Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][CH:6]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Cc2cccnc2)cc1
Temperature: 0 °C

Procedure:
3-Benzylpyridine (13.52 g, 0.080 mole) and nitric acid (70%, 100 ml) are stirred at 50° C. for 6 hr. The solution is poured into ice-water (1500 ml). The mixture is made alkaline by the careful addition of 50% aqueous sodium hydroxide and then extracted 4 times with 300 ml of ether. The extracts are washed with brine, dried (MgSO4), filtered, and concentrated. The crude product is crystallized from acetone-hexane giving 5.67 g of 3-(4'-nitrobenzyl)pyridine. The filtrate is concentrated and the residue is chromatographed in two equal portions (4.66 g each) over two Merck size C Lobar columns. The columns are eluted with 50% ethyl acetate-hexane. A less polar product [1.83 g, 3-(2'-nitrobenzyl)pyridine], mixed fractions (1.67 g), and additional 3-(4'-nitrobenzyl)pyridine (2.55 g) after crystallization from acetone-hexane, total 7.92 g, 0.037 mole, 46%). Two recrystallizations from acetone-hexane gives the titled product as colorless needles, having a melting point of 87°-88° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([NH:14][C:15]1[C:16]([NH:21][C:22]([O:24][CH:25]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:13])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:38]=[CH:39][CH:40]=1)[C:12]([NH:14][C:15]1[C:16]([NH:21][C:22]([O:24][CH:25]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: O=C(Nc1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)OC(c1ccncc1)C1CCNCC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccccc1NC(=O)c1cccc(O)c1)OC(c1ccncc1)C1CCNCC1
Yield: 48 %

Procedure:
A mixture of N1-(3-benzyloxybenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2-benzenediamine (75 mg, 0.14 mmol) and 5% palladium-on-carbon (200 mg) in ethanol (4 mL) was placed under an atmosphere of hydrogen (1 atm). After consumption of the starting material, the mixture was filtered through diatomaceous earth and the filtrate concentrated in vacuo yielding 30 mg (48%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=1[Cl:21].N>>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)[CH:17]=[CH:18][C:13]=1[Cl:12]
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Cl)c(Cl)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.50 (s, 1H), 7.72 (d, J=8.3 Hz 1H), 7.86 (dd, J=8.3, 1.9 Hz 1H), 8.12 (d, J=2.0 Hz, 1H), 8.17 (ddd, J=9.1, 2.8, 1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.97 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 311 (M+H)+, 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9](N)=[O:10].C1(C)C=CC=CC=1.OS(O)(=O)=O.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:34][CH3:33])=[O:10]
Reactant: NC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 90 °C

Procedure:
5 g of (+)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetamide was dissolved in 45 ml methanol, followed by 15 mL of toluene. 5 mL (0.28 mol) of conc. H2SO4 was instantly added and another 10 mL of conc. H2SO4 was slowly added later, while maintaining the temperature at 90° C. After that, the reaction mixture was refluxed at 90° C. for 13 hrs. The solvent was distilled off under reduced pressure. To the residue, 50 mL of water was added and the pH of reaction mixture was adjusted between 9 to 10 using aq. sodium carbonate. The residue was extracted with 100 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and evaporated under vacuum. The combined eluent was evaporated at reduced pressure to yield 2.8 g of crude product purified by column chromatography, using hexane:ethyl acetate (9:1) as eluent.
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44](=[O:59])[NH:45][C@H:46]([C:54]3[S:55][CH:56]=[CH:57][N:58]=3)[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44](=[O:59])[NH:45][C@H:46]([C:54]1[S:55][CH:56]=[CH:57][N:58]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:69])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 75.3 %

Procedure:
According to general procedure A, from #53 (701 mg, 0.726 mmol) in dichloromethane (10 mL, 0.07 M) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane). The residue was diluted with diethyl ether and heptane and was concentrated in vacuo to afford #54 (406 mg, 75%) as a white solid. LC-MS: m/z 743.6 [M+H+], retention time=0.70 minutes; HPLC (Protocol A): m/z 743.4 [M+H+], retention time=6.903 minutes, (purity >97%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [8.64 (br d, J=8.5 Hz) and 8.86 (br d, J=8.7 Hz), total 1H], [8.04 (br d, J=9.3 Hz) and 8.08 (br d, J=9.3 Hz), total 1H], [7.77 (d, J=3.3 Hz) and 7.80 (d, J=3.2 Hz), total 1H], [7.63 (d, J=3.3 Hz) and 7.66 (d, J=3.2 Hz), total 1H], 7.13-7.31 (m, 5H), [5.39 (ddd, J=11, 8.5, 4 Hz) and 5.53 (ddd, J=12, 9, 4 Hz), total 1H], [4.49 (dd, J=9, 8 Hz) and 4.60 (dd, J=9, 7 Hz), total 1H], 3.16, 3.20, 3.21 and 3.25 (4 s, total 6H), 2.93 and 3.02 (2 br s, total 3H), 1.21 (s, 3H), 1.13 and 1.13 (2 s, total 3H), [1.05 (d, J=6.7 Hz) and 1.10 (d, J=6.7 Hz), total 3H], 0.73-0.80 (m, 3H).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([NH2:32])=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30]([NH2:32])=[O:31])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: NC(=O)CCl
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(N)=O)ccc-2c(C(=O)OCC)c1N
Yield: 26 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-chloroacetamide the title compound of m.p. 208-210° C. is obtained in 26% yield.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[SH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:14]
Reactant: O=C(O)c1ccccc1S
Reactant: CCCCC(CC)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC(CC)COC(=O)c1ccccc1S
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
2-Ethyl-1-hexanol (21.0 g, 0.161 mol), 2-mercaptobenzoic acid (25.0 g, 0.162 mol), toluene (200 mL), and concentrated sulfuric acid (0.2 mL) were placed in a 500-mL three-neck round-bottom flask equipped with a magnetic stirring bar, a water separator, and a reflux condenser. After the mixture had been heated under reflux with stirring for 6 h, the solid 2-mercaptobenzoic acid had disappeared, and 2.90 mL (0.161 mol) of water had been collected by the water separator. The mixture was allowed to cool to room temperature and washed in succession with 20 mL of saturated NaHCO3 solution and two 50-mL portions of brine. Then the organic layer was dried over anhydrous MgSO4 and freed of solvent by rotary evaporation under vacuum to give 40.9 g (95%) of residual 2-ethylhexyl 2-mercaptobenzoate as a mobile straw-colored oil; 1H NMR (400 MHz, in CDCl3 w/TMS, ppm) 0.88-0.97 (m, 6H, 2CH3), 1.3-1.5 (m, 8H, 4CH2), 1.68-1.78 (m, 1H, CH), 4.21-4.29 (m, 2H, OCH2), 4.73 (s, 1H, SH), 7.1-7.3 [m, 3H, H-4 and H-5 with d (J=3.2 Hz) for H-3 at 7.29], 8.01 (d, J=7.6 Hz, H-6); {1H}13C NMR (100 MHz, in CDCl3 w/TMS, ppm) 166.99 (C═O), 138.49 and 126.39 (C-1 and C-2), 132.53, 131.77, 131.12, and 124.82 (C-3, -4, -5, and -6), 67.86, 39.19, 30.92, 29.33, 24.34, 23.35, 14.44, and 11.46 (8 aliphatic Cs).
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:4][CH2:3][CH:2]([F:1])[CH2:7][CH2:6]1
Reactant: CC(=O)Nc1ccc(NCC2CC=C(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCC(F)CC2)c(N)c1

Procedure:
N-(4-{[(4-Fluorocyclohex-3-en-1-yl)methyl]amino}-3-nitrophenyl)acetamide (340 mg, 1.11 mmol) was dissolved in 25 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus at rt for 48 h. The solution was filtered through celite and the solvent was evaporated. Yield: 308 mg (99%). MS (ESI) (M+H)+ 279.95.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:23][NH:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:26]1>CN1C(=O)CCC1.CCOC(C)=O>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[N:7][C:2]([N:24]([CH3:23])[C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]3[C:31]4[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=4[N:33]=[CH:34][N:35]=3)[CH2:26]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1ccc(S(=O)(=O)N(C)C)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 200 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of 6-chloro-N,N-dimethylpyridine-3-sulfonamide (1 mmol) and DIPEA (2.5 mmol) in NMP (2 mL) was added (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.5 mmol). The reaction mixture was stirred at 200° C. for 60 minutes in microwave reactor. After cooling to room temperature, the mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated. The residue was purified by chromatography with MeOH/H2O to give the title compound in yellow in 8% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[NH2:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[NH2:25][C:26]1[C:27]([C:32]([NH:1][CH2:2][C@H:3]2[C@H:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=3)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ncccc2N)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 3-aminopyridine-2-carboxylic acid, and by a method similar to that of Example 39, step A, the title compound was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C:9]2[C:18](=[O:19])[C:17]3[C:16]([OH:20])=[CH:15][C:14]([O:21][C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[C:13]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:12]=3[O:11][C:10]=2[C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C@H:5]([OH:46])[C@H:4]([OH:47])[C@H:3]1[OH:48].P([O-])(O)(O)=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C:9]2[C:18](=[O:19])[C:17]3[C:16]([OH:20])=[CH:15][C:14]([OH:21])=[C:13]([CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:12]=3[O:11][C:10]=2[C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[C@@H:5]([OH:46])[C@@H:4]([OH:47])[C@@H:3]1[OH:48]
Reactant: COc1ccc(-c2oc3c(CC=C(C)C)c(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc(O)c3c(=O)c2O[C@@H]2O[C@@H](C)[C@H](O)[C@@H](O)[C@H]2O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Product: COc1ccc(-c2oc3c(CC=C(C)C)c(O)cc(O)c3c(=O)c2O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O)[C@@H]2O)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Fifty grams icariin were added into sodium dihydrogen phosphate-disodium hydrogen phosphate buffer (pH5.5) and 100 ml β glucose. 100 ml of β glucosidase was added and the solution was heated to 40° C. with stirring for 24 hours in order to remove glucoside. Then stop heating and repeatedly extract with ethyl acetate. The ethyl acetate layer was pooled and dried. Then repeatedly extract with methanol. The HPLC analysis confirmed that the content of pure icariside II 50.1%. Thus extract comprising icariside II is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[N:13]=[CH:14][CH:15]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[OH-:16].[Na+]>O1CCOCC1>[CH:15]1[CH:14]=[N:13][N:12]2[C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:2](=[O:16])[CH2:3]2
Reactant: [OH-]
Reactant: ClCc1nc2ccccc2c2ccnn12
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1Cn2nccc2-c2ccccc2N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3.1. A solution of 11.4 g of 5-(chloromethyl)pyrazolo[1,5-c]quinazoline in 160 ml of dioxan is added dropwise within 15 min. to a mixture of 130 ml of 1N aqueous sodium hydroxide solution and 130 ml of dioxan cooled to 0° to 5° C. The cooling is removed and the mixture is stirred at room temperature for 2.5 h. Then, the reaction mixture is poured into 600 ml of saturated aqueous sodium chloride solution and extracted four times with dichloromethane. The dichloromethane extracts are evaporated in a vacuum. The residue (5.4 g) is crystallized from dichloromethane/diethyl ether. There are obtained 4.15 g of 5H-pyrazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 236°-240° C.
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:4]=1.O>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: S
Reactant: N#Cc1cnc(-c2ccccc2)nc1N
Solvent: c1ccncc1
Solvent: O
Product: NC(=S)c1cnc(-c2ccccc2)nc1N
Reaction time: 8 h

Procedure:
Hydrogen sulfide is passed through a solution of 4-amino-2-phenyl-5-pyrimidinecarbonitrile (9.811 g., 0.050 mole) in dry pyridine (125 ml.) for one hour. The emerald green solution is stored overnight at 5° C. The solution is poured into water (500 ml.) with stirring. After stirring for one hour at ambient temperature, the pale yellow solid which separated is collected by filtration, dried at 110° C./0.1 mm. The yield of product melting at 197° C. dec. (uncorr.) was 10.481 g. (91.0%). The initial product is recrystallized from toluene (Darco G-60) affording yellow needles melting at 198° C. dec. (uncorr.) in a yield of 7.733 g. (67.1%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([F:28])[CH:30]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc(OC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), (3-fluoro-4-methoxyphenyl)boronic acid (3.0 g), triethylamine (6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride (50 mL) was added copper(II) acetate (3.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.62 g, 65%).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([Mg]Br)C.[CH2:23]=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOCC.C1COCC1>[C:1]12([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH:23]=[O:24])[C:12]=3[OH:18])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C=O
Reactant: Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
Into a 100 ml reactor thoroughly dried and purged with nitrogen, 11.22 g (46.30 mmol) of 2-(1-adamantyl)-4-methylphenol and 100 ml of THF were introduced. To the reactor, 16.20 ml of an ether solution containing 48.60 mmol of ethylmagnesium bromide was dropwise added at 0° C. over a period of 30 minutes, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 2.5 hours. Then, 300 ml of toluene was added, and the system was heated to 100° C. to give an opaque white slurry. After the slurry was cooled to room temperature, 3.80 g (126.54 mmol) of paraformaldehyde and 7.10 ml (70.17 mmol) of triethylamine were added, followed by stirring at 85° C. for 30 minutes. The reaction solution was allowed to cool to room temperature and then quenched with 10% hydrochloric acid. The organic layer was concentrated, and the solid precipitated was vacuum dried to obtain 10.51 g (yield: 84%) of 3-(1-adamantyl)-5-methylsalicylaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[Br:7].S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[S:5][C:6]=1[Br:7]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(Br)s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(Br)s1
Yield: 96.4 %

Procedure:
To a suspension of 23.75 g (83.06 mmol) of 4,5-dibromo-2-thiophencarboxylic acid in 235 mL of methanol was slowly added 15.5 mL (284 mol) of 98% sulfuric acid at room temperature. The mixture was refluxed for 23 hours. The resulting solution was concentrated to thick slurry under reduced pressure and diluted with 240 mL of dichloromethane. To this ice-cooled solution 190 mL of 17% NaOH was slowly added, under vigorous stirring. The aqueous layer was separated and extracted again with 120 mL of dichloromethane. The combined organic extracts were dried over Na2SO4 then concentrated to dryness to afford 24.02 g of product as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:36])[NH:34][NH2:35])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33](=[O:36])[NH:34][NH2:35])([CH3:31])([CH3:30])[CH3:29].[C:1]([OH:19])(=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
6.06 g (20 mmol) stearic acid chloride is dissolved in 10 ml dry THF. 2.77 ml (20 mmol) triethylamine and 2.91 g (22 mmol) tert-butylcarbazate, dissolved in 10 ml THF, are added dropwise with stirring at room temperature over a 10 min period, and the mixture is stirred for 30 min. The reaction mixture is filtered and the solvent is removed under vacuum. The oily residue is taken up in 50 ml ethyl acetate and extracted twice with 70 ml H2O. The organic phase is dried over Na2SO4 and filtered, and the solvent is evaporated under vacuum. The oily residue is dissolved in 50 ml warm ethanol and stored for 12 h at +4° C. The white precipitate is filtered and washed twice with 30 ml ethanol each. After drying under high vacuum, 3.6 g stearic acid tert-butylcarbazate is obtained; Rf=0.9 (ethyl acetate/n-hexane 2/1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23]CC2C=COC=2)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[OH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(O)c(-c3nc4cc(-c5ccccc5)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(3-furanylmethoxy)phenyl)-5-phenylbenzoxazole (144 mg, 0.28 mmol) and 1,2,4-benzenetricarboxylic anhydride (73 mg, 0.38 mmol) the title compound was obtained (100 mg, 55%). 1H NMR (DMSO) δ 8.48(dd, 1H), 8.39(s, 1H), 8.25(d, 1H), 8.21(d, 1H), 8.17(d, 1H), 8.00(d, 1H), 7.82(m, 3H), 7.70(dd, 1H), 7.57(t, 2H), 7.46(t, 1H), 7.38(d, 1H). MS 477 m/z (M+H)+.