Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1[O:7][C@H:6]([O:8][C@:9]2([CH2:18]O)O[C@H](CO)[C@@H](O)[C@@H:10]2O)[C@H:5]([OH:20])[C@@H:4](O)[C@@H:3]1O.C1C2C(=CC=CC=2)C=CC=1.C(OC(C)C)(=O)C(C)O>CC(O)C>[OH:20][CH:5]([CH:4]=[CH2:3])[C:6]([O:8][CH:9]([CH3:18])[CH3:10])=[O:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: CC(C)OC(=O)C(C)O
Solvent: CC(C)O
Solvent: c1ccc2ccccc2c1
Product: C=CC(O)C(=O)OC(C)C
Temperature: 160 °C
Yield: 36.1 %

Procedure:
An autoclave (50 cc microclave) is charged with 8.0 g of 2-propanol, 0.2249 g of sucrose (0.6569 mmol), 119.7 mg naphthalene (internal standard) and finally with 159.7 mg Sn-BEA (prepared according to U.S. Pat. No. 6,306,364). The autoclave is closed, charged with 20 bar of argon and heated to 160° C. After the temperature reaches 100° C., the mechanical stirrer is started (500 rpm) and the mixture is heated for 20 hours under these conditions. GC-analysis of the reaction mixture shows that 0.68 mmol of isopropyl lactate is formed (26%) together with 0.237 mmol isopropyl 2-hydroxy-3-butenoate (12%).
Reaction SMILES: [OH:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:45][CH2:46][C:47]([CH2:49]Cl)=[CH2:48].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:45][CH2:46][C:47](=[CH2:48])[CH2:49][O:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:39])([CH3:40])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cn3)nc(OCC(F)(F)F)n2)cc1
Yield: 43.7 %

Procedure:
A suspenssion of tert-butyl (3-(6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (90 mg), 3-chloro-2-(chloromethyl)prop-1-ene (27.2 mg) and K2CO3 (40.1 mg) in acetone (6 mL) was heated to reflux for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give desired product tert-butyl 3-(6-(6-(4-(2-(chloromethyl)allyloxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate (45 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]#[N:4].N>[Ni].CO>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][C:6]=1[CH2:5][CH:2]([NH2:1])[CH2:3][NH2:4]
Reactant: N#CC(N)CC1=Cc2ccccc2CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(N)CC1=Cc2ccccc2CC1
Reaction time: 16 h

Procedure:
A mixture composed of 2.57 g (13 mmol) of the nitrile obtained in Step 3, 120 ml of CH3OH, 2 g of Raney nickel and 50 ml of a solution of NH3 in CH3OH (7N) is hydrogenated under a pressure of one atmosphere for 16 hours. After filtration over Celite, the solution is concentrated and the residue is chromatographed on silica, eluting with a mixture of CH2Cl2 /CH3OH/NH4OH conc.=90/10/1, to yield the expected compound in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:24]C(=O)C(F)(F)F)[C:5]2=1.[C:31]([O-])([O-])=O.[K+].[K+].O>CO>[NH2:24][C:6]1[C:5]2[C:4]3[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][C:18]=4[CH3:31])[CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ncccc1C(=O)Nc1cc(Cl)cc2c1[nH]c1cncc(N)c12
Temperature: 60 °C
Yield: 55.6 %

Procedure:
N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide (41 mg, 0.092 mmol, 1 equiv.) was suspended in 5 ml of MeOH and a 2 ml aqueous solution of K2CO3 (127 mg, 0.92 mmol, 10 equiv.) was added thereto. The resulting clear solution was heated at 60° C. for 16 hr and then allowed to cool to RT. Additional water was added producing fine solids that were captured by filtration, washed once with 10 ml of 5% MeOH in Et2O, and dried under high vacuum to give 18 mg of N-(4-amino-6-chloro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as powdery yellow solids (56% yield).
Reaction SMILES: [N:1]([C@@:4]1(/[CH:32]=[CH:33]/[P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[C@@H:11]2[C@@H:7]([O:8]C(C)(C)[O:10]2)[C@H:6]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5]1)=[N+:2]=[N-:3]>C(O)(C(F)(F)F)=O.O>[N:1]([C@@:4]1(/[CH:32]=[CH:33]/[P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[C@@H:11]([OH:10])[C@@H:7]([OH:8])[C@H:6]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:5]1)=[N+:2]=[N-:3]
Reactant: CCOP(=O)(/C=C/[C@@]1(N=[N+]=[N-])O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOP(=O)(/C=C/[C@@]1(N=[N+]=[N-])O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
Compound 36.4 (122 mg, 0.18 mmol) was dissovled in a mixture of TFA in water (1.5 mL TFA in 0.2 mL water). The solution was stirred at r.t. for 30 min and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with EtOAc to 20% MeOH in EtOAc to give compound 36.5 (68 mg, 70% yield).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][N:8]1[C:12]([OH:13])=[C:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:10]([CH3:24])=[N:9]1.C(N(CC)CC)C.[C:32](Cl)(=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CCOCC>[CH3:7][N:8]1[C:12]([O:13][C:32](=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:10]([CH3:24])=[N:9]1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)Oc1c(C(=O)c2ccc(Cl)cc2Cl)c(C)nn1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
In 10 ml. of benzene is dissolved 0.285 g. of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole and then 0.2 ml. of triethylamine is added thereto. Under ice-cooling, a solution of 0.27 g. of lauroyl chloride in 5 ml. of benzene is added dropwise thereto. After completion of the dropwise addition, the resulting mixture is stirred at room temperature for 19 hours. After completion of the reaction, ether is added to the reaction mixture, which is then washed successively with water, 1N HCl, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. Then, the reaction mixture is dried over anhydrous sodium sulfate and the solvent is distilled off from the reaction mixture. The resulting residue is recrystallized from n-hexane under cooling with dry-ice to give 0.46 g. of the desired product as white crystals melting at 56° C. Yield 98.0%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:42][C:43](OC)=[O:44])[O:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:42][CH2:43][OH:44])[O:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@]1(OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CO[C@@]1(CCO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methyl 2-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)acetate (7) (0.48 g, 0.77 mmol) was dissolved in THF (8 mL) under an atmosphere of Ar and cooled to 0° C. DIBAL-H (2 mL of a 20% solution in toluene) was added dropwise. The reaction mixture was stirred at room temperature for 0.75 h, then cooled again to 0° C. and stirred with Rochelle's salt for 2 hours. The mixture was extracted with Et2O (3×). The organic layers were combined, washed with H2O (1×), dried (Na2SO4) and concentrated to a syrup (0.46 g, 100%). LC/MS 98.5% (ELSD) tR=3.10 min, calcd for C37H42O7: 598.29, found 621.3 (M+Na)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1>>[N:13]1[C:12]2[CH:16]=[CH:17][S:18][C:11]=2[C:10]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)=[N:15][CH:14]=1
Reactant: OCC1(CO)CCC1
Reactant: Clc1ncnc2ccsc12
Product: OCC1(COc2ncnc3ccsc23)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a using [1-(hydroxymethyl)cyclobutyl]methanol and 4-chlorothieno[3,2-d]pyrimidine. 1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 7.87 (d, J=5 Hz, 1H), 7.49 (d, J=5 Hz, 1H), 4.69 (s, 2H), 3.61 (d, J=6 Hz, 2H), 3.36 (t, J=6 Hz, 1H), 2.01-1.82 (m, 6H). GC-MS m/z 251 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:33])[CH2:19][N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.[F-].[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]>[OH:33][CH:18]([C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1cc(-c2cnc3ccc4ccc(C(O)CN5CCN(C(=O)OC(C)(C)C)CC5)cc4c(=O)c3c2)cn1
Reaction time: 19 h

Procedure:
tert-Butyl 4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.138 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58 mg, 0.28 mol), Pd2(dba)3 (6 mg, 0.007 mmol), (tBu3)PBF4 (4 mg, 0.014 mmol), and potassium fluoride (27 mg, 0.46 mmol) were combined in a sealed tube which was evacuated and backfilled with argon three times. Fully degassed DMF (1.5 mL) was added. The tube was placed in an oil bath at 115° C. and stirred for 19 hours. The reaction mixture was poured into an ethyl acetate/brine mixture and extracted with ethyl acetate. Combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via reverse phase HPLC (10-42% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 9.00 (d, 1H); 8.55 (d, 1H); 8.23 (d, 1H); 7.91 (s, 1H); 7.80 (s, 1H); 7.76 (dd, 1H); 7.60 (d, 1H); 7.34 (d, 1H); 7.23 (d, 1H); 4.95 (d, 1H); 3.98 (s, 3H); 3.56-3.51 (m, 4H); 2.78-2.53 (m, 6H); 1.46 (s, 9H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C29H34N5O4) [M+H]+, 516.3; found 516.3.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:13].[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: FC(F)Oc1ccccc1N1CCNCC1
Temperature: 0 °C
Yield: 13.6 %

Procedure:
A mixture of 2-difluoromethoxyaniline (5.14 g, 32.3 mmol) and bis(chloroethyl)amine hydrochloride (5.8 g, 32.5 mmol) in 50 mL of n-butanol was heated at reflux for 48 hours. Potassium carbonate (8.9 g, 64.5 mmol) was added and heated at reflux for approximately 24 hours. The mixture was extracted with 2N hydrochloric acid and the extract cooled to approximately 0° C. and then basified with sodium hydroxide to give a precipitate. The precipitate was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography eluting with 5% methanol/methylene chloride. Product fractions were combined and concentrated. The residue was crystallized from hydrochloric acid in methanol to give 1-[2-(difluoromethoxy)phenyl]piperazine hydrochloride (1.32 g, 4.38 mmol), m.p. 165°-176° C.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[N:8]1([CH2:13][C:14]2[CH:33]=[CH:32][C:17]([O:18][C@H:19]3[CH2:22][C@H:21]([CH2:23][NH2:24])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3.5 mL, 49 mmol) was added to a solution of example 395, tert-Butyl ({trans-3-[4-(Pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)carbamate (2.16 g, 6 mmol) in dichloromethane (20 mL). The reaction mass was stirred at room temperature for 2 h and evaporated in vacuo. The residue was diluted with water (50 mL), and the obtained solution was extracted with CH2Cl2. The organic layer was discarded. The aqueous one was alkalized with 10 N NaOH to pH 12 and extracted with CHCl3 (3×50 mL). The combined extracts were dried and evaporated to afford compound 10 (aap327) (1.4 g, 91%) as a yellow oil. LCMS-data: M+H 261.2, 262.2 (calc 260.38). 1H NMR-data (DMSO-d6): 7.17 (d, 2H, Ph, J=8.6 Hz); 6.72 (d, 2H, Ph, J=8.6 Hz); 4.65-4.76 (m, 1H); 3.47 (s, 3H, CH2); 2.63 (d, 2H, CH2, J=6.6 Hz); 2.32-2.42 (m, 4H); 2.18-2.28 (m, 3H); 2.00-2.13 (m, 2H); 1.60-1.72 (m, 4H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19](C)[C:20](=O)OC(C)(C)C)[S:16]2)[C@H:12]([F:28])[C@@H:11]1[OH:29])(C(C)(C)C)(C)C.Cl>CO>[F:28][C@H:12]1[C@H:13]2[N:14]=[C:15]([NH:19][CH3:20])[S:16][C@H:17]2[O:18][C@H:10]([CH2:9][OH:8])[C@H:11]1[OH:29]
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: Cl
Solvent: CO
Product: CNC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl (-(3aR,5R,6R,7S,7aR)-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-fluoro-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.200 g, 0.444 mmol) in dry MeOH (6 mL) was bubbled HCl gas for 30 sec. The mixture was stirred at room temperature for 5 h. After the solvent was evaporated under reduced pressure, the residue was neutralized with 1.0 M NH3 in MeOH and purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:8) followed by recrystallization from MeOH/Et2O, affording -(3aR,5R,6R,7S,7aR)-7-fluoro-5-(hydroxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.093 g, 89%). 1H NMR (400 MHz, CD3OD) δ 6.62 (d, J=6.5 Hz, 1H), 4.89 (td, J=3.5 Hz, 51.0 Hz, 1H), 4.54 (ddd, J=3.5, 6.5, 20.6, 1H), 3.98-3.94 (m, 1H), 3.90-3.84 (m, 1H), 3.83-3.81 (m, 1H), 3.75 (dd, J=5.4, 12.2 Hz, 1H), 2.99 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 90.63 (d, J=181.3 Hz), 88.53 (d, J=2.3 Hz), 73.60 (d, J=4.3 Hz), 66.02 (d, J=17.3 Hz), 64.80-64.50 (m), 62.44, 31.38; MS, (ES, m/z) [M+H]+ 237.1.
Reaction SMILES: [C:1]([O:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:15](=[O:28])[C:16]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[N:18]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[OH2:36].[OH2:37].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>ClCCl.CO>[C:1]([O:4][CH2:5][S:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[C:15](=[O:28])[C:16]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:17]=3[N:18]=2)=[CH:11][CH:12]=1)(=[O:37])=[O:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OCSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: O
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCS(=O)(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylthio)methyl acetate (1.00 g, 1.98 mmol) in dry dichloromethane (30 mL) and methanol (10 mL), magnesium monoperoxy phthalate hexahydrate (1.08 g, 2.18 mmol) is added at 0° C. and the resulting mixture is stirred for 18 h at rt. Then the reaction mixture is quenched with the addition of 10% sodium bicarbonate solution and extracted with dichloromethane (3×). The organic part separated is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylsulfonyl)methyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([OH:25])=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1.[ClH:27].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([O:25][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][O:28][CH2:33][CH2:32]3)=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCCS1

Procedure:
The benzopyran of Example 25 is reacted with γ-morpholinobutyric acid, hydrochloride salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[C:20]([F:22])[CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(F)cc(Br)c2)cc1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 3-bromo-5-fluoro-benzaldehyde (2.03 g, 10 mmol) in ethanol (20 mL) was heated to reflux for 2 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.25 g, 64%) as a white solid: LC/MS m/e calcd for C16H13BrFNO2 M+: 350.2, observed: 350.2, 352.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.[C:32](OC)(OC)(OC)[CH2:33][CH3:34]>>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][C:26]6[N:29]=[C:32]([CH2:33][CH3:34])[NH:30][C:25]=6[CH:24]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5ccc(N)c(N)c5)cc4C3)c2C1
Reactant: CCC(OC)(OC)OC
Product: CCc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 18 omitting step 1 and by using 4-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]benzene-1,2-diamine and trimethyl orthopropionate in step 2. 1H NMR (400 MHz, d6-DMSO): 8.69 (s, 1H), 7.94 (s, 1H), 7.84-7.78 (m, 3H), 7.60 (m, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.04 (d, 1H), 5.09 (s, 2H), 4.48 (m, 2H), 4.19 (m, 2H), 3.18 (dd, 2H), 2.70 (t, 2H), 2.54 (s, 2H), 1.58 (t, 2H), 1.45 (t, 3H), 0.85 (s, 6H); MS (EI) for C28H31N5O: 454 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([NH:15][NH2:16])[CH:8]=1)(=[O:6])=[O:5])[CH3:2].[CH2:19]([CH2:21][CH2:22][CH2:23][C:24](CC([O-])=O)=[O:25])[CH3:20]>>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([N:15]2[C:24](=[O:25])[CH2:23][C:22]([CH2:21][CH2:19][CH3:20])=[N:16]2)[CH:8]=1)(=[O:5])=[O:6])[CH3:18]
Reactant: CCN(CC)S(=O)(=O)c1ccc(OC)c(NN)c1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2cc(S(=O)(=O)N(CC)CC)ccc2OC)C(=O)C1

Procedure:
From the reaction of N,N-diethyl-3-hydrazino-4-methoxybenzenesulfonamide and ethylbutyrylacetate, N,N-diethyl-3-(4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-4-methoxybenzenesulfonamide is obtained. Subsequent reaction with 2-ethylaniline yields N,N-diethyl-3-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-4-methoxybenzenesulfonamide, oil
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(F)c(F)c2F)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,3,4-trifluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (2.3 mg) with purity >90%. MS (pos) m/z 381.4.