Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].C1C2C3C=CC=CC=3OC=2C=CC=1.C(Br)C=C.C[Si](C)(Cl)Cl.[C:24]1([CH2:30][CH2:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[OH:36][C:32]([CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:33][CH2:34][CH3:35])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: c1ccc2c(c1)oc1ccccc12
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 0.3 h

Procedure:
Magnesium (9.1 g, 0.374 mole) was suspended in THF (99 mL) containing dibenzofuran (1.4109 g) as an internal standard substance and allyl bromide (0.28 g) was added at 31° C. in a thin stream. Thereto was added 2.5 mL of a mixed solution (143 mL) of dimethyldichlorosilane (1.84 g, 14.2 mmole), 1-phenyl-3-hexanone (47.1 g, 0.267 mole), ethyl chloroacetate (34.8 g, 0.284 mole), allyl bromide (0.28 g, 2.3 mmole) and THF (49 mL) at 30° C. in a thin stream. After 18 min, exothermic heat was observed and the internal temperature rose to 32.5° C. After 34 min from the addition in a thin stream, the remaining mixed solution was added at an internal temperature of 32-36° C. over 3 hr in a thin stream. Thereafter, ethyl chloroacetate (10.2 g, 83.2 mmole) was added at an internal temperature of 32-35° C. over 1 hr in a thin stream and thermally insulated at an internal temperature of 36° C. for 1 hr. The title compound in the reaction mixture was analyzed and a reaction mixture containing the title compound (52.5 g, yield 74.3%) was obtained (quantitative analysis by HPLC). The NMR data were the same as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)(=O)=O)=CC=1>>[CH:54]1([CH2:53][N:31]2[C:30]3[CH2:29][CH2:28][CH:27]([CH2:26][C:3]4[N:4]=[CH:5][N:6]([C:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:2]=4[CH3:1])[C:39](=[O:40])[C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CC2CCc3c(c4ccccc4n3CC3CCCC3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
Using the procedures described above for Intermediate 10, 1,2,3,9-tetrahydro-3-[[5-methyl-1(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H -carbazol-4-one (500 mg) was treated with sodium hydride (73% dispersion in oil; 38 mg) and was then stirred with cyclopentanemethanol (p-toluenesulphonate) (292 mg) for 24 h. Work up and FCC as described above gave the title compound (283 mg), m.p. 177°-179°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI.O>C1COCC1>[CH3:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a solution of 2,6-diaminopyridine (10 g, 91.63 mmol) in dry THF (100 mL) was added K2CO3 (18.8 g, 136.23 mmol) and CH3I (13 g, 91.63 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added (10 mL) and the mixture was extracted with EtOAc (100 mL). The EtOAc layer was dried and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, chloroform) to give 2-methylamino-6-aminopyridine (1.1 g, 10%) as a brown solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[K+].[K+].[CH:26]([C:29]1[N:33]=[C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:31][N:30]=1)([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[F:11][C:12]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:37]2[CH2:36][CH2:35][CH:34]([C:32]3[O:31][N:30]=[C:29]([CH:26]([CH3:28])[CH3:27])[N:33]=3)[CH2:39][CH2:38]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(Cl)ncnc1Cl
Reactant: Nc1cc(F)ccc1F
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(C2CCN(c3ncnc(Nc4cc(F)ccc4F)c3C#N)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) and 2,5-difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0° C. was added K2CO3 (203 mg, 1.47 mmol) The completion of the reaction was monitored by TLC (EtOAc:Hex=1:1, Rf=0.90). After the reaction was complete, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (340 mg, 1.47 mmol) and K2CO3 (406 mg, 2.94 mmol) were added at 0° C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40° C. and maintained for 1 h. The reaction was cooled to rt, poured in to H2O (50 mL) and extracted with EtOAc (50 mL, two times). The EtOAc was dried over MgSO2 and concentrated under vacuum. The crude product was purified over SiO2 (EtOAc:Hex=1:1, Rf=0.44) to afford the desired Compound B131 (465 mg; 71.1%). 1H-NMR (DMSO-d6): 9.32 (1H, s), 8.19 (1H, s), 7.40-7.08 (3H, m), 4.54 (2H, m), 3.48-3.32 (4H, m), 3.07-3.01 (2H, m), 2.18-2.14 (2H, b), 1.96-1.86 (2H, m), 1.27 (6H, d) ppm. LCMS: 426.43.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2]([NH:11][NH2:12])=[N:3][CH:4]=1
Reactant: Fc1cc(I)c(F)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(I)c(F)cn1
Temperature: 50 °C
Reaction time: 19 h
Yield: 35 %

Procedure:
A solution of 2,5-difluoro-4-iodopyridine (1.35 g, 5.602 mmol) in ethanol (7 mL) was treated with hydrazine hydrate (2.75 mL) and the mixture was stirred at 50° C. for 19 hours. The mixture was concentrated in vacuum and the resulting solid triturated with water, filtered, rinsed with more water and dried to yield the title compound (0.57 g, 35%) that was used in the following steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CNc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-toluidine (10 g), ethyl bromoacetate (10.3 ml), sodium acetate (7.6 g) and water (5 ml in ethanol (50 ml) was stirred at room temperature overnight. The product was filtered off as the hydrobromide salt. Yield 11.6 g.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=[O:20].O>C(#N)C.O>[CH3:16][C:7]1([OH:20])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8]1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Temperature: 0 °C

Procedure:
To a solution of 5.0 g of 2,6-di-t-butyl-p-cresol in 90 ml of acetonitrile/water (5/1) was added 10.5 g of bistrifluoroacetoxyiodobenzene with stirring at 0° C. After stirring for 30 minutes, 90 ml of water was added and the reaction solution was extracted three times with 50 ml of dichloromethane and washed four times with 60 ml of water. Organic layers were dried over anhydrous sodium sulfate, then concentrated under reduced pressure and the precipitating crystal was filtered to give a crude crystal, which was recrystallized from hexane to give 4-methyl-4-hydroxy-2,6-di-t-butylcyclohexa-2,5-diene-1-one as a pale yellow solid. The yield was 3.0 g (55%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1.O>ClCCl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-1-Boc-piperidine (300 mg, 1.50 mmol) in dichloromethane (2.0 mL) was added a solution of methanesulfonyl chloride (348 μL, 4.49 mmol) in dichloromethane (1 mL) followed by a solution of pyridine (485 μL, 5.99 mmol) in dichloromethane (1 mL), and the reaction stirred at rt for 16 h. Water (10 mL) was added, the mixture separated and the organic layer washed with 1M HCl (10 mL), sodium bicarbonate solution (10 mL) then brine (2×10 mL). The solution was dried (MgSO4) and solvent removed in vacuo. The crude material was purified by chromatography using dichloromethane/methanol (95:5) as the eluent to give the title compound as an off-white powder. δH (CD3OD): 4.46-4.40 (1H, m), 4.09-3.97 (2H, m), 3.53-3.40 (1H, m), 3.0 (3H, s), 2.93-2.81 (2H, m), 2.01-1.93.(2H, m), 1.50-1.37 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[C:16]12([C:26]([OH:28])=O)[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])/[C:4](=[N:8]/[C:26]([C:16]23[CH2:17][CH:18]4[CH2:24][CH:22]([CH2:21][CH:20]([CH2:19]4)[CH2:25]2)[CH2:23]3)=[O:28])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)CCCBr
Reactant: Cc1nc(N)sc1C
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CCCC(C)C)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, 1-bromo-4-methyl-pentane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 0.87 (d, J=6.55 Hz, 6 H) 1.18-1.27 (m, 2 H) 1.54-1.62 (m, 1 H) 1.62-1.76 (m, 8 H) 1.84 (d, J=2.50 Hz, 6 H) 1.94-2.03 (m, 3 H) 2.15 (s, 3 H) 2.20 (s, 3 H) 3.98-4.11 (m, 2 H); MS (ESI) m/z 374 (M=H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].[H][H].Cl>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][C:3]([O:6][CH3:7])=[O:8])=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(=O)OC
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(Cl)cc1
Yield: 58.8 %

Procedure:
Into a 1000 ml three necked flask equipped with an additional funnel, and condenser was added 15.4 g of 60% sodium hydride (0.63 mole). The sodium hydride was washed twice with hexane and then suspended in 300 ml of tetrahydrofuran and 29 g of dimethyl carbonate (0.32 mole). The reaction mixture was brought to reflux and a solution of 50 g (0.32 mole) of 4-chloroacetophenone in 50 ml of tetrahydrofuran was added over 30 minutes. After hydrogen evolution had ceased the reaction was cooled and poured onto ice. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl ether. The organic layer was dried, concentrated, and distilled at 15 torr bp 180°-205° C. to give 40 g of methyl 3-(4-chlorophenyl)-3-keto-propanoate. NMR data was consistent with the structure.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].Cl.FC1(F)C(C)CC[NH:19]C1.CC([C:43]1[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[C:45](C(F)(F)F)[CH:44]=1)C(NC1(C2C=CC=CC=2)CCC(=O)CC1)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCl>[F:50][C:49]([C:47]1[CH:48]=[CH:43][CH:44]=[CH:45][C:46]=1[CH2:12][C:11]([NH2:19])=[O:13])([F:51])[F:52]
Reactant: CC1CCNCC1(F)F
Reactant: CC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.9 %

Procedure:
Sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added to a solution of (RS)-3,3-difluoro-4-methylpiperidine hydrochloride (Description 60, 67 mg, 0.44 mmol), (RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide (Example 3, 150 mg, 0.33 mmol) and triethylamine (110 mL, 0.88 mmol) in dichloroethane (30 mL) and the mixture was stirred at room temperature for 72 hours. Saturated aqueous sodium hydrogen carbonate (3 mL) and dichloromethane (5 mL) were added and the layers were separated. The organic fraction was poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (95:5:1), to give trans-(RS)-α-methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide (16 mg, 7%); 1H NMR (360 MHz, CD3OD) δ 1.33 (3H, d, J 6.5 Hz), 1.35–2.05 (9H, m), 1.63 (3H, s), 2.36–2.63 (4H, m), 2.74–2.78 (1H, m), 2.95–3.05 (1H, m), 3.83 (1H, q, J 7.2 Hz), 7.12–7.39 (5H, m), 7.79 (2H, s), and 7.81 (1H, s); m/z (ES+) 557 (M+1); cis-(RS)-α-methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide (12 mg, 5%); 1H NMR (400 MHz, CD3OD) δ 1.22–1.28 (1H, m), 1.44 (3H, d, J 6.8 Hz), 1.43–1.54 (1H, m), 1.62 (3H, s), 1.72–1.85 (4H, m), 2.00–2.09 (2H, m), 2.42–2.61 (5H, m), 2.91–3.00 (2H, m), 4.02 (1H, q, J 6.8 Hz), 7.12–7.28 (5H, m), 7.94 (2H, s), and 8.14 (1H, s);. m/z (ES+) 557 (M+1); (2R*,4′R*)-trans-, (2S*,4′R*)-trans-, (2R*,4′R*)-cis-, and (2S*,4′R*)-cis-α-methyl-N-[4-(3,3-difluoro-4-methylpiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide as a mixture of diastereoisomers (13 mg, 5%); 1H NMR (360 MHz, CD3OD) δ 1.36 (3H, d, J 7.2 Hz), 1.45 (3H, d, J 6.8 Hz), 1.53–1.83 (6H, m), 1.84–1.98 (2H, m), 2.09–2.25 (2H, m), 2.37–2.51 (2H, m), 2.58–2.92 (3H, m), 2.98–3.03 (1H, m), 3.89 and 4.09 (total 1H, each q, J 7.2 Hz)}, 7.13–736 (5H, m), and 7.80–8.18 (3H, m); m/z (ES+) 577 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38]>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][O:27][C:35]([O:36][CH2:37][CH3:38])=[O:39])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 3.7 g of the compound of Example 43 in 20 ml of chloroform is added 1.5 g of triethylamine, and to the mixture with stirring at -10°--2° C. is added 1.4 g of ethyl chlorocarbonate dropwise. After completion of the addition, the whole mixture is stirred at 0° C. for 3 hours, and then at room temperature for 2 hours. The reaction solution is washed with water, dried and concentrated, and then the resulting residue is recrystallized from isopropyl ether to give 3.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-ethoxycarbonyloxyethyl)-1H-pyrazolo[3,4-b]-pyridine as white crystals, melting at 103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and propionyl chloride (25 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH2:1][C:2]12[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]1([OH:22])[O:4][C:5]1[C:10]2=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.C(N([CH2:28][CH3:29])CC)C.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[C:30]([NH:1][C:2]1([C:10]2[CH:9]=[CH:8][C:7]([CH:11]([CH3:12])[CH3:13])=[CH:6][C:5]=2[O:4][C:3](=[O:4])[CH2:2][CH2:10][CH2:9][CH2:28][CH3:29])[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:3]1=[O:22])(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21N
Solvent: ClCCl
Product: CCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCC)C(=O)c2ccccc2C1=O
Reaction time: 5 h
Yield: 85 %

Procedure:
A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.20 g, 2.01 mmol) and hexanoyl chloride (0.22 g, 1.69 mmol) and then stirred for 5 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (0.14 g, 46%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[CH2:31](C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1)[CH3:32].NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([CH2:31][CH3:32])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CCc1cc2c3ccccc3c(CNC(C)(CO)COS(C)(=O)=O)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-ethyl-6-chrysenecarbaldehyde (15A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 189°-192° (dec), (EtOH/Et2O), (C, H, N, S).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([NH:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[NH:24][C:23]1=[O:33])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:45][C:46]([NH:48][CH2:49][C:50](O)=[O:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:38]([O:45][C:46]([NH:48][CH2:49][C:50]([N:30]1[CH2:31][CH2:32][C:25]2([NH:24][C:23](=[O:33])[N:22]([NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:34][CH:35]([CH3:37])[CH3:36])[C:26]2=[O:27])[CH2:28][CH2:29]1)=[O:51])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(C(=O)CNC(=O)OCc3ccccc3)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A mixture of 0.257 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide and 0.209 g of N-(benzyloxycarbonyl)glycine in 5 ml of dry dimethylformamide was stirred and cooled to ice temperature. The mixture was treated with 0.225 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and was then stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed successively with water, 5% aqueous sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue triturated with ether and there was obtained 0.261 g of N-[8-{N-(benzyloxycarbonyl)aminoacetyl]-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.[O:18](C(C(F)(F)F)=O)[C:19]([C:21]([F:24])([F:23])[F:22])=O>FC(F)(F)C(O)=O>[F:22][C:21]([F:23])([F:24])[C:19]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[N:1]=[C:19]2[C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1)=[O:18]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(Nc2ccc(N)nc2)c(N)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1ccc(NC(=O)C(F)(F)F)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of N5-(2-Amino-4-methoxy-phenyl)-pyridine-2,5-diamine (150 mg, 0.65 mmol) in trifluoroacetic acid (5 ml) was added (CF3CO)2O (5 ml). The resultant solution was allowed to stir at 80° C. for 4 hours. The reaction progress was monitored by TLC (EtOAc/petroleum ether=1:2). The mixture was concentrated under reduced pressure on a rotary evaporator. The reaction mixture was then quenched by adding 30 ml of 10% NaHCO3. The resultant solution was extracted three times with 50 ml of EtOAc and the organic layers were combined and dried over Na2SO4. After removal of the drying reagent by filtration, the crude product, 2,2,2-Trifluoro-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyridin-2-yl]-acetamide (ff), was obtained by removal of the solvent under reduced pressure and it was used directly in the next step without purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])=[N:5]/[O:6][CH3:7].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>C1COCC1.O>[CH3:1][NH:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CO
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of (E)-N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (0.10 g) in THF (10 ml), sodium hydride (60% oily suspension) (0.02 g) was added thereto, and the resultant mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 2-chloro-5-trifluoromethylpyridine (0.10 g) was added, and stirring was continued at 60° C. for 1 hour. The reaction mixture was cooled, diluted with water, followed by extraction with dichloromethane. The solvent was dried over anhydrous sodium sulfate, and after removal of the solvent, purified by silica gel column chromatography and recrystallized from n-hexane to give 0.11 g of the objective compound.