was stirred at overnight room temperature. The reaction mixture was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The obtained crystals were subjected to recrystallization from diisopropyl ether to give N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-{(4-(2,2,2-trifluoroethoxy)phenyl)methyl}urea (0.54 g). melting point: 138° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:36]1[O:46]C2C(=C(C=CC=2)C=O)[O:37]1>>[CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[C:7]2[O:46][CH2:36][O:37][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc2c1OCO2
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: CN(C)C(=O)OC(c1cccc2c1OCO2)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using 2,3-(methylenedioxy)benzaldehyde in place of benzaldehyde. Pale yellow oil (65 mg, 82%);
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:44])=[C:4]([CH3:43])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18](CC4C=CC=CC=4)[CH2:19][CH2:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:41]=1[CH3:42].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([CH3:44])=[C:4]([CH3:43])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:41]=1[CH3:42]
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(N(CCC(c3ccccc3)c3ccccc3)Cc3ccccc3)CC1)O2
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 94.5 %

Procedure:
To a solution of 1-[(5-amino-2,3dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-benzyl-N-(3,3-diphenylpropyl)-4-piperidinamine (1.5 g) in ethanol (50 mL) was added 0.30 g of 5% palladium on carbon (50% hydrous) and the mixture was stirred in a hydrogen atmosphere at 5 atmospheric pressure and 40° C. for 6 hours. This reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 1.2 g of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(3,3-diphenylpropyl)-4-piperidinamine. Yield 94%. This product was treated with 4N-HCl solution in ethanol and the resulting trihydrochloride was recrystallized from ethanol/diethyl ether to provide 1.3 g of the title compound. Yield 82%.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:20]1[CH2:23][CH:22]([C:24]2[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[N:37]=[CH:38][NH:39]4)[CH3:33])[CH:27]=[C:28]([Cl:31])[C:29]=2[CH3:30])[CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[Cl:31][C:28]1[C:29]([CH3:30])=[C:24]([CH:22]2[CH2:21][N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:23]2)[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[CH3:33])[CH:27]=1.[C:15]([OH:17])([C:14]([F:19])([F:18])[F:13])=[O:16]
Reactant: COC(=O)Cl
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CC(c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (1.6 pt, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H24ClN6O3 (M+H)+: m/z=431.2. found: 431.1. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (1H, br s), 8.18 (2H, m), 7.46 (1H, s), 5.68 (1H, m), 4.31 (3H, m), 4.14 (1H, m), 4.02 (1H, m), 3.75 (3H, s), 3.55 (3H, s), 2.16 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:24]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][Br:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To [3-(4-bromo-2-hydroxymethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.7 g, 1.86 mmol) in 1,4-dioxane (10 mL) was added phosphorus tribromide (0.19 mL, 2.04 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, 0.6 g of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26])#[N:19]>>[CH2:13]([C:7]1([CH2:15][CH3:16])[C:6]2[CH:17]=[C:2]([NH:1][C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([CH:21]=3)[C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[N:10]([CH3:11])[C:9](=[O:12])[O:8]1)[CH3:14]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-cyano-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.40 (s, 1H), 7.38 (t, J=8.9 Hz, 1H), 7.27 (m, 2H), 7.14 (dd, J=8.6, 2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 3.27 (s, 3H), 1.98 (m, 4H), 0.81 (t, J=7.4 Hz, 6H); MS (ESI) m/z 354 ([M+H]+); MS (ESI) m/z 352 ([M−H]−); Anal. calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C, 65.58; H, 5.65; N, 11.36.
Reaction SMILES: [C:1]([NH:8][S:9]([C:12]1([CH:15]=O)[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[C:1]([NH:8][S:9]([C:12]1([C:15]#[CH:17])[CH2:14][CH2:13]1)(=[O:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a stirred solution of compound 80 (230 mg, 0.92 mmol) in MeOH (5 mL) at 0° C. was added K2CO3 (255 mg, 1.84 mmol), and Ohira-Bestmann reagent (215 g, 1.10 mmol) (Tetr. Lett. 2008, 49, 4454). The mixture was stirred at room temperature for 16 hrs and was concentrated under reduced pressure. Water, EtOAc, and citric acid were added to bring pH to 4-5. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 81 in 85% yield.