Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:21]=1)[CH:3]1[CH2:19][CH2:18][C:6]2([CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4]1.Cl>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH:3]1[CH2:19][CH2:18][C:6]2([CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4]1)[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:21]=1
Reactant: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.3 %

Procedure:
To a suspension of tert-butyl 8-(methyl(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.5]decane-2-carboxylate (0.22 g, 0.50 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 3.5 M). The mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The residue was diluted with DCM (10 mL) and saturated Na2CO3 (10 mL) and then extracted with DCM/MeOH (v/v)=10/1 (30 mL×4). The combined organic layers was dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/2M NH3 in MeOH (v/v)=5/1) to give the title compound as a yellow solid (0.12 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH:22]([N:29]2[C:37]3[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40](O)=[O:41])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:45]=[CH:44][C:21]([CH:22]([N:29]2[C:37]3[C:32](=[CH:33][C:34](/[C:38](/[CH3:43])=[CH:39]/[C:40]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:41])=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccc(F)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccc(F)cc2)c1

Procedure:
0.6 g of compound 57 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.91 g of ethyl 4-(2-aminophenoxy)butyrate and 0.79 g of 3-[1-(4-fluorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[S:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[NH:29][C:30]5[C:35]([CH:36]=4)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=5)(=[O:27])=[O:26])[CH2:21][CH:20]3[CH2:38][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].CCOCC>C(Cl)Cl>[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([S:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:15]3[S:14][C:11]4[CH2:12][NH:13][CH:8]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:9][C:10]=4[N:16]=3)=[O:18])[CH:20]([CH2:38][C:39]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[O:40])[CH2:21]1)(=[O:26])=[O:27])=[CH:36]2
Reactant: CC(C)(C)OC(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CS(=O)(=O)C1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3CC(=O)N3CCOCC3)sc2CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
In methylene chloride (5 ml) was dissolved 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-[[(morpholin-4-yl)carbonyl]methyl]piperazine (585 mg), followed by the addition of trifluoroacetic acid (2 ml). The resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added and the resulting mixture was extracted with methylene chloride (to which N,N-dimethylformamide was added in a small amount). The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. To the residue was added a 1N aqueous hydrochloride in ethanol (1 ml) and the solvent was distilled off under reduced pressure, whereby the hydrochloride (585 mg, containing two molecules of N,N-dimethylformamide). A 100 mg portion of the resulting hydrochloride was added to methylene chloride (3 ml), followed by the addition of triethylamine (0.5 ml) and methanesulfonyl chloride (20 mg). The resulting mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=9:1). The solid thus obtained was dissolved in methylene chloride, followed by the addition of ether for crystallization, whereby the title compound (34.2 mg) was obtained as a white solid.
Reaction SMILES: I[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]([CH3:7])[N:6]=1.C([Mg]Cl)(C)C.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:7][N:5]1[C:4]2[CH:8]=[CH:9][S:10][C:3]=2[C:2]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])=[N:6]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2sccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccsc12
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
To a solution of 3-iodo-1-methyl-1H-thieno[3,2-c]pyrazole (290 mg, 1.10 mmol) in THF (6 mL) at −15° C. was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.66 mL, 1.32 mmol). The bright yellow heterogeneous reaction mixture was stirred at −15° C. for 20 min then tributylchlorostannane (0.36 mL, 1.32 mmol) was added dropwise. Stirring was continued at −15° C. for 20 min then at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) gave 298 mg (63%) of 1-methyl-3-tributylstannanyl-1H-thieno[3,2-c]pyrazole as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.36 (d, J=5.3 Hz, 1H), 6.90 (d, J=5.3 Hz, 1H), 4.06 (s, 3H), 1.54-1.67 (m, 6H), 1.36 (dq, J=14.7, 7.3 Hz, 6H), 1.13-1.22 (m, 6H), 0.90 (t, J=7.3 Hz, 9H).
Reaction SMILES: Cl[Si:2](Cl)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:16]([C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]=1[OH:46])[C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:38]([C:36]1[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]2[O:46][Si:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:31][C:18]3[C:19]([C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=3[S:16][C:32]=2[CH:37]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[Si](c1ccccc1)(c1ccccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)S2
Temperature: 92 °C
Yield: 43.3 %

Procedure:
A solution of 12.66 grams of dichlorodiphenylsilane in 50 ml of toluene at 5°-10° C. is added dropwise to a solution of 22.14 grams of 2,2'-thiobis(4,6-di-tert-butylphenol) and 10.12 grams of triethylamine in 100 ml of toluene. The reaction mixture is heated at 92° C. until the reaction is complete as evidenced by the disappearance of the phenolic absorption in the IR spectrum. The triethylamine hydrochloride is removed by filtration and the solvent is removed in vacuo. The residue is recrystallized from 2-butanone to give 13.49 grams (43%) of a white solid: mp 202°-205° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]2[S:34][C:28]3=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=[C:27]3[CH:26]=2)(=[O:24])=[O:23])[C:16]1=[O:35].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[K+].[K+]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][N:21]([S:22]([C:25]1[S:34][C:28]2=[N:29][C:30]([Cl:33])=[CH:31][CH:32]=[C:27]2[CH:26]=1)(=[O:24])=[O:23])[CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:7][CH:2]=2)[C:16]1=[O:35]
Reactant: COC(=O)CBr
Reactant: O=C1C(NS(=O)(=O)c2cc3ccc(Cl)nc3s2)CCCN1c1ccc(-n2ccccc2=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CN(C1CCCN(c2ccc(-n3ccccc3=O)cc2)C1=O)S(=O)(=O)c1cc2ccc(Cl)nc2s1

Procedure:
The compound of Example 3 was treated with methyl bromoacetate in the presence of potassium carbonate using the procedure described for the preparation of compound 9, Part A. Purification by flash chromatography provided the title compound. MS(ESI+) (M+H)+. 1HNMR (CDCl3) δ 8.08 (m, 1H); 7.89 (s, 1H); 7.48 (m, 1H); 7.39 (m, 2H); 7.31 (m, 4H); 6.78 (m, 1H); 6.36 (m, 1H); 4.72 (m, 1H); 4.27 (m, aH); 3.83 (m, 1H); 3.78 (s, 3H); 3.74 (m, 1H); 3.66 (m, 1H); 2.60 (m, 1H); 2.16 (m, 3H). MS m/z 586.9 (M+H)+. HRMS calcd for C26H24N4O6S2Cl: 587.0826. Found: 587.0813.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([CH:3]=[CH:2][CH2:1][NH2:4])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NCC=CC(=O)OCc1ccccc1

Procedure:
10.4 ml of allylamine and 19 ml of triethylamine are dissolved in 50 ml of absolute toluene. A 50% solution of benzyl chloroformate in toluene (46.8 ml) is added dropwise to the solution, which has been cooled in an icebath, while stirring. The mixture is stirred at room temperature for a further 1 hour in order to complete the reaction. A precipitate which has formed is filtered off. After that, the filtrate is concentrated and dried to constant weight under high vacuum (70° C., 0.5 mbar).
Reaction SMILES: Cl.O1CCCCC1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[O:23][C:24]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=4[CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:24]2[O:23][C:22]([CH2:21][CH:18]3[CH2:19][CH2:20][N:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[CH2:16][CH2:17]3)=[CH:26][C:25]=2[CH:27]=1
Reactant: FC(F)(F)c1ccc2oc(CC3CCN(c4ccc(OC5CCCCO5)cc4)CC3)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc(N2CCC(Cc3cc4cc(C(F)(F)F)ccc4o3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1 N hydrochloric acid was added to an ethanol solution of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(5-trifluoromethylbenzofuran-2-ylmethyl)piperidine (2.3 g) and stirred at 80° C. for 1 hour. After being cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture and concentrated under reduced pressure. The residue was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the title compound as a pinkish white amorphous compound (1.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[C@@H]2C3[CH:46]=[CH:47][S:48]C=3CC[C@H]2CCC)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:19]3[CH:46]=[CH:47][S:48][C:20]=3[CH2:22][CH2:21][C@H:26]2[CH2:25][CH2:24][CH3:23])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.50, 7.35-7.31, 7.11, 6.91, 5.21, 4.59, 2.82, 2.64, 2.48, 2.05, 1.82, 1.43-1.35, 1.25, 1.18, 0.94; HRMS (FAB) calcd for C25H29Cl2N3S+H 474.1537, found 474.1526.
Reaction SMILES: O.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:15]2=[O:24])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.Cl>CN(C)P(=O)(N(C)C)N(C)C>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([O:23][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:22])[C:15]2=[O:24])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(N)n1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)OCc2ccccc2)C1=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture comprising 2 g of 5-[1-(2-aminothiazol-4-yl)-1-ethoxycarbonylmethylene]rhodanine-3-acetic acid monohydrate, 3 g of benzyl bromide, 1.1 g of triethylamine and 10 ml of hexamethylphosphoric triamide was stirred at room temperature for 16 hours. The reaction mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography using as eluent a 8:2:1 by volume mixture of hexane, ethyl acetate and acetic acid, giving the desired compound as yellow crystals.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][OH:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.CN(C)C=O.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>O>[CH3:1][C@H:2]([CH2:8][CH2:9][O:10][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@H](C)CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C[C@H](C)CCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 37 g. (0.253 m) of methyl 3-(R)-methyl-5-hydroxypentanoate and 37 g. (0.543 m) of imidazole in 500 ml. of dimethylformamide was added 37 g. (0.249 m) of t-butyldimethylsilyl chloride and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted (4×100 ml.) with ether. The combined extracts were washed with 10% hydrochloric acid, a saturated sodium bicarbonate solution, water and a brine solution, and dried over magnesium sulfate. Removal of the solvent gave 121.88 g. of crude product which, on distillation, gave 107.12 g. of pure product, b.p. 80°-81° C./0.4 torr.
Reaction SMILES: [OH-].NN.Br[C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]([F:27])([F:26])[O:13][C:14]2[CH:15]=[C:16]([F:25])[C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([F:20])[CH:19]=2)=[C:7]([F:28])[CH:6]=1.B([O-])=O.[Na+].[CH2:33]([CH:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([F:50])[CH:42]=2)[CH2:37][CH2:36]1)[CH3:34]>C1COCC1.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.O>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([F:25])[C:17]=1[C:21]([F:24])([F:23])[F:22])[O:13][C:12]([F:27])([F:26])[C:8]1[C:9]([F:11])=[CH:10][C:5]([C:44]2[CH:45]=[CH:46][C:41]([CH:38]3[CH2:37][CH2:36][CH:35]([CH2:33][CH3:34])[CH2:40][CH2:39]3)=[CH:42][C:43]=2[F:50])=[CH:6][C:7]=1[F:28]
Reactant: Fc1cc(OC(F)(F)c2c(F)cc(Br)cc2F)cc(F)c1C(F)(F)F
Reactant: CCC1CCC(c2ccc(B(O)O)c(F)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: O=B[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)CC1

Procedure:
0.11 ml (2.33 mmol) of hydrazine hydroxide is added to a mixture of 9.70 g (22.1 mmol) of 5-((4-bromo-2,6-difluorophenyl)difluoromethoxy)-1,3-difluoro-2-(trifluoromethyl)benzene, 12 ml (18 mmol) of 1.5 N aqueous sodium metaborate soln. and 0.62 g (0.88 mmol) of bis(triphenylphosphine)palladium(II) chloride in 150 ml of THF at room temperature. 6.1 g (24.3 mmol) of 4-(4-ethylcyclohexyl)-2-fluorobenzeneboronic acid are added, and the mixture is heated at the boil for 18 h. After cooling, water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 4-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-4′-(4-ethylcyclohexyl)-3,5,2′-trifluorobiphenyl as a colourless solid having an m.p. of 77° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C.O>[Br:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:11][N:10]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a 100 ml three necked round bottom flask, sodium hydride (60% in paraffin) (0.744 g, 0.0186 mole) was taken in DMF (10.0 ml). To this, 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethyl propan-1-one (5.0 g, 0.1773 mole) in DMF (15 ml) was slowly added at 0° C. over 15 min under nitrogen atmosphere. After addition was complete, the reaction mixture was stirred for 10 min at same temperature followed by dropwise addition of SEM chloride (3.1 g, 0.0186 mole) at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 30 min. After completion of the reaction, the reaction mixture was poured in water and the aq. Layer was extracted with ethyl acetate. Organic layers were combined, washed with brine solution, dried over Na2SO4, filtered and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 10-15% ethyl acetate in hexanes to yield 7.0 g of 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[S:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH2:27])[C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.Cl.C(N(CC)CC)C>>[S:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH:27][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: NCCc1csc2ccccc12
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCc4csc5ccccc45)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared as in Example 1 using 6-chloropurine riboside (1.15 g, 4 mmol), 2-(3-benzo[b]thienyl)ethylamine.HCl (CAS Number 148585-66-1) (1.0 g, 4.6 mmol), and triethylamine (1.1 g, 11 mmol); yield 1.5 g (88%), mp 173°-174° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:44][C:45](=[O:57])[NH:46][CH2:47][CH2:48][CH:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([CH3:43])([CH3:42])[CH3:41].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:56][CH:49]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:48][CH2:47][NH:46][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:57])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with {4-[3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 33 supra) (618 mg, 1.0 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (300 mg, 1.2 mmol), DavePhos (78 mg, 0.20 mmol), K2CO3 (166 mg, 1.2 mmol), Pd2(dba)3 (44 mg, 0.05 mmol) and 1,4-dioxane (20 mL). The mixture was stirred at 130° C. for 8 hours under an atmosphere of N2. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure and the residue was purified first by column chromatography (ethyl acetate:petroleum ether, 1:3), then by prep-HPLC to give {4-[3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 71 mg, 9.0%).
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH2:15]([OH:18])[CH2:16][CH3:17]>>[CH2:15]([O:18][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:16][CH3:17]
Reactant: CCCO
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Product: CCCOc1cc2c(cn1)[nH]c1ccccc12
Reaction time: 0.25 h

Procedure:
184 mg of 3-amino-β-carboline are mixed with 0.5 ml of i-amylnitrite in 15 ml of n-propanol at room temperature and stirred for 15 minutes. Then it is heated for 4.5 hours to 80° C. bath temperature. After concentration, it is chromatographed on silica gel with methylene/chloride/acetone=1:1 as eluant. After concentration and recrystallization of the corresponding fractions from diisopropyl ether/cyclohexane, 120 mg of 3-propoxy-β-carboline with a 147°-151° C. melting point are obtained.