Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=O)[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.[CH3:32][NH:33][CH3:34].[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][N:33]([CH3:34])[CH3:32])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2
Reactant: CNC
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CN(C)Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (0.18 g) in methanol (3 mL) was added a 2 molar methanolic solution of dimethylamine (0.24 mL). After one hour stirring at room temperature, decaborane was added (15 mg) and the mixture stirred one more hour before being concentrated under reduced pressure. The residue was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (100 mg, 52%). Rf=0.2 (3:1 EA/heptane). MS (ES): M/Z [M+H]=481. 1H NMR: (400 MHz, CHLOROFORM-d): 1.81 (s, 3H), 2.31 (s, 6H), 3.75 (d, J=13.5 Hz, 1H), 3.92 (d, J=13.5 Hz, 1H), 5.12 (d, J=13.8 Hz, 1H), 5.52 (d, J=13.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.36 (s, 1H), 7.81 (d, J=1.7 Hz, 1H) and 7.95 (br. d, J=8.7 Hz, 3H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][CH:6]([C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH:6]([C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C=Cc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CCc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reaction time: 0.75 h
Yield: 52.3 %

Procedure:
0.19 g (0.560 mmol) of methyl 4-[α-(2-dimethylaminoethoxy)benzyl]cinnamate was dissolved in 4 ml of methanol and 13 mg (0.056 mmol) of nickel chloride hexahydrate was then added. Forty-two mg (1.12 mmol) of sodium boronhydride was further added thereto under ice-cooling in divided portions for 1 hour and stirred for further 45 minutes. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in chloroform and washed with water and brine. After the organic phase was dried (MgSO4), the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 (v/v)) to obtain 0.10 g (0.293 mmol) of methyl 3-{4-[α-(2-dimethylaminoethoxy)benzyl]phenyl}propionate as a colorless oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[C:14]12([N:24]=[C:25]=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:25]([NH:24][C:14]23[CH2:23][CH:18]4[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]4)[CH2:21]2)[CH2:15]3)=[O:26])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)NC23CC4CC(CC(C4)C2)C3)c1O
Yield: 56.5 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (120 mg, 0.54 mmol) and 1-adamantyl isocyanate (115 mg, 0.64 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), gave the desired product (122 mg, 56%). LC-MS (m/z) 400.0 (M+).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:46][C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>O1CCCC1>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:46][C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[CH:8][CH:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]1
Reactant: Sc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CSc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a solution of 100 mg (0.22 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 10 ml of tetrahydrofuran were added 68 mg (0.66 mmol) of triethylamine and thereafter dropwise at 0° C. 25 mg (0.26 mmol) of methanesulphonyl chloride. The reaction solution was stirred at room temperature for 90 minutes, thereafter 38 mg (0.33 mmol) of 2-mercaptopyrimidine were added and the mixture was stirred at room temperature for a further 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was taken up in 20 ml of methylene chloride and then extracted with 10 ml of water. The organic phase was dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 5:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 100 mg (82% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(pyrimidin-2-ylsulphanylmethyl)-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 542 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[C:15]([O:19][C:20](=[O:27])[C:21](=[N:25]O)[C:22](=O)[CH3:23])([CH3:18])([CH3:17])[CH3:16].O>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:22]([CH3:23])=[C:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[NH:25][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14])[CH3:2]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Temperature: 75 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A stirred solution of 3-oxo-butyric acid tert-butyl ester (32 g, 0.2 mol) in glacial acetic acid was added dropwise with an aqueous solution of sodium nitrite (13.8 g, 0.2 mol sodium nitrite in 20 ml of water) while maintaining the temperature at 0˜5° C. Upon completion of the addition, the reaction mixture was stirred in an ice-water bath for 1 hour and at room temperature for another 3 hours. The solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester was obtained which was used as such. A mixture of 3-oxo-glutaric acid diethyl ester (40 g, 0.2 mol) in 90 ml of glacial acetic acid was added with the above solution of 2-hydroxyimino-3-oxo-butyric acid tert-butyl ester and zinc dust (26 g, 0.4 mol) alternatively at a rate to maintain the reaction temperature below 65° C. Upon completion of the addition, the mixture was stirred at 75° C. for 2 hours, added with cold water (100 ml), and the mixture was stirred at room temperature for 1 hour. The zinc dust was removed by filtration and the filtrate was extracted with ethyl acetate (100 ml×3). The combined organic extracts were washed with water (100 ml×3), saturated sodium bicarbonate solution (100 ml×4), and brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (60 g, 88.5%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C@H:11]([OH:22])[C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1ccc(F)cc1OCc1ccccc1
Yield: 81.4 %

Procedure:
(3S,4S)-1-(2-hydroxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.94 g) was treated with benzyl bromide (0.48 ml) and potassium carbonate (0.53 g) in DMF (5 ml) at room temperature for 2 hr. The mixture was diluted with EtOAc and washed with water twice, dried and evaporated. The residual oil (1.43 g) was chromatographed over silica gel (30 g), eluting with a mixture of hexane and EtOAc (40:1) to give a second crop of colorless oil of (3S,4S)-1-(2-benzyloxy-4-fluorophenyl)-4-tert-butyldimethylsilyloxy-3-pentanol (0.79 g, total yield 81.4%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:11]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:11]2[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1nnc(C2CCCCC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCCCC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-Cyclohexyl-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized from a dimethyl formamide-water mixture to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer having a melting point of 237° to 239° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:10])=[N:17][N:16]=[N:15]2)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnnn1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
A suspension of N-(4-bromo-2-nitro-phenyl)-acetamide (1.18 g, 4.55 mmol) in acetonitrile (25 mL) was cooled to 0° C. and then treated with sodium azide (838 mg, 13.65 mmol). The reaction mixture was then treated with trifluoromethanesulfonic anhydride (2.88 g, 10.25 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (70 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-nitro-phenyl)-5-methyl-1H-tetrazole (1.16 g, 90%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C8H6BrN5O2 (M+) 282.9705, found 282.9700.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH2:34][C@H:35]5[CH2:37][O:36]5)[CH2:26][CH2:25]4)[C:18]3=[O:38])[CH:11]=2)[CH2:7][CH2:6]1>CN(C=O)C>[CH:5]1([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH2:34][C@H:35]([OH:36])[CH2:37][NH:4][CH2:3][CH2:1][OH:2])[CH2:25][CH2:26]4)[C:18]3=[O:38])[CH:11]=2)[CH2:6][CH2:7]1
Reactant: NCCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H](O)CNCCO)CC2)c1=O
Temperature: 50 °C

Procedure:
Ethanolamine (1 mL) was added to N-cyclopropyl-4-methyl-3-{3-[(1-{2-[(2R)-oxiran-2-ylmethoxy]phenyl}cyclopropyl)amino]-2-oxopyrazin-1(2H)-yl}benzamide (Example 299a, 7.81 g) in DMF (3 mL). The reaction was heated at 50° C. overnight. The reaction mixture was partitioned between water and DCM. The combined organics were dried (MgSO4), filtered and evaporated. Purification by preparative HPLC (Xbridge column, eluting with a gradient of acetonitrile in 0.2% (v/v) aqueous ammonia) gave the title product (0.102 g) after solvent removal and trituration with diethyl ether.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[C:31]([C:34]1([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:42][C:41]2[C:36](=[C:37]([O:49]C)[C:38]([O:47][CH3:48])=[C:39]([O:45][CH3:46])[C:40]=2[O:43]C)[CH2:35]1)([OH:33])=[O:32]>O>[C:31]([C:34]1([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:42][C:41]2[C:40](=[O:43])[C:39]([O:45][CH3:46])=[C:38]([O:47][CH3:48])[C:37](=[O:49])[C:36]=2[CH2:35]1)([OH:33])=[O:32]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCC(=O)O)(C(=O)O)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCC(=O)O)(C(=O)O)C2)C1=O
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A water (1 ml) solution of CAN (287 mg, 0.523 mmols) was dropwise added to an acetonitrile (2 ml) solution of 8-(2-carboxy-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (88.6 mg, 0.209 mmols) with cooling with ice and then stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate only) followed by recrystallization from hexane-ethyl acetate to obtain the entitled compound (32 mg) as crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>C(Cl)Cl>[CH2:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCNCc1ccc(OC)cc1OC
Reaction time: 8 h
Yield: 40 %

Procedure:
0.5 ml of 1-Bromo-3-butene (4.926 mM) and 0.94 ml of diisopropyl ethylamine (5.396 mM) were added to the reaction solution containing 0.74 ml of 2,4-dimethoxybenzylamine (a) (4.926 mM) dissolved in methylene chloride with stirring and the solution was left alone at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 436 mg of the pure title compound (b) (yield: 40%).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([NH2:24])[CH:18]=2)=[N:6][C:5]1=[O:25])([CH3:3])[CH3:2].[CH:26](OCC)(OCC)OCC>CCOC(C)=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH:26]=[N:24][C:19]=3[CH:18]=2)[NH:6][C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)n1c(=O)nc(-c2ccc(O)c(N)c2)c2cc3c(cc21)OCO3
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)NC(c2ccc3ocnc3c2)c2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 1-isopropyl-6,7-methylenedioxy-4-(3-amino-4-hydroxyphenyl)quinazolin-2(1H)-one (93 mg) in triethyl orthoformate (3 mL) was refluxed for 1 h, cooled to rt, diluted with EtOAc (30 mL), washed with water, saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to yield the title compound as a tan solid (70 mg, 71%), mp: 84-86° C. 1H NMR (CDCl3): 8.12 (s, 1H), 7.72 (s, 1H), 7.59 (d, J=8.3, 2H), 7.39 (d, J=8.3, 1H), 6.71 (s, 1H), 6.28 (s, 1H), 5.92 (s, 1H), 5.90 (s, 1H), 5.49 (s, 1H), 5.14 (s, 1H), 4.45 (m, 1H), 1.58 (d, J=6.6, 3H), 1.55 (d, J=6.6, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O.O>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCO2
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.5 %

Procedure:
To a solution of 2,3-dihydrobenzofuran (15.0 g, 125 mmol) in tetrahydrofuran (300 mL) was added N-bromosuccinimide (24.5 g, 138 mmol) at 0° C. The reaction solution was stirred at room temperature for 50 minutes, then, water was added, the solution was extracted with ethyl acetate, and the organic layer was washed with brine. Anhydrous magnesium sulfate was added to the organic layer for drying, which was then filtered, the filtrate was concentrated in vacuo, the residue was purified by NH silica gel column chromatography (hexane), and the title compound (24.0 g, 97%) was obtained as a colorless oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:20]([OH:24])(=[O:23])[CH:21]=[CH2:22].C=CC1C=CN=CC=1.Cl>>[C:20]([O:24][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)(=[O:23])[CH:21]=[CH2:22]
Reactant: C1=COCC1
Reactant: C=CC(=O)O
Agent: C=Cc1ccncc1
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OC1CCCO1
Temperature: 25 °C

Procedure:
To a 100 mL 3-neck round bottom flask equipped with a stir bar, condenser, and addition funnel was added 39 mL of dihydrofuran (FW 70.09, d=0.927), and 0.18 g of phenothiazine. Acrylic acid (19 mL, FW 72.06, d=1.05) was added dropwise slowly with stirring. A mild exotherm (55° C.) occurred. After cooling to room temperature, 0.415 g of poly(4-vinylpyridine hydrochloride) was added and the reaction was stirred overnight. The acid catalyst was then filtered off and 0.2 g each of calcium hydride and potassium carbonate was added to the filtrate. After removal of excess dihydrofuran on a rotovap, 10 mg of DPPH (2,2-diphenyl-1-picrylhydrazyl hydrate) was added and the slurry was vacuum distilled at 200 mtorr at 26° C. to give 26.0 g of 2-tetrahydrofuranyl acrylate.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][NH:20][C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][CH2:42]Br)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O.O1CCCC1>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]([CH2:42][CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:38])[N:20]=[C:11]3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1n[nH]c2c1CCc1cnc(Nc3ccccc3)nc1-2
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(nn1CCCNC(=O)OC(C)(C)C)-c1nc(Nc3ccccc3)ncc1CC2

Procedure:
500 mg of ethyl 8-anilino-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (1.5 mmol) were dissolved in 10 mL of dry dimethylformamide and 1.63 mL of 1 M lithium tert-butoxide in tetrahydrofuran were added to the cooled solution. After 30 minutes under stirring at 0° C. a solution of 432 mg of tert-butoxycarbonylaminopropyl bromide in 8 mL of dry tetrahydrofuran were added dropwise. After a night at room temperature the mixture was poured into a solution of NaH2PO4 and extracted with dichloromethane. The organic layer was then dried over Na2SO4 and the solvent evaporated, giving an oil that was treated according to the following step 7, without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.[I-:13].[Na+].ClC(OC(Cl)C)=O.C1(C)C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][I:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: [I-]
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 8.0 grams (0.048 mole) of 3-(4-methoxyphenyl)propanol and 7.9 grams (0.053 mole) of sodium iodide in 50 mL of acetone was stirred, and 5.7 mL (0.053 mole) of 1-chloroethyl chloroformate was slowly added. Upon completion of addition, the reaction mixture was heated to reflux where it was stirred for four hours. After this time the reaction mixture was cooled, and 50 mL of toluene was added. The acetone was removed by distillation after which the reaction mixture was heated for one hour at reflux in the toluene. The reaction mixture was then cooled and poured into 300 mL of water. The mixture was extracted with 200 mL of diethyl ether. The ether extract was washed with 100 mL of an aqueous 5% sodium thiosulfate solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, and the oil was dissolved in methylene chloride and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 40:1 petroleum ether and diethyl ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 3-(4-methoxyphenyl)propyl iodide. The NMR spectrum was consistent with the proposed structure.