Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[O:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][NH:10][CH2:11][CH2:12]1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCOCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 17 %

Procedure:
A mixture of 4,7,10,13-tetra(p-toluenesulfonyl)-1-oxa-4,7,10,13-tetraazacyclopentadecane prepared as in Example 17A (10.9 g, 0.0131 mole) and concentrated H2SO4 (70 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting brown solution, ethanol (140 ml) was added dropwise with stirring at 5° C., followed by ethyl ether (340 ml). The gummy brown solid was filtered and dissolved in H2O (100 ml). The pH of the solution was adjusted to 10 with 10N NaOH and the solution was extracted with 6×100 ml CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude product was purified by crystallization from hexane to give 0.49 g (17% yield) of the product as colorless needles: mp 80-1° C.; 1H NMR (CDCl3) δ 1.98 (br s, 4 H), 2.76 (m, 16 H), 3.61 (m, 4 H); Exact mass (M+H)+ : calcd., 217.2028; Found: 217.2051 (C10H25N4O) .
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:21]=[CH2:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:25]1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:21]2[CH2:22][O:25]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]([CH3:20])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OO1
Reactant: C=Cc1ccc(OCc2ccccc2)c2[nH]c(=O)c(C)cc12
Solvent: CC(C)=O
Product: Cc1cc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 8-benzyloxy-3-methyl-5-vinyl-1H-quinolin-2-one (300 mg) is added to a 0.1M solution of dimethyldioxirane in acetone (12.4 mL). After stirring at room temperature for 2 hours, the solvent is removed in vacuo to yield the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:19]1[C:27](O)=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=1)([CH2:17][OH:18])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:19]3=[CH:20][C:21]4[O:25][CH2:24][O:23][C:22]=4[CH:26]=[C:27]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.16 (d, 1H), 7.15 (s, 1H), 6.84 (dd, 1H), 6.45 (s, 1H), 6.06 (s, 1H), 5.86 (dd, 2H), 4.90 (ABq, 2H), 3.83-3.60 (m, 2H), 1.74-1.64 (m, 2H), 1.39-1.28 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.1, 157.2, 149.1, 144.6, 142.0, 130.3, 130.1, 127.0, 120.0, 116.5, 107.6, 102.5, 101.5, 93.3, 77.3, 59.6, 40.6, 29.0, 27.0, 22.3, 14.0; MS (ES+) m/z 430 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[C:4]=2[CH:3]=1.C1COCC1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:4]=2[CH:3]=1
Reactant: COC(=O)CCC1(CCC(=O)OC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCC1(CCC(=O)O)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 1 h
Yield: 81 %

Procedure:
Dimethyl 3,3′-(2,7-dibromo-9H-fluorene-9,9-diyl)dipropanoate (1.23 g, 2.5 mmol) is transferred to a small round bottom flask equipped with a Teflon-coated stirbar. A mixture of THF:MeOH:H2O, 3:2:1, (10 mL) is added and the mixture is stirred for 1 hr. Then a 1 mL portion of 1M NaOH (aq) is added and the mixture is stirred overnight. The next day the water layer is isolated and extracted with 20 mL portions diethyl ether three times. Next the water layer is acidified to ˜pH 2. The water layer is extracted three times with 20 mL portions of dichloromethane. The organic layers are combined and dried with Mg2SO4. The organic solution is filtered and the solvent evaporated to obtain the product as an off-white solid (948 mg, 90% yield).
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH3:24][O:23][C:22]1[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]=2[CH:21]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: COc1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(C#N)c1
Yield: 50 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used o-methoxyphenyl boronic acid. The title compound (80 mg) was obtained as a white solid, in 50% yield.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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]>[C:22]([O:21][C:19](=[O:26])[NH:20][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cccc(Cl)c1-n1cc2c(Br)nccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nccc2nn(-c3c(F)cccc3Cl)cc12
Temperature: 60 °C
Yield: 74 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine (166 mg, 0.51 mmol), tert-butyl carbamate (297 mg, 2.54 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), Xantphos (29 mg, 0.05 mmol) and potassium phosphate tribasic (216 mg, 1.02 mmol) in toluene (5 mL) and water (1 mL) was degassed with argon then heated at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and then filtered through Celite® washing with ethyl acetate. The filtrate was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-35% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (137 mg, 74% yield). LCMS (Method C): RT=2.30 min, m/z: 348 [M−C4H7+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9](Br)=[CH:8]2)=[O:4].[C:24]1([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCCC2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 120 °C
Yield: 75.9 %

Procedure:
A mixture of 3-bromo-1-cyclopentylmethyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (300 mg, 0.79 mmol), PhSnBu3 (0.31 mL, 0.94 mmol), and PdCl2(PPh3)2 (111 mg, 0.16 mmol) in DMF (15 mL) was heated at 120° C. under nitrogen atmosphere for 3 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added until pH was about 2-3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (3-35% EtOAc/hexanes+1% AcOH) to give 227 mg of the title compound as a yellow solid. MS: (+) m/z 379.38 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:20]([CH2:19][CH3:18])[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)C(CC)Oc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of 30 g of p-hydroxyacetophenone and 30 g of potassium carbonate was stirred in 500 ml of ethanol at 60° C. for 30 minutes. After cooling to room temperature, 52 g of ethyl 5-bromo-2,2-dimethylpentanoate was added to the reaction mixture. The resulting mixture was heated under reflux overnight while stirring. The solvent was removed from the reaction mixture by distillation and, 500 ml of chloroform and 300 ml of a 5% aqueous hydrogen sodium carbonate solution were added to the residue. After stirring the mixture, the chloroform layer was fractionated and washed successively with water and then with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of chloroform by distillation gave a residual oily substance. The oily substance was subjected to silica gel column chromatography and eluted using chloroform as an eluant to give 42 g of ethyl p-acetylphenoxy-2,2-dimethylpentanoate as an oily substance. The thus obtained oily substance was dissolved in 1.6 l. of anhydrous methylene chloride and 24 g of bromine was dropwise added to the solution under ice cooling while stirring to allow to react for 3 hours. To the reaction mixture was added 1 liter of ice water. After thoroughly stirring, the organic layer was successively washed with water and with a saturated aqueous sodium chloride solution followed by drying over anhydrous sodium sulfate. Removal of methylene chloride by distillation gave the desired product, ethyl 5-[p-(bromoacetyl)phenoxy]-2,2-dimethylpentanoate, as an oily substance.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]([OH:8])[CH2:6][CH:7]=1)[CH3:2].[CH3:9][C:10]1([CH3:20])[C@@H:12]([CH:13]=[C:14]([Cl:16])[Cl:15])[C@H:11]1[C:17](Cl)=[O:18].C(C1CC(O)CC=1C)C.Cl/C(/C(F)(F)F)=C\[C@@H]1[C@H](C(Cl)=O)C1(C)C>>[CH3:9][C:10]1([CH3:20])[C@@H:12]([CH:13]=[C:14]([Cl:15])[Cl:16])[C@H:11]1[C:17]([O:8][CH:5]1[CH2:6][CH:7]=[C:3]([CH2:1][CH3:2])[CH2:4]1)=[O:18]
Reactant: CCC1=CCC(O)C1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Cl)Cl
Agent: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: CCC1=C(C)CC(O)C1
Product: CCC1=CCC(OC(=O)[C@@H]2[C@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 85.1 %

Procedure:
(RS)-3-ethyl-3-cyclopenten-1-ol (500 mg) and (1R)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (1014 mg) were respectively used instead of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol and (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride used in Example 1 above and the reaction procedures were carried out in the same manner as in Example 1 to afford 1150 mg of (RS)-3-ethyl-3-cyclopentenyl (1R)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 132). Yield 80% nD25 1.5063
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH:14]=[CH:13]2.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](ON2C(=O)CCC2=O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>ClCCl.C(OCC)(=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([C:15]3[CH:14]=[CH:13][C:12]4[C:17](=[CH:18][CH:19]=[C:10]([Cl:9])[CH:11]=4)[CH:16]=3)(=[O:21])=[O:22])[CH2:28][CH2:27]2)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reaction time: 8 h
Yield: 81 %

Procedure:
Triethylamine (2.92 ml) was added to a mixture of 1-(6-chloronaphth-2-ylsulphonyl)piperazine hydrochloride (6.93 g) in dichloromethane (100 ml). 1-(1-(t-butoxycarbonyl)piperidin-4-ylcarbonyloxy)-2,5-dioxopyrrolidine (6.25 g) was added and the mixture stirred overnight. The mixture was evaporated to give a solid which was suspended in ethyl acetate (200 ml). Water (50 ml) was added and the ethyl acetate phase separated, washed with water (4×50 ml), brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel using a 75:25 mixture of ethyl acetate/hexane as eluent to give 1-(t-butoxycarbonyl)-4-(1-(6-chloronaphth-2-ylsulphonyl)piperazin-4-ylcarbonyl)piperidine (8.1 g);
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:31])[CH2:18][C:19]1[C:23]2[CH:24]=[C:25]([F:30])[C:26]([OH:29])=[C:27]([F:28])[C:22]=2[O:21][CH:20]=1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[C:25]([F:30])=[CH:24][C:23]4[C:19]([CH2:18][C:17]([OH:31])=[O:16])=[CH:20][O:21][C:22]=4[C:27]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)Cc1coc2c(F)c(O)c(F)cc12
Product: O=C(O)Cc1coc2c(F)c(OCc3cccnc3SC3CCCC3)c(F)cc12
Yield: 83.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (19 mg, 0.08 mmol) obtained in Step C of Preparation Example 8 and (5,7-difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Step C of Preparation Example 50 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (28 mg, 81%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(O[C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:21]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (446 mg), (R)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (450 mg), potassium carbonate (692 mg) in DMF (5.0 ml) was stirred at 85° C. for 6 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (354 mg). Physical properties: m/z [M+H]+ 431.1
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(S[C:28]1[S:29][C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N+:32]=1[CH2:33][CH3:34])C.C(N(CC)CC)C>CO>[CH2:33]([N:32]1[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[S:29](=[C:6]2[C:5](=[O:7])[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3][CH:2]2[CH3:1])[CH2:28]1)[CH3:34]
Reactant: CCSc1sc2ccccc2[n+]1CC
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CS(=C2C(=O)N(c3ccccc3)NC2C)c2ccccc21
Reaction time: 0.17 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with a methanol solution of 2-ethylthio-3-ethylbenzothiazolium tosylate. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 10 minutes, then concentrated and treated with isopropanol. The mixture was heated to dissolve the product, then water was added to cloud, and the mixture cooled to give crystals: 3.22 g (48%), mp 144°-147.5° C., λmax=379 (ε=25,000).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:28]=1.[CH3:29][N:30]([CH2:32]N(C)C)[CH3:31].C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:29][N:30]([CH3:32])[CH3:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:6]=2[CH:28]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cc3ccccc3)n1-2
Reactant: CN(C)CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CN(C)CC(c1ccccc1)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 0 °C

Procedure:
A stirred solution of 8-chloro-1-benzyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.85 g., 0.01 mole) in dry dimethylformamide (50 ml.) was cooled, under nitrogen, in an ice bath and treated with N,N,N',N',-tetramethyldiaminomethane (1.229 g., 0.012 mole) and then dropwise with acetyl chloride (0.923 ml., 0.013 mole). The mixture was kept in the ice bath for 2 hours, poured into a mixture of ice and saturated aqueous sodium bicarbonate solution and extracted several times with chloroform. The extracts were washed with a dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove dimethylformamide. The residue was chromatographed on silica gel (200 g.) with methanol. The product thus obtained was crystallized from diethylether to give 8-chloro-1-[2-(dimethylamino)-1-phenylethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in six crops; 0.483 g. of melting point 168.5°-170° C; 1.436 g. of melting point 169°-170.5° C. and 0.471 g. of melting point 169°-170.5° C., 0.530 g. of melting point 168.5°-170° C.; 0.231 g. of melting point 169°-170° C. and 0.269 g. of melting point 169°-170.5° C. The analytical sample was crystallized from ethyl acetate-Skellysolve B hexanes and had a melting point of 169.5°-171.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][C:11](=O)OCCCl)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+].[C:22](O)(=[O:24])C>O>[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([NH:10][CH2:11][CH2:22][OH:24])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1c(NC(=O)OCCCl)cc([N+](=O)[O-])c(N)c1C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(NCCO)cc([N+](=O)[O-])c(N)c1C

Procedure:
0.0417 mole (12 g) of β-chloroethyl 4-amino-5,6-dimethyl-3-nitrophenylcarbamate is suspended in 36 ml of 96° alcohol. A solution of 6.2 g of caustic soda pellets of 97% strength in 15 ml of water is added in small portions with stirring; the reaction mixture is heated to the refluxing temperature of the alcohol. After being heated for 2 hours the reaction mixture is poured into 200 g of iced water and acidified with acetic acid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]CC)=[O:15])=[N:12][CH:13]=1)=[CH2:7])[CH3:4].Cl>C(O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)=[CH2:7])[CH3:4]
Reactant: C=C(OCC)c1ccc(C(=O)OCC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(OCC)c1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
A 5 N sodium hydroxide solution (2 mL) was added to a solution of ethyl 5-(1-ethoxyvinyl)pyridine-2-carboxylate (100 mg) in ethanol (5 mL). The mixture was stirred at room temperature for two hours. After confirming completion of the reaction, the reaction solution was neutralized with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (92 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:5]2.ClCCl.[CH3:27][N:28]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[CH2:5]2)#[N:28]
Reactant: CN1CCCC1=O
Reactant: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(Br)cc3C2)CC1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(C#N)cc3C2)CC1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
To a 5 mL microwave vial was charged with tert-butyl 4-(5-bromo-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate (370 mg, 0.97 mmol), zinc cyanide (114 mg, 0.97 mmol) and palladium triphenylphosphane (1:4) (56 mg, 0.049 mmol). Above mixture was dissolved in N-methyl-2-pyrrolidinone (1 mL). The reaction vial was degassed, filled with N2 and heated in microwave reactor at 85° C. for 2 hr, then at 100° C. for 20 min. To above reaction was added dichloromethane (5 mL), washed with small amount of water. The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained as white solid after purification by flash column chromatography. LC-MS (IE, m/z): 328.3 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.47 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 2.4-3.6 (m, 13H), 1.5 (s, 9H).