Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH:35]=[CH:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:32][CH:33]=[CH:34][CH2:35][CH2:36]1
Reactant: C1=CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CC=CCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and 1,2,3,6-tetrahydropyridine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80 (s, 1H), 6.05 (m, 1H), 5.79 (m, 2H), 3.4-3.8 (m, 12H), 3.41 (t, J=7.5 Hz, 4H), 2.5 (m, 2H); MS (DCI) m/z 416 (M+H)+;
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9])(=O)C.CO[C:16]1C=CC(CN2N=NC(CC(OCC)=O)=N2)=C[CH:17]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccnc(N)c1
Temperature: 105 °C

Procedure:
2-(Acetylamino)isonicotinic acid (13 g, 73.60 mmol) synthesized by the method of Example 7, (A) was added with ethanol (50 ml) and toluene (150 ml) and heated to 100-110° C. The mixture was added dropwise with concentrated sulfuric acid (7 ml) and heated for 11 hour with stirring. The reaction solution was returned to room temperature and poured into saturated aqueous sodium hydrogencarbonate cooled with ice. The mixture was extracted with chloroform and the collected organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 7.6 g (23% for the two steps) of the title compound as pale yellow crystals without purification.
Reaction SMILES: N1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)C=CN=N1.[O:55]1CC[CH:57](N)[CH2:56]1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:43][CH:41]([F:42])[C:30]1[C:31]2[C:32]([F:40])([F:39])[CH2:33][CH2:34][C:35]([F:37])([F:38])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:8][CH:7]3[CH2:57][CH2:56][O:55][CH2:6]3)[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Reactant: NC1CCOC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NC3CCOC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (25) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with tetrahydrofuran-3-amine and 23B. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J=7.6 Hz, 1H), 8.06 (s, 1H), 7.43-7.26 (m, 2H), 7.24-7.14 (m, 1H), 6.95-6.63 (m, 2H), 6.42 (d, J=5.9 Hz, 2H), 5.22 (m, 1H), 5.04 (s, 2H), 4.66 (m, 1H), 4.01 (m, 2H), 3.93-3.84 (m, 1H), 3.76 (m, 1H), 3.02 (m, 2H), 2.51 (m, 4H), 2.37 (m, 1H), 1.99 (m, 1H). MS (m/z) 742.15 [M+H]+.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1.CC(C)=[O:21].O>[B-](F)(F)(F)F.[Ag+].CO>[OH:21][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: CC(C)=O
Reactant: O=C(O)CCCCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 100) in 500 ml. of acetone and 325 ml. of water at 3°C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0°-3°C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66°C., λ max.MeOH = 223 mμ (7800); ν max (KBR) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm-1 (olefin group).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:13][CH2:12][CH2:11][CH:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2cccs2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCC2CC(c3cccs3)=NO2)CC1
Yield: 92.4 %

Procedure:
3-(3-(2-Thienyl)-4,5-dihydroisoxazol-5-yl)propanal (21.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 31.0 mg (92.3%) of the target compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([CH:12]([C:38]([O:40][CH3:41])=[O:39])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([O:28]CC1C=CC(OC)=CC=1)=[O:27])=[O:11].C1(OC)C=CC=CC=1>O>[CH3:8][O:9][C:10]([CH:12]([C:38]([O:40][CH3:41])=[O:39])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([OH:28])=[O:27])=[O:11]
Reactant: COC(=O)C(C(=O)OC)c1c(C(=O)OCc2ccc(OC)cc2)cc([N+](=O)[O-])c2ccccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)C(C(=O)OC)c1c(C(=O)O)cc([N+](=O)[O-])c2ccccc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Trifluoroacetic acid (36 mL) was added in one portion to a mixture of 5 (9.20 g, 19.7 mmol) and anisole (12.16 g, 20 mmol), and the resulting solution was stirred at 20° C. for 10 min and then diluted with cold water (800 mL). The precipitated semi-solid was collected, dissolved in EtOAc and the solution was washed with water, dried (Na2SO4) and then concentrated under reduced pressure below 30° C. The residue was triturated with iPr2O to provide a crude product, which was recrystallised from EtOAc/iPr2O/petroleum ether/AcOH (1drop) to give 1-[di(methoxycarbonyl)-methyl]-4-nitronaphthalene-2-carboxylic acid (6) (6.37 g, 93%), mp 153-154° C. (dec.). 1H NMR [(CD3)2SO] δ 14.1 (br s, 1H, CO2H), 8.62 (s, 1H, H-3), 8.36 (d, J=8.2 Hz, 1H, H-5), 8.30 (d, J=8.7 Hz, 1H, H-8), 7.92 (br t, J=7.6 Hz, 1H, H-6), 7.84 (br t, J=7.7 Hz, 1H, H-7), 6.65 (s, 1H, ArCH), 3.63 (s, 6H, 2×CO2CH3). Anal. Calculated for C16H13NO8 : C, 55.3; H, 3.8; N, 4.0. Found: C, 55.4; H, 3.8; N, 3.7%.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:22][NH:23][C:24]([NH2:26])=[S:25]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:26]=[C:24]([NH:23][CH3:22])[S:25][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CNC(N)=S
Solvent: CCO
Product: CNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.355 g, 0.959 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-methylthiourea (0.086 g, 0.959 mmol). The solution was heated to reflux for 14 hours and cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in ethyl acetate (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate and filtered. Isooctane was added to the filtrate until the solution became cloudy yielding a pale yellow fluffy solid which was collected by vacuum filtration. This solid was dissolved in methylene chloride and washed with sodium carbonate solution (10% solution), dried over sodium sulfate, and concentrated yielding a solid. This solid was recrystallized from methylene chloride-isooctane yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-methylaminothiazole (0.135 g, 39%) as a pale yellow powder: mp 243°-244° C.; 1HNMR 400 mHz 7.90 (q, J=4.76 Hz, 1 H), 7.81 (d, J=8.50 Hz, 2 H), 7.49-7.43 (m, 2 H), 7.41 (t, J=8.70 Hz, 2 H), 7.19 (t, J=8.95 Hz, 2 H), 3.22 (s, 3 H), 2.90 (d, J=4.80 Hz, 3 H); MS (FAB) m/z 363 (M+H). HRMS Δ=-0.2 mmu.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[N+](C1C=CC=CC=1)([O-])=O.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>ClCCCl>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:26](=[O:28])[CH3:27])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(=O)oc2c(C(C)=O)c(O)cc(O)c12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a mixture of 5,7-dihydroxy-4-propyl-coumarin (2.06 g 9.36 mmol) and anhydrous AICI3 (2.53 g, 18.7 mmol) was added 1,2-dichloroethane (120 mL). The resulting suspension was heated to 75° C. with vigorous stirring. After 30 minutes of stirring, a brown slurry was obtained, then nitrobenzene was introduced into the mixture resulting in an orange colored solution. A solution of anhydrous AICI3 (2.53 g, 18.7 mmol) and acetic anhydride (0.88 μL, 9.36 mmol) in 1,2-dichloroethane (40 mL) was added dropwise over a period of 1-2 hours. After addition, the mixture was allowed to stir at 75° C. for another two hours and subsequently cooled to room temperature. The resulting mixture was poured into ice and 1N HCl. The precipitated product was filtered and then taken into ethyl acetate and the aqueous solution was extracted throughly with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting solid was purified by column chromatography (1:1 hexane/ethyl acetate) yielding 5,7-dihydroxy-8-acetyl-4-propyl-coumarin (0.30 g, 12%): mp. 221-224° C.; 1H NMR (DMSO-d6) δ 0.94 (t, 3H), 1.58 (sextet, 2H), 2.66 (s, 3H) 2.87 (t, 2H), 6.01 (s, 1H), 6.29 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][C:15](OCC)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:20]1([C:26]2[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][CH2:14][C:15]3[N:30]4[N:31]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:27]=[CH:28][C:29]4=[N:32][N:33]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: CCOC(=O)CCc1ccnc2cc(OC)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(CCc3nnc4ccc(-c5ccccc5)nn34)ccnc2c1

Procedure:
Ethyl 3-(7-methoxyquinolin-4-yl)propanoate (156 mg, 0.60 mmol) was combined with 1-(6-phenylpyridazin-3-yl)hydrazine (115 mg, 0.62 mmol) and pTsOH.H2O (140 mg, 0.72 mmol). The mixture was microwaved at 150° C. for 60 minutes. The residue was taken up in DMSO and purified by HPLC and neutralized to yield the desired product as an off-white solid. (ESI, pos. ion) m/z: 382.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([O-:15])=[O:14])=O.Cl.[C:23]1(C)C=CC=C[CH:24]=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5]/[CH:10]=[C:12](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[C:13]([O:15][CH2:23][CH3:24])=[O:14]
Reactant: COc1ccccc1N
Reactant: Cc1ccccc1
Reactant: O=CC(C(=O)[O-])c1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccccc1OC)c1ccccc1
Yield: 68 %

Procedure:
A solution of 2-methoxyaniline (1.20 ml, 10.64 mmol) and ethyl ∀-formylphenylacetate (2.25 g, 1.1 eq) in toluene (20 ml ) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 2.15 g (68%) of compound 3 (Z isomer) in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[OH-].[NH4+:18]>C(O)(C)(C)C>[NH2:1][C:2]1[N:18]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]([OH:3])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)c1oc(N)nc1C(C)(C)C
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1nc(N)nc(C(C)(C)C)c1O
Yield: 34 %

Procedure:
A solution of 1-[2-amino-4-(1,1-dimethylethyl)-5-oxazolyl]-2,2-dimethyl-l-propanone (15 g) in t-butanol (80 mL) and concentrated ammonium hydroxide (80 mL) is heated at 180° C. for 60 hours in a steel bomb. The reaction mixture is cooled and concentrated to half its volume on the rotovap. The product is extracted into ether (3×250 mL). The ether extract is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica, 20% EtOAc/hexane) to give pure 2-amino-4,6-bis(1,1-dimethylethyl)-5-hydroxypyrimidine (4.5 g, 34%) which crystallizes from cold hexane; mp 92°-93° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20]Cl)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1.[I-].[Na+]>CN(C)C=O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1
Reactant: CCNCC
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1 ml. of diethylamine in 5 ml. of dry dimethylformamide, 350 mg. of 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (obtained as in Preparation 3) is added and the mixture stirred under nitrogen at room temperature for about 4.5 hours. To the mixture, 50 mg. of sodium iodide is added and stirring is continued at room temperature for about 18 hours and then heated at about 100 to about 110° C. for about an additional 6 hours. It is then poured into ice water and extracted with chloroform. The extract is washed with water, dried over anhydrous potasssium carbonate and concentrated under vacuum. The residue is crystallized from ethyl acetate: Skellysolve B to give pure 8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (I).
Reaction SMILES: C([O:4][C:5](=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:22]([Br:23])=[C:21]([N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]3[N:41]=[CH:42][C:43]([C:44]4[CH:45]=[N:46][C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:48][CH:49]=4)=[C:19]3[N:18]=2)[CH2:13][CH2:12]1)[C:6]([O:8]CC)=[O:7])(=O)C.C1COCC1.[Li+].[OH-].Cl>O>[CH3:30][Si:29]([CH3:32])([CH3:31])[CH2:28][CH2:27][O:26][CH2:25][N:24]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:21]1[N:20]2[N:41]=[CH:42][C:43]([C:44]3[CH:45]=[N:46][C:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[CH:48][CH:49]=3)=[C:19]2[N:18]=[C:17]([CH:14]2[CH2:13][CH2:12][CH:11]([C:5](=[O:4])[C:6]([OH:8])=[O:7])[CH2:16][CH2:15]2)[C:22]=1[Br:23]
Reactant: CCOC(=O)C(OC(C)=O)=C1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(C(=O)C(=O)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL roundbottom flask was charged ethyl 2-acetoxy-2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (0.47 mmol, 400 mg), a solution of 2:1 THF:H2O (15 mL), and 1N LiOH(aq) (1.18 mmol, 1.18 mL). The resulting solution was stirred at room temperature for 18 hours. After 18 hours, the reaction was quenched with 1N HCl(aq) (1.18 mmol, 1.18 mL) and the solvent removed in vacuo. The resulting residue was taken on without further purification.
Reaction SMILES: [C:1]1([CH3:9])[C:2](=O)[C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[CH2:10]=[CH:11][CH:12]=[CH2:13].[Cl-].[Li+].[OH2:16]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:9][C:1]1[C:6](=[O:16])[C:5]2[CH2:10][CH:11]=[CH:12][CH2:13][C:4]=2[C:3](=[O:7])[CH:2]=1
Reactant: CC1=CC=CC(=O)C1=O
Reactant: O
Reactant: C=CC=C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC1=CC(=O)C2=C(CC=CC2)C1=O

Procedure:
In toluene (30 ml) and acetic acid (5 ml), were dissolved 7.0 g (0,057 mol) of toluquinone, to which 7.6 g (0.14 mol) of 1,3-butadiene were added at -10° C. under stirring. Thereafter, the resultant mixture was gradually heated and stirred further for 3 hours at 40° C. The liquid reaction mixture was washed with water, and an organic layer was dried and concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) and ethanol (50 ml) were added to the residue, and the mixture was stirred for 1 hour at 40° C. After the liquid reaction mixture was concentrated under reduced pressure, the residue was dissolved in a liquid mixture of toluene (50 ml), n-propanol (25 ml) and water (25 ml). To the solution, were added 1.0 g (0.23 mol) of lithium chloride, 5.0 g (0.29 mol) of cupric chloride dihydrate to stir the resultant mixture for 1 hour at 40° C. The liquid reaction mixture was poured into water (100 ml) to make extraction with toluene (50 ml × 2). The resulting organic layer was washed with water, dried and concentrated under reduced pressure to obtain a crude product of the title compound. This crude product was recrystallized from methanol (20 ml) to obtain 9.14 g of the title compound as yellow crystals (yield: 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>>[N:13]1[CH:14]=[CH:15][C:10]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:12]=1
Reactant: Clc1ccncc1
Reactant: O=C1CNCCN1
Agent: Cl
Product: O=C1CN(c2ccncc2)CCN1
Temperature: 200 °C
Yield: 23.5 %

Procedure:
An intimate mixture of piperazinone (4.2 g) and 4-chloropyridine hydrochloride (7.33 g) was stirred and heated at 200° C. for 10 minutes and allowed to cool. The product was purified by flash column chromatography and cluted with 1/9/0.1 v:v:v methanol/methylene chloride/0.88 S.G. aqueous ammonia. The solid thus obtained was recrystallised from ethanol to give 4-(4-pyridyl)piperazin-2-one (1.75 g); m.p. 268°-270° C.; NMR (d6DMSO) δ 8.2(3H,m); 6.8(12H,m); 3.85(2H,s); 3.52(2H,m); 3.31(2H,m); m/e 178(M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].N([O-])=O.[Na+].[BrH:30]>O1CCOCC1.O.[Cu]Br>[Br:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Br
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br

Procedure:
in a solution of 0.50 g of 3-(4-amino-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 1.0 ml of 1,4-dioxane and 2.0 ml of water, 1.0 ml of 47% hydrobromic acid was added, and stirred under reflux with heat for 1 hour. Then, the reaction mixture was cooled with ice, and a solution of 0.10 g of sodium nitrite in 1.0 ml of water was slowly added dropwise with stirring at a temperature of 5° C. or less, after the completion of the addition dropwise, continued to stir at the same temperature for further 1 hour. The diazo mixture was slowly added dropwise in a mixture of 1.0 ml of 47% hydrobromic acid and 0.28 g of copper (I) bromide at 60° C. with stirring, after the completion of the addition dropwise, continued to stir at 60° C. for further 2 hours. After the completion of the reaction, 10 ml of water was added in the reaction mixture, extracted with ethyl acetate (20 ml×2), the organic phases together were washed with water, then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:10) to obtain 0.43 g of the aimed product as pale yellow crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1
Reactant: CC(C)(N)CO
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: O
Product: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of 2,4-dichloronitrobenzene (VII, 20.0 g) and 2-amino-2-methyl-1-propanol (VIII, 80 ml) is stirred at 110° for 68 hr. After cooling to 20°-25°, adding water, extracting with methylene chloride, separating the phases and drying the organic phase over magnesium sulfate) gives the desired product sufficiently pure (>90%) to be carried on without further purification. An analytical sample is prepared by recrystallization from ethyl acetate/hexane to give the title compound, mp 102°-104°; IR (mineral oil) 3335, 2954, 2925, 1610, 1577, 1492, 1467, 1331, 1251, 1154 and 748 cm-1 ; NMR (CDCl3) 8.55, 8.13, 7.09, 6.59, 3.71, 2.11 and 1.48 δ; MS (m/z) 244, 213 and 166.