Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]1([C:31]2([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:34]1[CH2:33][CH2:32][C:31]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:36][CH2:35]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (50 mg, 0.133 mmol, 1 eq.) in 2 mL of ethanol was added tert-butyl N-(4-phenylpiperidin-4-yl)carbamate (44 mg, 0.16 mmol, 1.2 eq) and triethylamine (0.03 mL, 0.20 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 69 mg (84%) of tert-butyl N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}carbamate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.49 (m, 9H) 2.09-2.28 (m, 2 H) 2.43 (br. s., 2 H) 3.62 (br. s., 2 H) 4.96 (s, 1 H) 5.30 (br. s., 2H) 7.03-7.61 (m, 13H) 8.40 (s, 1 H), [M+H]+ 615.4.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]2[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=2[C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH3:43])[CH:35]=2)=[CH:21]1.[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(Cl)Cl.C1COCC1>[CH:46]1([NH:49][CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]3[C:30](=[O:45])[NH:31][C:32](=[O:44])[C:33]=3[C:34]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]([CH3:43])[CH:35]=3)=[CH:21]2)[CH2:48][CH2:47]1
Reactant: Cn1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: NC1CC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cn(CCCNC4CC4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a 0° C. solution of trifluoromethanesulfonic acid anhydride (188 mg, 0.67 mmol) in dry methylene chloride (15 mL) was added a solution of 3-[1-(3-hydroxy-propyl)-1H-indol-3-yl)-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (100 mg, 0.25 mmol) in THF (10 mL). After 2 hours, cyclopropylamine (200 μl, 5 mmol) was added and stirring continued over night. The reaction mixture was quenched with water. The organic phase was separated, washed with water (3×), dried, and evaporated. The residual red oil was purified by flash chromatography on silica gel eluting with a methylene chloride/ethanol gradient (98:2-5:5). Evaporation of the eluting solvent gave the title compound (70 mg, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[C:6]([CH:16]=1)[CH2:7][NH:8]C(=O)OC(C)(C)C.Cl.CO>CO>[ClH:1].[NH2:8][CH2:7][C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1N1CCOC1=O
Agent: Cl
Solvent: CO
Product: NCc1cc(Cl)ccc1N1CCOC1=O
Reaction time: 3 h
Yield: 146.1 %

Procedure:
(Step 3) To a solution of tert-butyl [5-chloro-2-(2-oxo-1,3-oxazolidin-3-yl)benzyl]carbamate obtained in Step 2 (2.21 g) in methanol (27 ml) was added 2N hydrogen chloride-methanol solution (10 ml) at room temperature, and the mixture was stirred for 3 hr. The reaction solution was concentrated under reduced pressure. The resulting crystals were collected by filtration, and washed with ethyl acetate to give 3-[2-(aminomethyl)-4-chlorophenyl]-1,3-oxazolidin-2-one hydrochloride (1.30 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[H-].[Na+]>CN(C=O)C>[Cl:11][C:9]1[C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[N:10]=1
Reactant: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Reactant: CC(=O)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a mixture of 2,6-dichloro-5-cyclopropylnicotinamide (2.00 g, 8.66 mmol) and 5-hydroxypentan-2-one (883 mg, 8.66 mmol) in DMF (30 mL) was added and NaH (416 mg, 10.4 mmol) in portions at 0° C. The mixture was stirred at r.t. overnight, quenched by water, extracted by EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give 6-chloro-5-cyclopropyl-2-(4-oxopentyloxy)nicotinamide (500 mg, 19.4%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:4]([N+:21]([O-:23])=O)[CH:3]=1.[K+].[Br-]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:10](=[O:20])[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[N+:21]2[O-:23]
Reactant: COc1ccc(CC(=O)Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2c(=O)[nH]c3cc(Cl)c(Cl)cc3[n+]2[O-])cc1
Yield: 75 %

Procedure:
The title compound was prepared according to the procedure described in the preceding example by substituting 127 (8 mmol) for 125. Yield: 75%; mp 262°-264° C. (from EtOH); IR (KBr) 3439, 3204, 2934, 2841, 1696, 1682, 1663, 1609, 1362, 1308, 1262 and 1184 cm-1 ; 1H NMR (in DMSO-d6) δ3.79 (s, 3H), 6.99 (d, 2H, J=8.7 Hz), 7.50 (s, 1H), 7.74 (d, 2H, J=8.7 Hz), 8.28 (s, 1H), 12.48 (br.s, 1H, N--H); HPLC: 97%; HRMS Calcd for C15H10N2O3Cl2 : 336.0068. Found: 336.0068.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:37]([N:39](C)[CH3:40])C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([N:39]([CH3:40])[CH3:37])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(N(C)C)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a pale yellow amorphous solid. IR (diffuse reflectance) 2971, 2932, 2890, 2875, 1608, 1563, 1482, 1442, 1389, 1366, 1352, 1207, 1175, 1090, 961 cm−1; OAMS supporting ions at: ESI+ 465.2; MS (EI) m/z 464 (M+); HRMS (FAB) calcd for C27H33CLN4O+H1 465.2421, found 465.2406. Anal. Calcd for C27H33ClN4O: C, 69.74; H, 7.15; N, 12.05. Found: C, 69.68; H, 7.16; N, 11.99.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.C(OCC)(=O)C.O>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([OH:1])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A solution of (S)-2-hydroxy-3-(4-hydroxy-phenyl)-propionic acid (3.00 g, 16.47 mmol) in ethanol (50 mL) was treated with benzyl chloride (4.20 g, 33.18 mmol) and potassium carbonate (4.60 g, 33.28 mmol) and the resulting mixture heated at reflux overnight. The mixture was cooled and treated with water (50 mL), and the resulting mixture stirred for 1 h. At this time ethyl acetate was added and the mixture acidified with 1N aqueous hydrochloric acid. The layers were separated and the aqueous phase extracted with ethyl acetate (3×). The organic phases were combined and concentrated in vacuo to an approximate volume of 10 mL. The resulting mixture was filtered and the isolated solid washed with diethyl ether and dried to afford (S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (3.00 g, 67%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH2:21][CH2:20]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][CH2:21][CH2:20]3)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc3c(c2)CCC3)c1C(=O)OC
Yield: 82 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 5-aminoindan (0.42 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.82 g of the product at 85:15 hexanes-ethyl acetate, in 82% yield: 1H NMR (CDCl3) δ 2.09 (m, 2H), 2.88 (t, J=7.4 Hz, 4H), 3.86 (s, 3H), 3.88 (s, 3H), 6.93 (dd, J=7.9 Hz, J=1.8 Hz, 1H), 6.99-7.06 (m, 2H), 7.12-7.21 (m, 1H), 7.25-7.29 (m, 1H), 7.40-7.71 (m, 1H), 8.07 (br, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:24])[CH:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:8]1[CH3:23])[CH3:6].[CH3:25]I.[NH4+].[Cl-]>C1COCC1>[C:19]([O:18][C:16]([C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH:5]([CH:4]([O:3][CH3:25])[CH3:24])[CH3:6])[C:8]=1[CH3:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CI
Reactant: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 27 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To dry THF (20 mL) was added NaH (60% in mineral oil, 2.37 g, 59.14 mmol). Then the mixture was stirred at 27° C. for 20 minutes, then tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (3.0 g, 9.86 mmol) was added. The mixture was stirred at 27° C. for 1 hour, then added by CH3I (13.99 g, 98.6 mmol). The mixture was stirred for 12 hours at 27° C. and then cooled to 0° C. Sat. NH4Cl was added and extracted with CH2Cl2. The extraction was dried over sodium sulfate, filtered and concentrated to give tert-butyl-1-(3-methoxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a yellow oil. (3.2 g, yield 100%) LCMS (M+H+) m/z: calcd. 319.41. found 318.9.
Reaction SMILES: OC[C:3]1[N:7]2[C:8]([CH2:12][N:13]([C:25](OC(C)(C)C)=O)[CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1.C[Si](I)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:23][C:21]([F:24])([F:22])[S:18]([NH:17][CH2:16][CH2:15][CH2:14][N:13]1[CH2:12][C:8]2[N:7]3[C:3](=[CH:4][N:5]=[C:6]3[CH:11]=[CH:10][CH:9]=2)[CH2:25]1)(=[O:19])=[O:20]
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(CO)n12
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 233 mg (0.50 mmol) of 3-hydroxymethyl-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 5.0 ml of chloroform was added 0.36 ml (2.50 mmol) of trimethylsilyl iodide. The mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted of the desired compound with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 109 mg of the desired compound (62.8%, a pale yellow liquid).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([NH2:12])=O.N#N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:10][NH2:12]
Reactant: NC(=O)c1cc2cccnc2[nH]1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1cc2cccnc2[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide (H-2) (805 mg, 5.0 mmol) in dried THF (10 mL) at 0° C. under 1 atm of N2 was slowly added LiAlH4 (570 mg, 15 mmol). The mixture was stirred at 80° C. overnight. The mixture was then cooled to 0° C. concentrated, and then purified by chromatography on silica gel to afford the title compound (720 mg). MS (m/z): 148 (M+1)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]2[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])[N:12]=1.[NH2:34][CH:35]1[C:38]([CH3:40])([CH3:39])[CH:37]([OH:41])[C:36]1([CH3:43])[CH3:42]>C(O)C>[OH:41][CH:37]1[C:38]([CH3:40])([CH3:39])[CH:35]([NH:34][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]3[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:12]=2)[C:36]1([CH3:43])[CH3:42]
Reactant: CC1(C)C(N)C(C)(C)C1O
Reactant: [O-][n+]1ccc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(O)C(C)(C)C1Nc1nc(NCc2c[n+]([O-])ccc2C(F)(F)F)ncc1C(F)(F)F
Temperature: 80 °C

Procedure:
DIEA (3.0 equiv.) was placed in a sealable flask with 3-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-4-(trifluoromethyl)pyridine 1-oxide (1.0 equiv.), 3-amino-2,2,4,4-tetramethylcyclobutanol (2.0 equiv.)(See J. Med. Chem. 2011, 54, 7693-7704 for preparation), and ethanol. The flask was purged with nitrogen and sealed. The reaction mixture was heated to 80° C. for 9 h. Standard work-up afforded the following compounds. Stereochemistry was assigned based on similar activity as other compounds provided herein in the biochemical assays described herein.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=O)[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:17](=O)[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NCC(Cc1ccc(OCc2ccccc2)cc1)NCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 126 mg (0.26 mmol) N-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-4-tert-butyl-benzamide in 1 mL dry THF was treated via dropwise addition with 0.78 mL (0.78 mmol) of a 1.0 M solution of borane-THF complex in THF. The resulting solution was heated under reflux for 8 hours. The mixture was cooled to 25° C. and 1 mL of 5 M HCL solution was carefully added, dropwise, followed by neutralization with saturated aqueous sodium bicarbonate. The mixture was extracted with three 7 mL portions of ethyl acetate. The combined extracts were washed with two 25 mL portions brine, dried over anhydrous magnesium sulfate and concentrated to a hazy oil. The oil was purified by column chromatography on silica gel with 5:5:1 ethyl acetate: hexanes:methanol as eluant. There was obtained 58 mg (49%) of a clear, colorless oil that slowly crystallized to white, waxy crystals of title product; mp 63-65° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[NH:24][C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][C:21]=2[C:20]=1[C:32]#[N:33].C(N(CC)CC)C>CN(C=O)C>[C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[C:20]([C:32]#[N:33])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 μL, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature overnight, then filtered and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 437.2, found 438.7 (M+1)+. Retention time 2.10 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.5, 8.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.21 (d, J=1.8 Hz, 1H), 1.51-1.49 (m, 2H), 1.36 (s, 9H), 1.18-1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].Cl>CN(C=O)C.O>[ClH:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:17]3=[O:27])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinedione was dissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[C:12]([CH3:27])=[N:13][N:14]([CH3:26])[C:15]=1[O:16][C:17]1[C:22]([F:23])=[CH:21][C:20](N)=[CH:19][C:18]=1[F:25].N(OC(C)(C)C)=O.[ClH:35]>C(#N)C.[Cu]Cl>[Cl:35][C:20]1[CH:21]=[C:22]([F:23])[C:17]([O:16][C:15]2[N:14]([CH3:26])[N:13]=[C:12]([CH3:27])[C:11]=2[C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[F:10])=[C:18]([F:25])[CH:19]=1
Reactant: Cl
Reactant: COc1cc(F)c(-c2c(C)nn(C)c2Oc2c(F)cc(N)cc2F)c(F)c1
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COc1cc(F)c(-c2c(C)nn(C)c2Oc2c(F)cc(Cl)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Copper(I) chloride (56 mg, 0.42 mmol) was added to a solution of 4-[[4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl]oxy]-3,5-difluorobenzenamine (prepared analogous to Synthesis Example 9) (132 mg, 0.346 mmol) in acetonitrile (5 mL). The stirred mixture was cooled using an ice-water bath, and tert-butyl nitrite (90% technical grade, 72 μL) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stirred at room temperature overnight, and then it was heated at reflux for 1 h. Hydrochloric acid (1 N, 5 mL) was added, and the mixture was extracted with ethyl acetate (˜20 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography through silica gel eluted with 20% ethyl acetate in hexane to give the title product, a compound of the present invention, as a viscous oil (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].F[C:27]1[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=1O)C(OC[C@@H](C)CC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][C:27]3[CH:28]=[CH:29][CH:38]=[CH:39][CH:40]=3)=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1Cl
Reactant: CC[C@H](C)COC(=O)c1ccc(O)c(F)c1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccccc3)cc2)cc1Cl

Procedure:
The reaction was performed as in Example 18 except using 3'-chloro-4'-octyloxybiphenyl-4-carboxylic acid instead of 3'-nitro-4'-tetradecyloxybiphenyl-4-carboxylic acid and (S)-2-methylbutyl 3-fluoro-4-hydroxybenzoate instead of (S)-2-methylbutyl 4-hydroxybenzoate. There was obtained 2-fluoro-4-(S)-2-methylbutyloxycarbonyl]phenyl 3'-chloro-4'-octyloxybiphenyl-4carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1c(Cl)cc2nc(S)oc2c1C
Reactant: CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc2nc(N3CCN(C)CC3)oc2c1C

Procedure:
5-Chloro-6,7-dimethyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (1.54 ml) was added dropwise to the solution and then the mixture was stirred with heating for 29 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-6,7-dimethyl-2-(4-methyl-1-piperazinyl)benzoxazole (260 mg).