Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.[C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])(O)=[O:13]>C(Cl)Cl>[NH2:3][C:12]([C:15]1[N:16]=[C:17]([CH:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]2[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[NH:18][C:19]=1[CH2:20][CH2:21][CH3:22])=[O:13]
Reactant: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(=O)O
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCc1[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)nc1C(N)=O
Reaction time: 1 h
Yield: 35.7 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00318 mole) was added to a solution of compound 105 (0.00159 mole) in DCM (160 mL) at room temperture. N,N′-methane-tetrayl-biscyclohexanamine (0.00206 mole) was added neat at room temperature. After 60 minutes, NH3 gas was bubbled in for 5 minutes, and a solid precipitated out. The mixture was allowed to sit over the weekend. The mixture was filtered, and the filtrate was extracted with saturated NaHCO3. The organic phases were dried over MgSO4, filtered, and concentrated. The residue was purified by liquid chromatography, yielding 0.21 g of 1,1-dimethylethyl 2-[4-(aminocarbonyl)-5-propyl-1H-imidazol-2-yl]-2,3-dihydro-1H-indole-1-carboxylate (compound 106).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])(C)[CH3:9].[CH2:41](NC)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:11]([CH3:41])[C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])[CH3:9]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Reactant: CCNC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)C(=O)COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.035 ml of ethylmethylamine (0.4 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 1-{3-[(Ethyl-methyl-carbamoyl)-methoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (27 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 585.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:54])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12.C(Cl)CCl>>[F:31][C:32]1[CH:33]=[C:34]([NH:54][C:17](=[O:19])[CH2:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:20])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)O)CC1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
To a solution of acid 42 (76 mg, 0.266 mmol) and HOBt (40 mg, 0.30 mmol) was added amine 9 (100 mg, 0.29 mmol) and the mixture was stirred at room temperature for 5 min. EDC (62 mg, 0.32 mmol) was added and combined mixture was stirred for additional 48 hours. Additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stiffed for a further 24 hours. Again additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for 24 hours more then partitioned between EtOAc and NaHCO3 solution. The organic phase was washed with brine, dried over anhydrous Na2SO4 then filtered and concentrated. The residue was purified by preparative HPLC to afford tert-butyl 4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)piperidine-1-carboxylate 42a (20 mg, 13% yield) as a white solid. This material was dissolved in a solution of TFA/DCM (1 mL/2 mL), stirred for 20 min and concentrated. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford the title compound 43 as a tris-trifluoroacetate salt (31 mg, 99%), white solid. NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.55 (d, 1H), 8.49 (bs, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.86 (dd, 1H), 7.55 (s, 1H), 7.49 (t, 1H), 7.39 (dd, 2H), 7.26 (s, 1H), 6.74 (d, 2H), 4.00 (s, 2H), 3.83 (m, 1H), 3.24 (m, 2H), 3.00 (m, 2H), 1.92 (m, 2H), 1.56 (m, 2H). MS (m/z): 509.1 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.[CH3:32][O:33][C:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)=[O:35].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][O:33][C:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:20][C:21]2[CH:22]=[CH:23][C:24]3[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=3[CH:30]=2)=[O:42])=[CH:39][CH:38]=1)=[O:35]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: COC(=O)Oc1ccc(C(=O)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(C(=O)Oc2ccc3ccc(=O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
13.4 g triphenylphosphine is added to a solution of 8.3 g 7-hydroxycoumarin, 10.0 g 4-methoxycarbonyloxybenzoic acid, 8.9 g diethyl azodicarboxylate and 50 ml tetrahydrofuran at 0° C. The reaction mixture was stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down, taken up in warm hexane, filtered to remove inorganic material and evaporated down again. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1/1 v/v) as eluent and recrystallisation from acetonitrile to yield 12.2 g of 2-oxo-2H-1-benzopyran-7-yl 4-methoxycarbonyloxybenzoate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[C@@H:6]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:7][C:8](=[O:27])[C@H:9]([CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].O>CO>[CH2:14]([O:13][C:11]([NH:10][C@H:9]([C:8]([NH:7][C@@H:6]([C:5]([OH:38])=[O:4])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:27])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide (15.4 g, 192 mL, 0.08 g/mL solution, 0.38 mol) was added to a solution of dipeptide 25 (187.1 g, ca. 0.38 mol), water (360 mL) and MeOH (ca. 6 L). The solution was stirred at room temperature until hydrolysis was complete (ca. 24 hours). The disappearance of the starting peptide was established by HPLC analysis. The solution was concentrated in vacuo to a residue which was dissolved in water (ca. 1 L). The aqueous layer (pH ca. 10) was then extracted with EtOAc (2×500 mL) in a separatory funnel. The resulting aqueous phase was adjusted to a pH of 5 with concentrated HCl at which point a crystalline precipitate formed. The solid was collected by vacuum filtration and dried in vacuo (148.4 g, 0.31 mol, 82%). The pH of the filtrate was adjusted to 4.5. A second crop of solid was again collected by vacuum filtration and dried in vacuo (20.2 g, 0.043 mol, 11%). 1H NMR showed both samples to contain dipeptide 26 in high purity. In two repetitions of this reaction, yields of 83% (ca. 0.06 mole scale) and 58% (ca. 0.3 mole scale) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([N:17]1[CH2:18][C@@H:19]([OH:20])[C@H:15]([NH:14][C:12](=[O:13])[C:11]2[CH:21]=[CH:22][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)[CH2:16]1)=[O:37]
Reactant: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)N1C[C@@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (50 mg, 0.15 mmol) in DMF (1.0 mL) was added DIPEA (95 mg, 0.32 mmol) and pivaloyl chloride (66 mg, 0.24 mmol). After stirring at rt overnight the mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and the solvent removed to give an oil, which after chromatography (silica, 1% MeOH/EtOAc) gave the product (36 mg, 63%). HRMS (M+H)=386.1880 expected, 386.1914 observed.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.F[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:17]([N:18]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]1=[O:3])[C:16]1[CH:19]=[CH:20][CH:13]=[CH:14][CH:15]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (Aldrich, 2.0 g, 13 mmol, 1.0 eq) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 ml) were stirred at room temperature for 3 h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP (0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resulting solution was stirred for 12 h. The reaction mixture was quenched with 1N aqueous HCl and the solution was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3×70 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid, that was used without further purification. 1H NMR (DMSO-d6) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H), 7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS(ESI+), Calcd.: 262.0879, found: 262.0885.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20](=[O:38])[N:21](COC(=O)C(C)(C)C)[CH:22]=[N:23]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1.N>C(Cl)Cl>[CH3:29][O:28][C:27]1[C:18]([O:17][CH:59]2[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][NH:21][C:20]2=[O:38]
Reactant: CN1CCC(O)CC1
Reactant: COc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2nc[nH]c(=O)c2c1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of di-tert-butyl azodicarboxylate (1.75 g ) in methylene chloride (3 ml) was added to a stirred mixture of 5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.55 g), triphenylphosphine (1.99 g), 4-hydroxy-1-methylpiperidine (0.75 g) and methylene chloride (12 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was stirred in a saturated methanolic ammonia solution for 48 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 6-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.92 g); NMR Spectrum: (DMSOd6) 1.7–1.9 (m, 4H), 1.95 (t, 2H), 2.15 (s, 3H), 2.7 (m, 2H), 3.85 (s, 3H), 4.08 (m, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.85 (s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]>CS(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(4-chlorophenyl)ethylene (7.0 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][N:7]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:36][CH:37]=3)[C:11]=2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1
Reactant: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(N)c2O1
Reactant: O=Cc1ccc(OCCCCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(NCc3ccc(OCCCCc4ccccc4)cc3)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 8-amino-4-(4-methoxy-4-oxobutyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (80 mg; prepared by subjecting the compound prepared in Example 3 to the same procedure as described in Example 29) and 4-(4-phenylbutoxy)benzaldehyde (60 mg) were dissolved in 1,2-dichloroethane (4 mL), and to this solution was added sodium triacetoxyborohydride (96 mg) with ice cooling, and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=8:2) to give the title compound (121 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (395 mg, 2.0 mmol) followed by triethylamine (198 mg, 2.0 mmol). The reaction mixture was stirred with heating at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 88.2%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].Br[CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31]>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1)=[C:8]2[C:12]([O:14][CH2:25][C:26]1[O:27][C:28](=[O:32])[O:29][C:30]=1[CH3:31])=[O:13])[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cccc(CO)c3)C[C@H]12
Reactant: Cc1oc(=O)oc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg) prepared by example 4 was dissolved in DMF (2.0 ml), and thereto 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (143 mg) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then thereto ice water was added. The mixture was extracted with ethyl acetate. The organic layer was washed three times with a cold saturated aqueous sodium chloride solution, followed by a cold saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative thin-layer chromatography (ethyl acetate/acetone) to give (5-methyl-2-oxo-1,3-dioxo1-4-yl)methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (62 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[CH:8]=2)[O:3]1.[OH-].[Na+]>CO>[CH3:1][CH:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1C=Cc2cc(C(=O)O)ccc2O1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a stirred solution of methyl 2-methyl-2H-chromene-6-carboxylate (225 mg, 1.10 mmol) in MeOH (5 mL) is added NaOH (5 mL of a 5% aqueous solution). The mixture is heated in a 60° C. oil bath for 40 min, followed by cooling to rt. The methanol is removed in vacuo and the remaining aqueous layer is acidified to pH=5 with 1N HCl. The solution is extracted with EtOAc (2×), washed with brine, dried (MgSO4) and concentrated in vacuo to afford 209 mg (100%) of 2-methyl-2H-chromene-6-carboxylic acid as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 13-12, 7.68, 7.65, 6.80, 6.53, 5.85, 5.10, 1.37.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([S:13]([O-:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].Br[CH2:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>CO>[CH2:21]([C:20]([CH2:23][CH3:24])=[CH:19][CH2:18][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14])[CH3:22]
Reactant: O=S([O-])c1ccccc1
Reactant: CCC(=CCBr)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=CCS(=O)(=O)c1ccccc1)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
1.85 gm of sodium carbonate and 18.5 gm of sodium phenyl sulfinate were introduced into 60 cc of methanol. Then 20 gm of 1-bromo-3-ethyl-2-pentene were added within the space of about 30 minutes at room temperature to the resulting suspension, which then was agitated for 1 hour and 30 minutes at room temperature. Then the reaction mixture was poured into ice-water and the organic phase was separated by decanting. The aqueous phase was extracted with ethyl ether and the ether extracts were combined with the principal organic solution. The solution thus obtained was dried over magnesium sulfate and the solvent was removed under reduced pressure to obtain 21.665 gm of (3-ethyl-2-pentenyl)-phenylsulfone. A sample of this product was rectified under reduced pressure and the boiling point was 125° C under 0.02 mm pressure of mercury and its refractive index nD23 = 1.530.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[C:23]1([NH2:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH:23]1([NH:29][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Nc1ccccc1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Solvent: O
Product: c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Yield: 51 %

Procedure:
0.300 g (0.90 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V) and 3 mL of phenylamine are combined, then reacted for 0.3 hours at 130° C. in the microwave. Then the reaction mixture is combined with water and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. The residue is triturated with diethyl ether and suction filtered. 0.18 g of product I (51%) is obtained (m.p. 174° C.-175° C.). 1H-NMR (400 MHz, DMSO): 8.59 (1H, s); 7.63 (2H, d); 7.31 (2H, t); 7.22 (2H, t); 7.03 (1H, t); 6.99 (2H, d); 6.80 (1H, t); 3.83-3.73 (4H, m); 3.31 (2H, t); 3.23 (4H, m); 3.12 (2H, t).