Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>O1CCCC1>[O:10]=[C:9]([CH3:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)Cc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 1-(4-aminophenyl)acetone (1.13 g, 7.57 mmol) and pyridine (1.84 ml, 22.7 mmol) in tetrahydrofuran (50 ml) was added 2,2,2-trichloroethyl chloroformate (1.57 ml, 11.4 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling and then at room temperature for 1 hour, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (1.44 g, 58.4%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:28][CH2:29][CH2:30][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH:16]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH2:15][N:11]1[C:10]2[CH2:9][CH2:8][N:7]3[CH2:28][CH2:29][CH2:30][CH:6]3[C:5]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]1=2)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2cnccn2)CCN2CCCC12
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2cnccn2)CCN2CCCC12
Temperature: 90 °C
Yield: 24.7 %

Procedure:
Methanesulfonicacid2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c] fluoren-6-yl)-1-pyrazin-2-yl-ethyl ester (280 mg, 0.65 mmol) was dissolved in 3 mL DMF, sodium azide (64 mg, 0.98 mmol) was added and heated at 90° C. for 1 h. The reaction mixture was monitored by LCMS. After consumption of starting material, the reaction mixture was cooled to RT, diluted with water (3 mL) and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 6-(2-azido-2-pyrazin-2-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 7.8 (d, 1H), 7.22 (d, 1H), 7.09 (t, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.6 (dd, 1H), 4.3 (m, 1H), 3.45 (m, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.6 (m, 1H), 2.45 (d, 3H), 2.2 (m, 1H), 1.9 m (1′H). Separation by chiral HPLC provided enantiomers II-261a-b.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:16]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Yield: 60 %

Procedure:
2,4 dichloropyrimidine and 3-formyl phenyl boronic acid were coupled following procedure A. The yield was 60%. LC-MS showed the product was >95% pure and had the expected M+H+ of 219. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 610.1 (s, 1H) 8.7 (d, 1H) 8.6 (m, 1H) 8.4 (m, 1H) 8.1 (m, 1H) 7.7 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:16]1([C:13](=[O:15])[CH:14]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-trifluoromethylbenzaldehyde and acetophenone, 1-phenyl-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][OH:7].[OH-].[K+].Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>C(#N)C>[F:1][C:2]([F:10])([F:11])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][O:7][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CN(CC(F)(F)F)C(=O)CO
Reactant: Clc1nc2ccccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CN(CC(F)(F)F)C(=O)COc1nc2ccccc2o1
Temperature: 20 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
17.1 g (0.1 mol) of N-(2,2,2-trifluoroethyl)-N-methyl-hydroxyacetic acid amide and 7 g of potassium hydroxide powder were initially introduced into 100 ml of acetonitrile at 20° C., and 15.3 g (0.1 mol) of 2-chlorobenzoxazole were added at a temperature between 20° and 40° C. The reaction mixture was stirred at 40° C. for one hour and at 20° C. for a further 15 hours and was concentrated and the concentrate was shaken with toluene and water. The organic phase was washed with dilute sodium hydroxide solution, washed until neutral, dried and filtered. The solvent was carefully distilled off from the filtrate under reduced pressure. 15 g (52% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-benzoxazol-2-yl-oxy-acetic acid amide of melting point 92° C. were obtained as the residue.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](OCC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[C:32]1(=O)[CH2:35]C[CH2:33]1>CCO.[Pd]>[CH:22]1([N:18]2[CH2:19][CH2:20][CH2:21][CH:15]([C:13]([N:11]3[CH2:10][CH:9]([O:8][C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH2:12]3)=[O:14])[CH2:16][CH2:17]2)[CH2:35][CH2:32][CH2:33]1
Reactant: O=C1CCC1
Reactant: Cc1ccc(OC2CN(C(=O)C3CCCN(C(=O)OCc4ccccc4)CC3)C2)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(OC2CN(C(=O)C3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 12 h
Yield: 40.2 %

Procedure:
A mixture of benzyl 4-({3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}carbonyl)azepane-1-carboxylate (37 mg, 87 μmol), cyclobutanone (13 μl, 0.18 mmol) and 5% Pd/C (5 mg) in EtOH (4 ml) were stirred under a hydrogen atmosphere for 12 hours. The reaction was then filtered over celite and concentrated. The residue was dissolved in EtOAc (30 ml) and washed with water (3×15 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 98:2:1 to 90:10:1 DCM/MeOH/2M NH3 in MeOH) to give the title product as colourless oil (12 mg, 40%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1.CO.[CH3:18][NH2:19]>CO>[CH3:18][NH:19][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc(OCCBr)cc1
Reactant: CN
Solvent: CO
Product: CNCCOc1ccc(OC(F)(F)F)cc1
Yield: 79 %

Procedure:
1-(2-Bromoethoxy)-4-(trifluoromethoxy)benzene (2.2 g, 7.72 mmol) was dissolved in methanol (20 ml), to which 40% methylamine methanol solution (20 ml) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride, and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to afford N-methyl-N-[2-(4-trifluoromethoxyphenoxy)ethyl]amine (1.44 g, yield 79%) as a pale yellow oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCCBr

Procedure:
A solution of 4-phenoxy-2-propylphenol (25.0 g, 0.11 mol), 1,4-dibromobutane ( 70.99 g, 0.33 mol) and cesium carbonate (39.28 g, 0.12 mol) in dry DMF ( 250 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (1:1) to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:23]N(C)C=O.IC>O>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][N:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N1CCC(CN(C)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 8.7 part of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine, 1.44 parts of a sodium hydride dispersion 60% and 270 parts of N,N-dimethylformamide was stirred for 1 hour at room temperature. 5.48 Parts of iodomethane were added dropwise slowly. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98.75:1.25 by volume) as eluent. The second faction was collected and the eluent was evaporated, yielding 7.6 parts (84%) of 1-acetyl-N-(2-benzothiazolyl)-N-methyl-4-piperidinemethanamine as a residue (intermediate 52).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH:10]=2)=[CH:5][CH:4]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C1=C(c2ccncc2)C2CCN1CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: c1cc(C2CN3CCC2CC3)ccn1
Yield: 96.5 %

Procedure:
By the procedure described in Example 6, hydrogenation of 3-(4-pyridinyl)-1-azabicyclo[2.2.2]oct-2-ene dihydrochloride (1.07 g, prepared as in Example 10c) gave 0.75 g of the title compound as the dihydrochloride salt; m.p. 210°-220° C.; Found: C, 54.18; H, 6.93; N, 10.54. C12H18N2Cl2.0.25H2O requires C, 54.25; H, 7.02; N, 10.54; δ(360 MHz, D2O) 8.772 (2H, d, J=6.8 Hz, py-H), 8.063 (2H, m, J=6.8 Hz, py-H), 4.00-3.30 (6H, m, H2 -2, H2 -6 and H2 -7) 2.60-1.85 (5H, m, H-4, H2 -5 and H2 -8); m/e 188 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:21])[CH:3]=1.N([C@H]1C[C@H]2C[C@@H]1CC2)=[C:23]=S>C(Cl)CCl>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([Cl:21])=[CH:3][C:2]4[NH:1][CH:23]=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1N
Reactant: S=C=N[C@H]1C[C@@H]2CC[C@H]1C2
Solvent: ClCCCl
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc[nH]c2cc1Cl

Procedure:
4,5-Diamino-2-chloro-N-(1H-indazol-6-yl)benzamide (0.3 mmol; see Example 171) was reacted with (1S,2S,4R)-2-Isothiocyanato-bicyclo[2.2.1]heptane (0.3 mmol) followed by cyclization in situ using EDC as described in general procedure B to provide 2-((1S,2S,4R))-bicyclo[2.2.1]hept-2-ylamino)-6-chloro-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)amide. MS: m/z 421 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].[F-].[Cs+]>C(COC)OC.C(O)C>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1)=[O:29]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (5 g, 12 mmol) was dissolved in dimethoxyethane (70 mL) and ethanol (7 mL). 4-Formylbenzeneboronic acid (2.0 g, 13 mmol) was added and argon was bubbled in the mixture, for 15 minutes. Cesium fluoride (4 g, 26 mmol) and tetrakistriphenylphosphine palladium (0.69 g, 0.6 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (100 mL/100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 3.42 g (76%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>ClC1C=CC=CC=1Cl.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:15]=[C:9]([C:9]([CH3:15])([CH3:10])[CH3:8])[C:8]2[O:12][C:11](=[O:13])[C:10](=[C:10]3[C:7]4[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:15]=[C:9]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:8]=4[O:12][C:11]3=[O:13])[C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1Cl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
10 g of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (prepared as described in Example 1 of U.S. Pat. No. 5,614,572) are introduced in 25 ml of 1,2-dichlorobenzene as initial charge and admixed with 0.5 g of 4-dimethylaminopyridine and 3 ml of thionyl chloride. The solution is then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively, but still controllable. Thereafter the reaction mixture is stirred at 100° C. for a further ½ h. The temperature is subsequently raised to the reflux point. After 75 min, the 1,2-dichlorobenzene is distilled off, at the end with reduced pressure. The isoxindigo is crystallized out by the addition of 30 ml of acetonitrile to the residue, filtered off, washed with acetonitrile and dried to leave 6.8 g (73% of theory) of 5,7,5′,7′-tetra-tert-butyl[3,3′]bibenzofuranylidene-2,2′-dione of the formula (XV).
Reaction SMILES: [CH2:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]Cl>CN(C)C=O>[CH2:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:15][CH3:22])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCl
Reactant: C=CCOC(=O)C(O)(Cc1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(Cc1ccccc1)(OC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a suspension of 0.75 g of 66% sodium hydride-paraffin in 20 cc of dimethylformamide was added a solution of 5.6 g of allyl α-benzyl-α-hydroxyphenylacetate in 10 cc of dimethylformamide under cooling, and the mixture was stirred for 1 hour. Successively, methyl chloride was introduced into the mixture. The reaction mixture was poured in ice-water and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride, and dried over sodium sulfate. Thereafter, ether was distilled out and paraffin was removed, whereby, 5.1 g oily allyl α-benzyl-α-methoxyphenylacetate, nD25 1.5488 was obtained.
Reaction SMILES: N[C:2]1[C:3]2[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([CH3:17])=[N:14][CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:9]=2)[N:7]=1.[I:33]CI.N(OCCC(C)C)=O.C(N(CC)CC)C>C(#N)C>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]2=[N:12][C:13]([CH3:17])=[N:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[C:2]([I:33])[C:3]3[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[NH:27][C:4]=3[N:5]=2)=[N:9]1
Reactant: ICI
Reactant: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Agent: CC(C)CCON=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncc2c(-c3nc(I)c4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
150 mg (0.34 mmol) of 4-amino-2-[1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one were admixed with 6.650 g (19.86 mmol) of diiodomethane and 402 mg (3.44 mmol) of isopentyl nitrite. The mixture was stirred at 85° C. for 8 h. 70 mg (0.69 mmol) of triethylamine were added and the mixture was again boiled under reflux at 85° C. After cooling, the mixture was diluted with acetonitrile and purified by means of preparative HPLC (eluent: acetonitrile/water with, gradient 30:70→95:5). 44 mg (purity 67%, 16% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:40]=[S:41]1(=[O:53])[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:51][CH2:52][N:47]([CH:44]4[CH2:43][CH2:42][S:41](=[O:40])(=[O:53])[CH2:46][CH2:45]4)[CH2:48][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C38H47N4O5SCl2 [(M+H)+] 741.2639, observed 741.2637.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][NH2:33].[BH4-].[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:33][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC)c4)cc23)CC1
Yield: 83.1 %

Procedure:
Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), methylamine (130 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give title compound (17.0 mg, 83%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1.[CH:48]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH2:49]>CCO>[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:37][CH2:38][N:39]([CH2:49][CH2:48][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:40][CH2:41]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: C=CS(C)(=O)=O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 90 °C

Procedure:
A mixture of the TFA salt of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.061 mmol) and methyl vinyl sulfone (318.4 mg, 3.0 mmol) in EtOH (2.0 mL) was heated at 90° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (125:10:1) afforded a fluorescent product which was subjected to HPLC purification to afford the title compound in TFA salt form. 1H NMR (DMSO-d6) δ 2.01-2.17 (4H), 2.19 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.15 (s, 3H, CH3), 3.23 (m, 2H), 3.51-3.75 (8H), 4.01 (m, 2H), 4.15 (m, 1H), 4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.36 (dd, J=7 Hz and 6 Hz, 1H), 7.59 (br s, 1H), 7.83 (br s, 1H), 11.14 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[CH3:28][C:29]1[C:30]2[CH:44]=[CH:43][CH:42]=[CH:41][C:31]=2[S:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:12]2[N:13]([C:14]([NH2:17])=[N:15][C:16]3[N:8]([CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH2:34][C:33]5[S:32][C:31]6[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=6[C:29]=5[CH3:28])[CH2:36][CH2:37]4)[CH:9]=[CH:10][C:11]=32)[N:18]=1
Reactant: Cc1c(CN2CCNCC2)sc2ccccc12
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN2CCN(CCn3ccc4c3nc(N)n3nc(-c5ccco5)nc43)CC2)sc2ccccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 1-[(3-methylbenzo[b]thiophen-2-yl)methyl]piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 2-(furan-2-yl)-7-(2-(4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=513.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.32 (s, 3H), 2.50 (m, 8H), 2.69 (t, 2H, J=6.4 Hz), 3.72 (s, 2H), 4.23 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 7.15 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.50 (br s, 2H), 7.68 (d, 1H, J=7.6 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=0.8 Hz).