Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)CC>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:27][CH:28]1[CH2:32][C:31]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=2[O:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[N:7]([C:34]3[CH:35]=[CH:36][C:30]4[O:29][CH:28]([CH3:27])[CH2:32][C:31]=4[CH:33]=3)[C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccc2c(c1)CC(C)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
A mixture of 4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.73 g), molecular sieves 4 A (0.51 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.81 g, 57%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]=[CH:12][CH3:13]>C1C2C(CCCC2)CCC1>[CH:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:13])[CH3:11]
Reactant: c1ccc2ccccc2c1
Reactant: C=CC
Solvent: C1CCC2CCCCC2C1
Product: CC(C)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
10 g of a perfluorodecanesulfonic acid C10F21SO3H was deposited via vacuum distillation on 75 g of porous chromosorb. 5 g of this catalyst was charged into a liquid-phase alkylation reactor together with 0.1 mol of naphthalene dissolved in 150 ml of decaline. Through the stirred solution, close to its boiling point (190° C.) propylene was passed through at a rate of 0.8 l/min. for one hour. Thereafter, the solution was stirred at the same temperature for one additional hour. After cooling, the catalyst was filtered off and the solution distilled in vacuum. The yield of isopropylnaphthalene obtained was 68% with an isomer composition of 92% β- and 8% α-isomer (analyzed by gas-liquid chromatorgraphy).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[H-].[Na+].[CH2:20]1[O:30][C:29]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][C:22]=2[O:21]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]3[O:30][CH2:20][O:21][C:22]=3[CH:23]=2)[S:7](=[O:17])(=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reaction time: 0.08 h
Yield: 71.7 %

Procedure:
To 4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.48 g, 5.84 mmol) in DMF (10 mL) was added sodium hydride (0.257 g, 60%, 6.4 mmol) and the mixture stirred for 5 minutes. 3,4-methylenedioxybenzyl chloride (2.2 g, 50 wt. % in dichloromethane, 6.4 mmol) was added and the mixture stirred at room temperature for 18 hours. Diluted with ethyl acetate (100 mL), washed with water (2×80 mL), brine (80 mL), dried over magnesium sulfate, removed solvent in vacuo, and crystallized from ethyl acetate/heptane to give the title compound (1.63 g, 72%);
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][C@H:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH2:19]([O:18][C:16]([C@H:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:15][C@H:14]2[C@H:13]1[O:34]2)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)[C@@H]1[C@@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Were prepared according to the procedure described in Tetrahedron, 1998, 54, 981-986 from (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid dibenzyl ester. To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid dibenzyl ester (7.5 g, 22.23 mmol) in DCE (80 mL) were added mCPBA (7.67 g, 44.5 mmol) and 4,4′-thiobis(6-tert-butyl-m-cresol) (0.797 g, 2.22 mmol). The reaction mixture was then heated to 90° C. overnight. Then was concentrated. The crude residue was diluted in CH2Cl2 (200 mL) and washed with an aq. solution of Na2S2O5 5% and with a sat. aq. solution of NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 8:2) give (1S,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid dibenzyl ester: MS (UPLC/MS): 354 [M+H]+, tR (HPLC conditions b): 2.24 min and (1S,2S,5R)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid dibenzyl ester: MS (UPLC/MS): 354 [M+H]+, tR (HPLC conditions b): 2.15 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[C:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:21]([O:25][C:26](=[O:43])[CH2:27][C:28]1[C:29]([CH3:42])=[N:30][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[C:32]=1[CH3:33])([CH3:24])([CH3:23])[CH3:22].C1(C)C(S([O-])(=O)=O)=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[C:21]([O:25][C:26](=[O:43])[CH2:27][C:28]1[C:29]([CH3:42])=[N:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:11]([C:8]3[O:9][C:10]4[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:7]=3[CH3:14])=[O:13])=[CH:39][CH:40]=2)[C:32]=1[CH3:33])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nn(Cc2ccc(N)cc2)c(C)c1CC(=O)OC(C)(C)C
Reactant: Cc1c(C(=O)O)oc2c(Cl)cccc12
Agent: CN(C)c1ccncc1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4c(Cl)cccc4c3C)cc2)c(C)c1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 7-chloro-3-methylbenzofuran-2-carboxylic acid (185 mg, 0.88 mmol) in 6 mL dichloromethane is added oxalyl chloride (0.123 mL, 1.14 mmol) and a drop of dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid tert-butyl ester (428 mg, 1 mmol) in form of the toluene sulfonate salt and diisopropylethylamine (0.39 mL, 2.27 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (11 mg, 0.09 mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is evaporated in vacuo to yield 426 mg of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+=508; Retention time HPLC: 1.60 min (method H)). b) To a solution of (1-(4-[(7-chloro-3-methyl-benzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert-butyl ester (426 mg, 0.84 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid (400 mL, 5.2 mmol) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated in vacuo, and the residue is suspended in water and treated with diethyl ether and the precipitating product is filtered off to yield 174 mg of the title compound (ESI mass spectrum: [M+H]+=452; Retention time HPLC: 1.39 min (method J)).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:60][C:57]1[S:58][C:59]2[C:51]([CH:46]3[CH2:47][O:48][CH2:49][CH2:50][O:45]3)=[CH:52][CH:53]=[C:54]([O:61][CH3:62])[C:55]=2[N:56]=1)=[O:8]
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(CCl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Reaction time: 2 h
Yield: 47.6 %

Procedure:
To a stirred solution of 503 mg (2.93 mmol) 2-chloromethyl-isonicotinic acid in 50 ml THF were added 1.28 g (3.38 mmol) HATU and 0.96 ml (5.63 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 600 mg (2.25 mmol) (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine was then added and stirring continued at room temperature for 24 h. The reaction mixture was then poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (acetone) followed by trituration in ether afforded 450 mg (48%) (+)-2-chloromethyl-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide as a light yelllow solid. [α]D20=+12.1° (c=0.41, CHCl3), ES-MS m/e (%):422 (M{37Cl}+H+, 35), 420 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[C:9]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:18]=[C:17]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[N:10]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(O)ccc23)n[nH]1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(O)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
To 2-((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-ol (50 mg, 0.14 mmol) in 1:3 DMSO/DCM was added Dess-Martin periodinane (81 mg, 0.19 mmol) in one portion. After stirring for 1 h at rt, the solution was cooled to 0° C. and quenched by addition of a 1:1 mixture of 10% sodium thiosulfate pentahydrate and saturated sodium bicarbonate. The resulting dark precipitate was collected and chromatographed on silica eluting with 2 to 10% MeOH/DCM. Trituration of the colored solid with MeOH afforded (4-fluorophenyl)(7-hydroxy-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a white solid (7 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 3H), 6.47 (bs, 1H), 7.06 (m, 2H), 7.13 (m, 1H), 7.38 (m, 2H), 8.06 (m, 2H), 8.57 (m, 2H), 10.41 (bs, 1H), 10.60 (bs, 1H), 12.15 (bs, 1H). LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][OH:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6](=[O:21])[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:6](=[O:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(CO)C21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Reaction time: 1 h

Procedure:
To a solution of 5-acetyl-2-(4-fluorobenzyl)-7-(hydroxymethyl)-2,5-diazabicyclo[4.1.0]heptane-3-one (1.3 g, 4.45 mmol) in 40 mL anhydrous THF under nitrogen, sodium hydride (60% in mineral oil, 231 mg, 5.78 mmol) was added. After stirring for 1 h, benzyl bromide (0.58 ml, 4.89 mmol) in THF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with chloroform three times. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel using hexanes and ethyl acetate as eluents to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6]2.CN(C=O)C.[Cl-:20]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([Cl:20])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C(=O)O)CCC2
Reactant: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(=O)Cl)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methoxyindan-6-carboxylic acid (3.84 g), DMF (0.1 ml) and tetrahydrofuran (50 ml) was added oxyalyl chloride (2.1 ml) dropwise. The mixture was stirred at room temperature for 1 hour, at the end of which time the solvent was distilled off to give 5-methoxyindan-6-carboxylic acid chloride. This chloride was dissolved in dichloromethane (50 ml) and after addition of 2,6-di-tert-butylphenol (4.12 g), tin tetrachloride (2.6 ml) was added dropwise with ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and, then, poured in diluted hydrochloric acid. The organic layer was washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added ethanol-hexane to give crystals of 5-(3,5-di-tert-butyl-4-hyroxybenzoyl)-6-methoxyindan (4.23 g, 55.7%). Recrystallization from ethanol gave colorless prisms, m.p. 154°-156° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][NH2:28]>C1COCC1.ClCCl>[CH3:27][NH:28][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 50 mL of THF was charged with solution of methylamine (0.62 g, 20 mmol) in 50 mL of dichloromethane, at room temperature. The reaction mixture was stirred for 30 min. The solvents were removed and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with aqueous solution of 10% potassium carbonate, water, brine, dried over magnesium sulfate and evaporated. Recrystallization of the product from ethyl acetate/hexane mixture afforded 1.67g (46.6%) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine methylamide, mp 173°-174° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([OH:16])[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([N:39]2[C:43]([CH3:44])=[N:42][N:41]=[N:40]2)[CH:30]=1)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([N:39]3[C:43]([CH3:44])=[N:42][N:41]=[N:40]3)[CH:30]=2)[C@@H:11]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnnn1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.6 mmol) was added to a stirred, cooled (0° C.) solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenylpiperidin-3-ol (138 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml). The mixture was stirred at room temperature for 30 minutes, cooled in ice and 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene (168 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml) was added. The mixture was stirred at room temperature for 66 hours, saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with ethyl acetate/hexane (40:60 increasing to 60:40) to give [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a pale yellow oil (133 mg, 51%), 1H (CDCl3) δ 7.69 (1H, s), 7.65 (1H, s), 7.52 (3H, m), 7.31-7.19 (3H, m), 5.68 (1H, br s), 4.77 (2H, s), 3.92 (2H, m), 2.78 (1H, m), 2.58 (3H, s), 2.00 (2H, m), 1.66 (2H, m), and 1.45 (9H, s). m/z 518 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH:30](C(OCC)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.O.[ClH:43].CO>>[ClH:43].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)cc2c1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
5.74 g of the compound obtained from Example 17 was dissolved in 200 ml of 5% HCl-methanol solution, and then 0.5 ml of distilled water was added thereto. This solution was stirred at room temperature for 24 hours. The solvent was distilled off and concentrated under reduced pressure. 20 ml of acetone and 100 ml of diethyl ether were added thereto, and the resulting solid was filtered and then dried to obtain 2.71 g of the object compound
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21](Cl)=[C:16]3[CH:15]=[N:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[C:25]([O:29][C:30](=[O:39])[NH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:21]2[N:20]=[CH:19][N:18]=[C:17]3[N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[N:14]=[CH:15][C:16]=23)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: FC(F)(F)c1cc(-n2ncc3c(Cl)ncnc32)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (147 mg, 0.4 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.44 mmole, 1.1 eq) and diisopropylethyl amine (0.44 mmol, 1.1 eq) were dissolved in THF (3 mL) and then stirred at room temperature over night. THF was removed in vacuo and the solid residue was re-dissolved in 30/70 mixture of water and ACN gave yellow solid. The solid was washed with water and dried in vacuo provided compound A44 as creamy green solid (179 mg, 82%), 1H NMR (CDCl3, 400 MHz) δ 1.43 (s, 9H), 1.75 (m, 2H), 1.98-1.97 (m, 2H), 2.04 (m, 2H), 2.95 (sb, 2H), 4.12 (q, 1H), 4.62 (m, 1H), 7.80 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 8.94 (s, 2H). Exact mass calculated for C24H26F6N6O2 544.2, Found 545.5 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:12])[C:10]=1[NH2:11])=[O:5])[CH3:2].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].[BH3-]C#N.[Na+].CC(O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:12])[C:10]=1[NH:11][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc(Br)c1N
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1[nH]cc(Br)c1NCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
3-Amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (0.136 g, 0.58 mmol) and isobutyraldehyde (0.067 g, 0.93 mmol) were stirred in CH2Cl2/MeOH (1:1, 3 mL) at r.t. for 2 h. NaCNBH3 (0.065 g, 1.04 mmol) and HOAc (0.035 g, 0.58 mmol) were added and the mixture was stirred at r.t. for 2 h and then stirred at 50° C. for 16 h. Additional isobutyraldehyde (1 equiv.) and NaCNBH3 (0.5 equiv.) were added and the mixture was continued stirring at 50° C. overnight. The reaction mixture was neutralized with 2 M NaOH solution and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (heptane/ethyl acetate gradient, 0 to 30% ethyl acetate), obtaining the title compound (0.040 g, 24%) as a white solid.