Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:9][CH:8]=1
Reactant: OC1COC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(OC2COC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 52.7 %

Procedure:
To oxetan-3-ol (112 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The reaction mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved in ethyl acetate (50 mL) and washed with 2 M NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (1:10) to give 3-(4-bromophenoxy)oxetane (140 mg, 53%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), δ 6.55 (d, 2H), 5.19-5.13 (m, 1H), 4.97-4.94 (m, 2H), 4.76-4.73 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:3]1[NH:18]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:18][N:3]1[CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
tert-Butyl [2-oxo-6-(3-trifluoromethylphenyl)piperidin-1-yl]carbamate (210 mg) was dissolved in chloroform (4 mL), followed by addition of trifluoroacetic acid (2 mL). After stirring at room temperature for four hours, concentration under reduced pressure gave the title compound (119 mg). The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH:9]([C:13](O)=[O:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1>C(Cl)Cl>[CH:1]1([N:7]2[CH2:8][CH:9]([CH2:13][OH:14])[CH2:10][C:11]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Agent: B
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CC(CO)CN1C1CCCCC1
Temperature: 0 °C
Yield: 65.4 %

Procedure:
Place 2-methylene-succinic acid (12.0 g, 92.2 mmol) and cyclohexylamine (9.15 g, 92.2 mmol) and heat to 160° C. for hours. Cool to give 18.8 g (96%) of 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid. Charge a flask with 1-cyclohexyl-5-oxo-pyrrolidine-3-carboxylic acid (16.2 g, 76.7 mmol), add methylene chloride (20 mL) and cool to 0° C. Slowly add borane in THF (1M, 115.1 mL, 115.1 mmol) and stir for two hours at 0° C. Quench the reaction with ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (1-5% methanol in methylene chloride) to yield 9.9 g (65%) of the title compound: Mass spectrum (apci) m/z=198.1 (M+H).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:16][CH:15]=2)[CH:8]=[CH:9][C:10]=1[CH3:11])[C:2]([NH2:4])=[NH:3].[CH3:29][NH:30][CH3:31]>C(O)CCC>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:7]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:5]([NH:1][C:2]4[N:4]=[C:5]([C:10]5[CH:29]=[N:30][CH:31]=[CH:8][CH:9]=5)[CH:6]=[CH:7][N:3]=4)[CH:6]=3)=[O:28])=[CH:19][CH:18]=2)[CH2:22][CH2:23]1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=N)N
Solvent: CCCCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A suspension of N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benz-amide (30 g, 79 mmol) in n-butanol (150 ml) at 120° C. under an atmosphere of nitrogen is treated with 3-dimethylamino-1-pyridin-3-yl-propenone (15.3 g, 87 mmol). The resulting suspension is heated at 150° C. for 5 hrs. The reaction mixtures becomes a homogeneous deep orange solution and dimethylamine is removed by the distillation of n-butanol (130 ml). n-Butanol (20 ml) is added during the distillation. Butyl acetate (60 ml) is added dropwise at 100° C. and the solution is cooled to 0° C. within 1 hr and stirred at 0° C. for 16 hrs. The resulting deep orange suspension is filtered off with suction, the isolated solid is washed with n-butanol (2×50 ml) and water (2×50 ml) and dried in vacuo at 60° C. Yield: 36.4 g of the title compound, 93% based on theory, as off-white crystals. (99.6% area by HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([C:30]2[CH:34]=[CH:33][O:32][N:31]=2)[CH2:14][C:15]([N:17]2[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][O:19][C:18]2=[O:29])=[O:16])=[CH:9][CH:8]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:22]([C@H:21]1[CH2:20][O:19][C:18](=[O:29])[N:17]1[C:15](=[O:16])[CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:40]([C:39]([F:38])([F:49])[F:50])=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)[C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1)c1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a solution of substituted aniline 27.3 (0.050 g, 0.100 mmol) in DCM (1 mL), was added TEA (14.1 μL, 0.100 mmol) and 4-(trifluoromethyl)benzoyl chloride (15.0 μL, 0.100 mmol). The reaction mixture was stirred for 16 hours and then concentrated to dryness under reduced pressure. The residue was purified by medium pressure chromatography (silica gel, 0 to 30% EtOAc:DCM) to give 27.4 (72 mg). MS ESI (pos.) m/e 670.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[Sn](Cl)Cl>>[Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([Br:10])[C:3]=1[N:4]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: Nc1c(Br)cc(Br)cc1Br
Reactant: O=C1C=CC(=O)O1
Agent: Cl[Sn]Cl
Product: O=C1C=CC(=O)N1c1c(Br)cc(Br)cc1Br
Temperature: 142 °C
Reaction time: 1.9 h

Procedure:
A mixture of 2,4,6-tribromoaniline (1.20g, 3.64 mmol), maleic anhydride (0.83g, 8.5 mmol) and tin(II) chloride (0.064g, 0.34 mmol) is heated to 142° C. with mixing and held at this temperature for 1.9 hours. The reaction mixture is cooled, extracted with xylene, filtered and the resulting filtrate water washed. Solvent removal yielded N-(2,4,6-tribromophenyl)maleimide. Analysis by High Pressure Liquid Chromatography (HPLC) showed conversion of 2,4,6-tribromoaniline to be 99.9% and selectivity to N-(2,4,6-tribromophenyl)maleimide based on reacted 2,4,6-tribromoaniline of 75.0%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39](Cl)=[O:40])[CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:39]([C:36]3[CH:35]=[C:34]([CH3:33])[O:38][N:37]=3)=[O:40])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OC(=O)c3cc(C)on3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) with 5-methylisoxazole-3-carbonyl chloride (10 mg) and N,N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].[Cl-].[NH4+]>C1CCCCC1>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH3:6]
Reactant: ClCCCCBr
Reactant: COc1cccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Product: COc1c(CCCCCl)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
A solution of N,N,N',N'-tetramethylenediamine (18.12 mL, 0.120 mole) in cyclohexane (36 mL) was treated with n-butyllithium (1.55M in hexane; 79.8 mL, 0.123 mole) at room temperature. A solution of 1-methoxynaphthalene (17.4 mL, 0.120 mole) in cyclohexane (20 mL) was added over 30 minutes, and the resulting solution was stirred for 1.5 hours. It was then cooled to 0°, and 1-bromo-4-chlorobutane (27.0 mL, 0.234 mole) was added over 15 minutes. The mixture was warmed to room temperature and stirred for 17 hours, then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The crude product was chromatographed with 98:2 hexane/ether to provide the title compound (11.60 g, 39%) as a pale yellow oil.
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[N:31]=[C:30]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)[N:29]=2)[CH:24]=[C:25](Br)[CH:26]=1.[OH-].[Na+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([C:21]2[CH:22]=[C:23]([C:28]3[N:33]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:31]=[C:30]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)[N:29]=3)[CH:24]=[C:25]([C:8]3[C:7]4[C:16]5=[C:15]6[C:4](=[CH:5][CH:6]=4)[CH:3]=[CH:2][CH:1]=[C:14]6[CH:13]=[CH:12][C:11]5=[CH:10][CH:9]=3)[CH:26]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3)nc(-c3cc(-c4ccc5ccc6cccc7ccc4c5c67)cc(-c4ccc5ccc6cccc7ccc4c5c67)c3)n2)cc1
Yield: 51 %

Procedure:
In a stream of argon, 1.20 g (4.87 mmol) of 1-pyreneboronic acid, 1.50 g (3.03 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolyl-1,3,5-triazine and 57 mg (0.081 mmol) of dichlorobis-(triphenylphosphine)palladium were suspended in 135 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 3.81 mL (15.2 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 2 hours. Then, 29 mg (0.041 mmol) of dichlorobis(triphenylphosphine)palladium was added, followed by distillation under reflux for 2 hours. Further, 0.20 g (0.81 mmol) of 1-pyreneboronic acid was added, followed by distillation under reflux for 2 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene. The recrystallization by o-xylene was repeated three times in total to give 1.14 g of the target 2-[3,5-di(1-pyrenyl)phenyl]-4,6-di-p-tolyl-1,3,5-triazine as grayish white solid (yield: 51%).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=S)[CH3:2].[CH3:6][C:7]1([CH3:31])[CH2:16][CH2:15][C:14]2[N:13]=[CH:12][N:11]=[C:10]([N:17]3[CH2:23][C:22]4[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:21]=4[O:20][CH2:19][CH2:18]3)[C:9]=2[CH2:8]1>>[CH3:6][C:7]1([CH3:31])[CH2:16][CH2:15][C:14]2[N:13]=[CH:12][N:11]=[C:10]([N:17]3[CH2:23][C:22]4[CH:24]=[C:25]([C:8]5[CH:7]=[CH:2][C:1]6[N:3]=[C:4]([NH:13][CH2:14][CH3:15])[NH:11][C:10]=6[CH:9]=5)[CH:26]=[CH:27][C:21]=4[O:20][CH2:19][CH2:18]3)[C:9]=2[CH2:8]1
Reactant: CCN=C=S
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 15 by using ethyl isothiocyanate in step 1 and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 3. 1H NMR (400 MHz, d6-DMSO): 8.37 (s, 1H), 7.56 (d, 1), 7.43 (dd, 1H), 7.38 (s, 1H), 7.20 (s, 2H), 7.00 (d, 1H), 4.62 (s, 2H), 4.29 (m, 2H), 3.83 (m, 2H), 3.35 (q, 2H), 2.70 (t, 2H), 2.47 (s, 2H), 1.60 (t, 2H), 1.19 (t, 3H), 0.86 (s, 6H); MS (EI) for C28H32N6O: 469 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C#N)c1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C(C)(C)C#N)c1
Reaction time: 16 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.76 g, 20.3 mmol) and diisopropyl azodicarboxylate (DIAD, 4.7 g, 23.2 mmol) in THF (20 ml) was added drop wise to a solution of 2-(3-hydroxyphenyl)-2-methylpropanenitrile (Step B, 3.2 g, 19.8 mmol) and triphenylphosphine (5.28 g, 20.1 mmol) in THF (50 ml) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 16 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH2:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O.C([BH3-])#N.[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][NH:13][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: O=C1CCCCN1
Reactant: NCC(O)C1COc2ccccc2O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: OC(CNC1CCNCC1)C1COc2ccccc2O1
Temperature: 25 °C

Procedure:
The [2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amine prepared in Preparation A' (50 g) and piperidone (85 g) are dissolved in 500 ml of ethanol. Seventy-five grams of sodium cyanoborohydride is added, and the mixture is maintained at room temperature for 12 hours and cooled and evaporated. The product is recovered by adding aqueous ammonia to the residue and extracting with methylene chloride. Three 100 ml portions of methylene chloride are used which are combined, washed twice with 50 ml of water and evaporated to a semi-solid. Upon addition of ether, the product crystallizes and is recovered by filtration. The resulting crude mixture is boiled gently in 100 ml of diethyl ether and then evaporated to a residue and triturated with hexane to yield pure material, 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=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.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
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: Cc1ccccc1
Product: Nc1ccc(-c2cccc(Cl)c2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-bromobenzotrifluoride (Dakwood Products, Inc.) (500 mg, 2.1 mMol), 3-chlorophenylboronic acid (970 mg, 6.2 mMol, 3 equiv) (Aldrich), Pd(PPh3)4 (70 mg, 0.018 mMol, 0.03 equiv), Na2CO3 (2 M solution in H2O, 5 mL, 10 mMol, 4.76 equiv), and toluene (14 mL) is stirred at reflux for 1 h. The reaction mixture is allowed to cool to rt and filtered through a pad of celite, washing the filter cake with CH2Cl2 and H2O. The layers are separated and the aqueous phase is extracted with CH2Cl2 (2×60 mL). The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. MPLC (CH3CN/H2O/TFA) purification of the crude material affords the title compound: MS: 270.0 [M-2]−; HPLC DtRet=4.9.
Reaction SMILES: [CH3:1][C:2]([N+:16]([O-:18])=[O:17])([CH3:15])[CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)O.S(Cl)([Cl:21])=O>O>[Cl:21][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[C:2]([CH3:15])([N+:16]([O-:18])=[O:17])[CH3:1]
Reactant: CC(C)(C(O)c1ccc2ccccc2c1)[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: O
Product: CC(C)(C(Cl)c1ccc2ccccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 2-methyl-1-(naphthalen-2-yl)-2-nitropropanol (1.23 g) obtained in Step 3 was added thionyl chloride (3.1 ml), and the resulting mixture was heated under reflux for 1 hr, and stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=93:7). Recrystallization from a solution of n-hexane:ethyl acetate=4:1, yielded title compound (776 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:13])[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c(CO)nc2ccc(Cl)nc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.20 g of 5-chloro-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 44), 2.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.51 ml of tributylphosphine, 1.53 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 2:1 to 1:1 by volume as the eluent, to give 1.29 g of the title compound, melting at 97°-99° C. (softening).
Reaction SMILES: C([N:8]1[CH2:20][C@@H:19]2[C@H:10]([C:11](=[O:25])[NH:12][C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)C1C=CC=CC=1.[ClH:26].[H][H]>CO.CCOCC.[Pd]>[ClH:26].[F:24][C:21]([F:22])([F:23])[C:14]1[C:13]2[NH:12][C:11](=[O:25])[C@@H:10]3[CH2:9][NH:8][CH2:20][C@H:19]3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C1Nc2c(cccc2C(F)(F)F)[C@@H]2CNC[C@@H]12
Yield: 60 %

Procedure:
To a solution of (±)-trans-2-benzyl-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]quinolin-4(9bH)-one from Example 5, Part B (30 mg, 0.087 mmol) in 10 mL of methanol was added HCl (0.25 mL of a 2M solution in ether, 0.5 mmol) and 10% Pd/C catalyst (10 mg). The resulting mixture was shaken in a Parr apparatus under 65 psi of hydrogen for 3 h. The reaction was filtered through a pad of Celite and concentrated in vacuo. The resulting solid was triturated several times with ether and dried in vacuo to afford 15 mg (60%) of the title compound of Example 6 as an off-white solid. 1H NMR (DMSO-D6): δ 10.09 (broad s, 1H), 9.90 (broad s, 1H), 9.69 (s, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.24 (t, 1H), 3.95-3.88 (m, 1H), 3.52-3.38 (overlapping m, 2H), 3.32-3.20 (overlapping m, 2H), 3.08-2.98 (m, 1H). LRMS (ESI): 257.10 (M+H)+.
Reaction SMILES: [Si](OCCN1[CH2:15][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:13]([C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35](COCC[Si](C)(C)C)[CH:36]=[CH:37][N:38]=5)=[CH:30][CH:29]=4)=[C:21]3[N:20]=2)[C:12]1=[O:47])(C(C)(C)C)(C)C.FC(F)(F)C(O)=[O:51]>ClCCl>[NH:35]1[CH:36]=[CH:37][N:38]=[C:34]1[C:31]1[CH:32]=[CH:33][C:28]([C:27]2[CH:26]=[N:25][N:22]3[CH:23]=[CH:24][C:19]([N:13]4[C@@H:14]([CH:16]([CH3:18])[CH3:17])[CH2:15][O:47][C:12]4=[O:51])=[N:20][C:21]=23)=[CH:29][CH:30]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (15 mg, 0.022 mmol) in dichloromethane (0.3 mL) and trifluoroacetic acid (0.3 mL) was stirred at ambient temperature for 24 hours. The solvents were evaporated, and the residue was taken up in MeOH. A few drops of 1N LiOH solution was added. The mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (12% MeOH in dichloromethane) to give (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (5 mg, 52%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=7.6 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.16 (s, 2H), 3.2-3.8 (m, 7H), 2.91 (m, 1H), 1.12 (d, 3H), 0.89 (d, 3H). LCMS (APCI+) m/z 432.3 [M+H]