Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10](O)[CH2:11][CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:25]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cccc([C@@H](O)CC[C@H](O)c2cccc([N+](=O)[O-])c2)c1
Product: O=[N+]([O-])c1cccc([C@H]2CC[C@H](c3cccc([N+](=O)[O-])c3)N2c2ccc(C(F)(F)F)cc2)c1
Yield: 19 %

Procedure:
The product from Example 205A and 4-aminobenzotrifluoride were processed using the method described in Examples 55C and 55D to afford the title compound (0.27 g, 19%). MS (ESI) m/z 858 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=3[N:13]=[N:14][N:15]=2)[CH:2]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1cccnc1
Product: NC(=O)c1cccc2c(NCc3cccnc3)nnnc12

Procedure:
Compound 3 was prepared following general synthetic scheme 7 wherein pyridin-3-ylmethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [281 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.38-9.32 (m, 2H), 8.66 (s, 1H), 8.54 (d, 1H), 8.50-8.48 (m, 2H), 8.05 (s, 1H), 7.99 (t, 1H), 7.82 (d, 1H), 7.38-7.35 (m, 1H), 4.93 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[N:13]O)[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>>[NH2:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:10]([OH:12])[CH3:11]
Reactant: CC(O)C(=NO)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)C(N)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well stirred solution of 1-(3,4-difluorophenyl)-2-hydroxy-propan-1-one-oxime (5.8 g, 28.4 mmol), was added a 1.0 M solution of LiAlH4 in ether (90 mL, 90 mmol) dropwise at 0° C. The resulting yellow solution was then stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and then carefully quenched sequentially with 3.5 mL of water, 3.5 mL of 3N NaOH followed by 10.5 mL of water. The resulting suspension was filtered thru a fritted glass funnel. To the residue was added 100 mL Et2O and the suspension was heated to reflux for 20 min. The suspension was filtered and was combined with the previous filtrate, dried over MgSO4, filtered and the solvent was removed in vacuo. 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol was obtained as a yellow glassy syrup (3.6 g, 66%) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[C:9]1[N:13]2[C:14]3[C:19]([N:20]=[C:21]([CH3:22])[C:12]2=[C:11]([CH3:24])[N:10]=1)=[CH:18][CH:17]=[C:16](F)[CH:15]=3.F[C:26]1C=C(Cl)C=CC=1[N+]([O-])=O>>[CH3:24][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:26])[N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:20]=[C:21]([CH3:22])[C:12]=12
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Cc1nc(-c2cc(Cl)ccc2Cl)n2c1c(C)nc1ccc(F)cc12
Product: Cc1ccccc1-c1nc(C)c2c(C)nc3ccccc3n12
Yield: 62 %

Procedure:
3,4-Dimethyl-1-(2-methylphenyl)imidazo[1,5-a]quinoxaline was synthesized in a manner similar to 1-(2,5-dichlorophenyl)-8-fluoro-3,4-dimethyl-imidazo[1,5-a]quinoxaline starting with 2-fluoro-4-chloronitrobenzene. A white solid was recovered (0.07 g) 62% yield. MS (ES) m/z 288.1 [M+1]+
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:7])([CH3:6])[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCc1ccsc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1
Reaction time: 16 h

Procedure:
tert-Butylchlorodimethylsilane (3.88 g) was added to a stirred solution of 2-(thiophen-3-yl)ethanol (3.00 g) and 1H-imidazole (4.78 g) in DMF (30 mL) cooled in ice bath. After 16 h, the reaction mixture was diluted with ethyl acetate (300 mL), washed with water (3×150 mL) and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane and then 1:5 ethyl acetate:isohexane, to collect the subtitled compound as an oil. Yield 5.2 g.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (77 mg, 81%), MS (ISP) m/z=361.4 [(M+H)+], mp 276° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[SH2:13].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:13])[NH2:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1cc(C#N)ccc1O
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1O
Temperature: 7 °C
Reaction time: 54 h
Yield: 93 %

Procedure:
A solution of 4-hydroxy-3-propylbenzonitrile (35.63 g, 0.221 mol) (Example 29 in DMF (300 mL) was saturated with hydrogen sulfide at rt (moderate flow over 45 min). Temperature was monitored (increase of about 7° C.). Diethylamine (45.73 mL, 0.442 mol) was added to the solution. The temperature rose to 10° C. and the already green reaction mixture became darker green. Hydrogen sulfide was passed through the solution for another 30 min (at this point the reaction temperature was 40° C.). The reaction mixture was warmed to 60° C. (gaseous evolution noted). Hydrogen sulfide was again passed through the solution at 60° C. over 2 h. The reaction mixture was cooled and stirred at rt for 54 h, and most of the solvent removed under reduced pressure. The resultant residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (4×100 mL), then brine, and dried over sodium sulfate, filtered, and concentrated. The resultant orange oil was triturated in hexanes (300 mL) and ether (25 mL) to give a yellow solid (39.97 g, 93%) after drying for 1 h under suction. LC/MS m/z 196.1 (M+H)+, RT 2.16 min. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.44 (s, 1H), 9.14 (s, 1H), 7.73-7.65 (m, 2H), 6.73 (d, 1H), 2.51-2.47 (m, 2H), 1.59-1.50 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]12[CH2:10][N:9](C(OCC)=O)[CH2:8][CH:7]1[N:6]([CH3:16])[CH2:5][CH2:4]2>Cl>[F:1][CH2:2][C:3]12[CH2:10][NH:9][CH2:8][CH:7]1[N:6]([CH3:16])[CH2:5][CH2:4]2
Reactant: CCOC(=O)N1CC2N(C)CCC2(CF)C1
Agent: Cl
Product: CN1CCC2(CF)CNCC12

Procedure:
7.1 g (26 mmol) of ethyl 5-fluoromethyl-2-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux overnight in 100 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 20 ml of water, the mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([CH:67]([CH3:69])[CH3:68])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][O:36]C3CCCCO3)[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]>CO>[C:18]([C:22]1[CH:23]=[C:24]([NH:43][C:44]([NH:46][C@@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C@H:50]([O:57][C:58]3[CH:59]=[CH:60][C:61]4[N:62]([C:64]([CH:67]([CH3:69])[CH3:68])=[N:65][N:66]=4)[CH:63]=3)[CH2:49][CH2:48]2)=[O:45])[N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH2:35][OH:36])[CH:28]=2)[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 55 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Pyridinium para-toluene sulfonate (44.0 mg, 0.17 mmol) was added to Intermediate 4c (124 mg, 0.17 mmol) in MeOH (3.0 mL). After 2 h, further pyridinium para-toluene sulfonate (100 mg, 0.39 mmol) was added, and the reaction stirred for 12 h. The reaction was then heated to 55° C. for 2 h, then cooled, and the solvent volume reduced to approximately ⅓ of its volume in vacuo. The residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted into EtOAc (3×), then the combined organic layers washed with brine, dried (MgSO4) and evaporated in vacuo. The product was purified by FCC, using 0-10% MeOH in DCM, then further purified by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% formic acid) to give the title compound (50.0 mg, 0.08 mmol, 47%). LCMS (Method 5): Rt 4.04 mins, m/z 624 [MH+]. 1H NMR (400 MHz, CDCl3): 1.30 (9H, s), 1.40-1.44 (3H, d, J 6.9 Hz), 1.44-1.47 (3H, d, J 6.9 Hz), 1.84-1.98 (1H, m), 2.00-2.10 (2H, m), 2.18-2.26 (1H, m), 3.16-3.26 (1H, sp, J 6.9 Hz), 3.87-3.92 (2H, m), 4.03-4.07 (2H, m), 5.01-5.09 (1H, td, J 8.9, 5.3 Hz), 5.14-5.17 (1H, t, J 4.0 Hz), 5.47-5.52 (1H, br d, J 8.7 Hz), 6.29 (1H, s) 6.60 (1H, br s), 6.80-6.84 (1H, m), 6.96-7.00 (1H, dd, J 9.9, 2.1 Hz), 7.07-7.11 (2H, m), 7.23-7.30 (5H, m), 7.38-7.40 (1H, d, J 1.6 Hz), 7.53-7.57 (1H, d, J 9.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:17]([O:19][C:20](=[O:27])[CH2:21][C:22](OCC)=[O:23])[CH3:18].C1CCN2C(=NCCC2)CC1>>[CH2:17]([O:19][C:20]([C:21]1[C:22](=[O:23])[NH:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:27])[CH3:18]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 185 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a mixture of (2-amino-5-chloro-phenyl)-phenyl-methanone (5 g, 21.58 mmol) and malonic acid diethyl ester (4.565 ml, 30.21 mmol) was added DBU (0.45 ml, 3.02 mmol) under nitrogen and the mixture was stirred at 180-190° C. for 16 h. After cooling, the crude residue was purified by flash column chromatography (100-200 mesh silica, eluting with 50% ethyl acetate in hexane) to afford pure 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (3.5 g, 49%) as off white solid. LC-MS: 328 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[CH3:25])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH:26]1([CH2:29][NH:30][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[CH3:25])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NCC3CC3)c2n1
Temperature: 120 °C
Yield: 9.6 %

Procedure:
To a solution of 8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 113, 40 mg, 0.114 mmol) in NMP (3 mL) was added cyclopropanemethylamine (0.1 ml, 1.140 mmol). The reaction mixture was heated to 120° C. for 18 hours. The reaction mixture was diluted with aqueous saturated NaHCO3 (20 mL) and EtOAc (2×20 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in EtOAc to give the title compound (4.2 mg, 10%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.[O-:10][C:11]#[N:12].[K+].Cl.[OH-].[K+]>O1CCCC1.O>[C:11]([N:4]1[CH:5]2[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]2)[CH2:2][CH2:3]1)(=[O:10])[NH2:12]
Reactant: N#C[O-]
Reactant: C1CN2CCC(CC2)N1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CCN2CCC1CC2
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
To a solution of 1,4-diazabicyclo[3.2.2]nonane (2.75 g) in a mixture of tetrahydrofuran (40 ml) and water (20 ml) was added potassium cyanate (2.65 g) at ambient temperature. The mixture was adjusted to pH 5.0 with concentrated hydrochloric acid and stirred at 50° C. for 40 minutes. The mixture was poured into 50% aqueous solution of potassium hydroxide. The resulted aqueous solution was extracted with chloroform. The extract was dried over anhydrous potassium carbonate and evaporated to dryness in vacuo. The crystalline residue was recrystallized from diethyl ether to give 4-carbamoyl-1,4-diazabicyclo[3.2.2]nonane (898.5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: CCCCC(=O)Cl
Product: CCCCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and valeryl chloride. m.p.: 159-160° C. 1H-NMR (CDCl3) δ: 9.94 (1H, br s), 8.28 (1H, d, J=9.2 Hz), 8.19 (1H, br s), 7.77 (1H, t, J=1.8 Hz), 7.70-7.58 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=1.8 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 2.49 (2H, t, J=7.3 Hz), 1.81-1.70 (2H, m), 1.51-1.37 (2H, m), 0.97 (3H, t, J=7.3 Hz)
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[O:46]1[C:50]([C:51](Cl)=[O:52])=[CH:49][CH:48]=[N:47]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:51]([C:50]2[O:46][N:47]=[CH:48][CH:49]=2)=[O:52])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Cl)c1ccno1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccno1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (70 mg, 0.11 mmol), 4-dimethylaminopyridine (30 mg, 0.25 mg), and isoxazole-5-carbonyl chloride (35 μL, 0.22 mmol) in 3.0 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.2 %

Procedure:
To a mixture of 2-nitroaniline (1 g, 7.23 mmol) in acetic acid (5 mL) was added phthalic anhydride (1.29 g, 8.7 mmol) followed by stirring at ambient temperature for 16 h. The mixture was then heated at reflux for 20 h. Upon cooling, a yellow precipitate formed and was collected by filtration. The filtrate was washed with acetic acid and was dried under a under a stream of air to give 2.35 g (100%) of 2-(2-nitrophenyl)isoindole-1,3-dione: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (m, 1H), 8.02–7.95 (m, 5H), 7.77 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:52]([F:55])([F:54])[F:53])=[C:15]([N:17]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36](=[O:46])(=[O:45])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:26][C:25]=3[F:47])[C:19]([CH2:48][CH2:49][CH2:50][CH3:51])=[N:18]2)[CH:16]=1>>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:52]([F:53])([F:54])[F:55])=[C:15]([N:17]2[C:21](=[O:22])[N:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[S:36](=[O:45])(=[O:46])[NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:26][C:25]=3[F:47])[C:19]([CH2:48][CH2:49][CH2:50][CH3:51])=[N:18]2)[CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: O=C(Cl)c1ccccc1
Product: CCCCc1nn(-c2cc(NC(=O)c3ccccc3)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 95 %

Procedure:
Benzoyl chloride was reacted with 2-[5-amino-2-(trifluoromethyl)phenyl]-4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 33, Step D) according to the procedure of Example 26 to give a 95% yield of the title compound as a white solid, mp 117°-120° C.; homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 774 (M+Li)+.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[N:24]=[C:23]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[CH3:39])[N:22]=3)[C@H:17]([CH3:40])[CH2:16]2)=[C:12]([CH3:14])[CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:24]=[C:23]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[CH3:39])[N:22]=[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:11]4[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:41])=[O:5])=[CH:13][C:12]=4[CH3:14])[CH2:16][C@H:17]3[CH3:40])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Stir a solution of (6-{4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridin-3-yl)-acetic acid tert-butyl ester (210 mg, 0.375 mmol) and 1 mL of TFA in DCM (10 mL) at room temperature for 16 h. Concentrate and partition between EtOAc and sat. NaHCO3. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify using flash chromatography eluting with MeOH-DCM (1:19) to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:32]4[CH2:31][CH2:30][N:29]([CH2:28][C:27]5[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:38])[F:22])=[CH:36][CH:35]=5)[CH2:34][CH2:33]4)=[O:19])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: FC(F)(F)c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Yield: 94 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and 1-(4-(trifluoromethyl)benzyl)piperazine (0.255 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(4-(trifluoromethyl)benzyl)piperazin-1-yl) ethanone as a white solid (0.501 g, 93.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[CH2:20]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperidine-4-carboxamide (100 mg), potassium carbonate (41 mg) and ethyl bromide (0.022 mL) in dimethylformamide (4 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in dichloromethane to give the title compound as a white solid (80 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CN1CCN(N)CC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 34 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.