Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C(OCCC2COC(C)(C)O2)=NC=NC=1)=O.[NH2:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48]([NH:50][C:51]1[C:52]([O:57][CH2:58][CH:59]2[CH2:63][O:62]C(C)(C)[O:60]2)=[N:53][CH:54]=[N:55][CH:56]=1)=[O:49]>>[NH2:34][C:35]1[S:39][C:38]([C:40]2[C:41]([F:47])=[CH:42][CH:43]=[CH:44][C:45]=2[F:46])=[N:37][C:36]=1[C:48]([NH:50][C:51]1[C:52]([O:57][CH2:58][CH:59]([OH:60])[CH2:63][OH:62])=[N:53][CH:54]=[N:55][CH:56]=1)=[O:49]
Reactant: CC1(C)OCC(COc2ncncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)O1
Agent: CC1(C)OCC(CCOc2ncncc2NC(=O)c2nc(-c3c(F)cccc3F)sc2N)O1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cncnc1OCC(O)CO
Yield: 49.3 %

Procedure:
Following the procedure described in Example 48, and substituting Compound 38 in Step (1) with 5-amino-2-(2,6-difluorophenyl)-N-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrimidin-5-yl)thiazole-4-carboxamide (36) (20 mg, 0.0432 mmol), the title compound 51 (9 mg, 0.0213 mmol) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[CH:6]=1)=[O:4].CO.Cl>[Pd].O>[CH3:17][O:16][C:14]([C:7]1[CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)=[O:15]
Reactant: COC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reaction time: 2 h
Yield: 92 %

Procedure:
5-Nitro-1,3-benzenedicarboxylic acid dimethyl ester (95.7 g, 0.4 mol) and 5% Pd/C (8 g) are loaded into a 2 L hydrogenation vessel equipped with a thermometer and a mechanical stirrer, that contains methanol (0.8 L) and 2M HCl (0.3 L; 0.6 mol). The obtained suspension is maintained under mechanical stirring and purged with nitrogen washings, at the end of which the hydrogenation reaction is carried out at a temperature comprised between 45 and 55° C. The reaction is complete in 2 hours. A nitrogen flow is then passed through the reaction vessel to wash out any hydrogen gas, the catalyst is filtered off and the obtained solution is evaporated under vacuum to yield a solid residue. The obtained product is loaded into a 5 L vessel, equipped with a mechanical stirrer, and containing deionized water (3 L) and 34% HCl (0.1 L). The obtained suspension is filtered from the insoluble residue and 2M NaOH is added to the filtrate up to pH 10. The solid product that crystallizes out is recovered by filtration, washed with deionized water and dried under vacuum in the presence of P2O5 yielding the compound of the title (77.0 g; 0.368 mol, yield: 92%).
Reaction SMILES: S[C:2]1[NH:3][CH:4]=[C:5]([C@@H:7]([OH:14])[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][OH:11])[N:6]=1.OO.C(=O)([O-])[O-].[Ba+2].S([O-])([O-])=O.[Na+].[Na+]>O>[NH:3]1[CH:4]=[C:5]([C@@H:7]([OH:14])[C@H:8]([OH:13])[C@H:9]([OH:12])[CH2:10][OH:11])[N:6]=[CH:2]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)c1c[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)c1c[nH]cn1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
Under nitrogen stream, to (1R,2S,3R)-1-(2-sulfanyl-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (10 g, 45.4 mmol) was added water (40 mL), and to the obtained suspension was added dropwise an aqueous diluted solution of 30% aqueous hydrogen peroxide (15.4 g, 136 mmol, 3.0 equivalents) in water (40 mL) over 10 min at 17 to 43° C. (the compound was gradually dissolved to give an uniform pale-yellow solution). The reaction mixture was stirred at 24 to 36° C. for 4 hr, and barium carbonate (27 g, 136 mmol, 3.0 equivalents) was added over 5 min at 24 to 26° C. (neutralized to pH 7), and the mixture was stirred at 25 to 26° C. for 1 hr and 20 min. The insoluble material was filtered off, and washed with water (40 mL). To the filtrate and washing was added sodium sulfite (11.4 g, 90.8 mmol, 2.0 equivalents) over 5 min at 20 to 32° C. The obtained aqueous solution was stirred at 26 to 32° C. for 1 hr and 30 min to give an aqueous solution of (1R,2S,3R)-1-(1H-imidazol-4-yl)butane-1,2,3,4-tetraol. To this aqueous solution was added sodium periodate (29.1 g, 136 mmol, 3.0 equivalents) over 10 min at 12 to 30° C., and the mixture was stirred at 27 to 30° C. for 1 hr and 30 min. To the reaction mixture was added sodium periodate (2.91 g, 13.6 mmol, 0.3 equivalents) at 27 to 30° C., and the mixture was stirred at 27 to 30° C. for 2 hr. The insoluble material was filtered off, and washed four times with water (10 mL). To the filtrate and washing was added methanol (500 mL), and the inorganic salt was filtered off, and washed twice with methanol (50 mL). To the filtrate and washing was added activated carbon (3 g, SHIRASAGI A, trade name), and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off, and washed with methanol. The filtrate and washing were concentrated under reduced pressure to give a crude compound (9.37 g). To the crude compound were added water (3 mL) and seed crystals for crystallization, and the mixture was stirred at room temperature for 24 hr, and then for 2 hr under ice-cooling. The crystals were collected by filtration, washed with cooled water (1 mL), and vacuum-dried (50° C.) to a constant amount to give 4(5)-formylimidazole (2.35 g). yield 54%.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[C:11]1([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1NN=C(C(=O)c1ccccc1)c1ccccc1
Yield: 101.8 %

Procedure:
A mixture of 2-methylphenyl hydrazine hydrochloride (0.79 g, 5.0 mmol) and 1,2-diphenyl-ethane-1,2-dione (1.05 g, 5 mmol) in 20 mL of glacial acetic acid was refluxed for 30 min. The reaction was poured into water and extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated to give 1.6 gram of 1,2-diphenylethane-1,2-dione (2-methylphenyl)-hydrazone as an orange solid. MS (ESI) m/z 315 ([M+H]+);
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]#[CH:36])[CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].C(N(CC)C(C)C)(C)C>COCCOCCOC.CC(OC)(C)C.Cl.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.[Cu]I>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:6]2[CH:7]=[C:2]([C:36]#[C:35][CH2:34][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])=[O:9])=[CH:11][CH:12]=1
Reactant: C#CCN1CCN(C)CC1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: COC(C)(C)C
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C#CCN2CCN(C)CC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1
Yield: 31.5 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone (0.5 g; 1.18 mmol), 1-methyl-4-prop-2-ynyl-piperazine (0.33 g; 2.37 mmol), PdCl2(PPh3)2 (0.158 g; 0.22 mmol), Cs2CO3 (1.0 g; 3.1 mmol) and CuI (50 mg; 0.26 mmol) are dissolved in diethylene glycol dimethyl ether (10 ml) and N,N-diisopropylethylamine (5 ml) and heated to 140° C. for 1 hour. The reaction mixture is diluted with TBME, filtered, evaporated and purified by chromatography (SiO2, EtOAc/MeOH/NH3conc 100/0/0>90/10/1) to yield the crude title compound as brown foam. The latter is dissolved in 2N HCl, washed with EtOAc, Na2CO3 added to the aqueous phase and extracted with EtOAc. The organic phase is filtered through Alox and evaporated to give the pure product as yellow foam (177 mg; 32%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]2>CC(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2[NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:30]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Temperature: 95 °C
Yield: 92.5 %

Procedure:
A mixture of 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.63 g, 4.74 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.16 g, 4.28 mmol) in IPA (80 mL) were heated at 95° C. for 5 h. The mixture was allowed to cool to RT, the yellow solid was collected via filtration and washed with Et2O to give the product tert-butyl 5-(6-acetoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.14 g, 3.96 mmol, 84%). HPLC retention time 9.649 min.
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.C([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCC(C)c2cc(-c3csc(C4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 150 mg (0.37 mmol) of 4-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidine hydrobromide and 109 μl (0.74 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N sodium hydroxide solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:47][C:48]1[O:52][N:51]=[C:50]([C:53](Cl)=[O:54])[CH:49]=1.CNC>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23]([N:24]5[CH2:25][CH2:26][N:27]([C:53]([C:50]6[CH:49]=[C:48]([CH3:47])[O:52][N:51]=6)=[O:54])[CH2:28][CH2:29]5)=[O:30])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:36][CH:37]=1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Reactant: Cc1cc(C(=O)Cl)no1
Agent: CNC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCN(C(=O)C(=O)NC34CCC(CC3)Cn3c4nc(C(=O)NCc4ccc(F)cc4)c(O)c3=O)CC2)no1
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
To a suspension N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.024 g, 0.038 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.027 mL, 0.153 mmol). After stirring for 5 min, 5-methylisoxazole-3-carbonyl chloride (0.011 g, 0.077 mmol) was added and the solution stirred at room temperature for 1 h. Dimethylamine (0.192 mL, 0.383 mmol) (2 M in methanol) was added and the solution stirred at room temperature for 1 h then concentrated. The residue was purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=10; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=XTERRA® 19×50 mm, C18, 5 μm (product elutes at 12.6 min) to give the title compound as a pale lavender solid (12.1 mg, 49% yield). 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, brs), 8.51 (1 H, d, J=5.80 Hz), 8.40 (1 H, d, J=5.19 Hz), 7.28-7.50 (2 H, m), 6.88-7.12 (2 H, m), 6.33 (1 H, d, J=2.14 Hz), 4.55 (2 H, t, J=6.26 Hz), 4.16 (2 H, brs), 4.02-4.14 (2 H, m), 3.89-4.00 (2 H, m), 3.80 (2 H, dt, J=18.08, 5.00 Hz), 3.50-3.68 (2 H, m), 2.53-2.77 (2 H, m), 2.48 (4 H, d, J=7.93 Hz), 1.87-2.15 (4 H, m), 1.72 (2 H, brs). LCMS (M+H) calcd for C30H33FN7O7: 622.24; found: 622.78.
Reaction SMILES: [CH2:1]([C:8]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[S:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:8]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[S:12][C:11](=[O:13])[N:10]([CH2:27][C:28]([OH:30])=[O:29])[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)O)C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Benzyl-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione (Example 6) (0.740 g, 1.96 mmol) in 34.5 mL of acetone was added t-butyl bromoacetate (4.227 g, 21.67 mmol) and potassium carbonate (2.75 g, 19.90 mmol) and the mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The mixture was filtered and concentrated in vacuo. Column chromatography provided the t-butyl ester of the title compound as a viscous yellow oil. This material was dissolved in 96 mL of dichloromethane and 17.8 mL of trifluroacetic acid was added and the mixture was stirred 2.5 h at room temperature under a nitrogen atmosphere. The mixture was concentrated in vacuo, triturated with hexane, and filtered. The solid was redissolved in dichloromethane and again concentrated in vacuo to give 0.720 g of the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>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].O1CCOCC1>[Br:23][C:21]1[N:22]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:9](=[O:15])[NH:10][CH2:11][CH2:12][N:13]3[CH3:14])=[CH:6][CH:7]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CN1CCNC(=O)C1c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 3-(4-aminophenyl)-4-methyl-piperazin-2-one 104c (590 mg, 2.88 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (770 mg, 2.88 mmol), cesium carbonate (2.06 g, 6.34 mmol) and 1,4-dioxane (20 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (166 mg, 0.288 mmol) and tris(dibenzylidene acetone)dipalladium(0) (47 mg, 0.144 mmol) were added and the reaction mixture was heated at reflux for 18 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (50 mL) and water (50 mL), and filtered, and the filter cake was washed with ethyl acetate (2×25 mL). The organic layer was separated, washed with brine (50 mL) and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography to afford 104d (850 mg, 60%) as an orange foam: MS (ESI+) m/z 492.1 (M+H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O[CH:5]=[C:6]1[CH2:14][CH2:13][C:12]2[N:11]([CH3:15])[N:10]=[CH:9][C:8]=2[C:7]1=O.[ClH:17]>CO.CCOCC.C(O)C>[ClH:17].[CH3:1][N:2]1[C:7]2[C:8]3[CH:9]=[N:10][N:11]([CH3:15])[C:12]=3[CH2:13][CH2:14][C:6]=2[CH:5]=[N:3]1
Reactant: Cn1ncc2c1CCC(=CO)C2=O
Reactant: CNN
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: Cn1ncc2c1CCc1cnn(C)c1-2
Temperature: 0 °C
Yield: 51 %

Procedure:
A solution of 3.2 ml of methylhydrazine in 30 ml of methanol was added dropwise to an ice-cold solution of 10.5 g of 1,5,6,7-tetrahydro-5-hydroxymethylene-1-methyl-4H-indazol-4-one in 200 ml of methanol. The reaction was heated at reflux for 3.5 hours and the solvent was then removed under reduced pressure. The residue was triturated with a mixture of ether and ethanol to give a crude tan solid. This solid was dissolved in a mixture of ether and ethanol and acidified with ethereal hydrogen chloride. The yellow precipitate which formed was separated by filtration and recrystallized from a mixture of ethanol and propanol to give 1,4,5,6-tetrahydro-1,6-dimethylbenzo[1,2-c:3,4-c']dipyrazole monohydrochloride as a yellow crystalline solid melting at about 222°-226° C. with decomposition (51% yield). This compound has the following structural formula: ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2cccc(Cl)c2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Yield: 36.1 %

Procedure:
A solution of the 9-[(3-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (480.5 mg, 1.31 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (325.7 mg, 1.43 mM) in 50 mL of toluene was stirred between 70-80° C. for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 172.6 mg (36%) of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow foam. 1H NMR (CDCl3) δ10.4 (s, 1H), 8.05 (d, 1H, J=8 Hz), 7.6 (d, 1H, J=8 Hz), 7.4 (m, 2H), 7.3-7.1 (m, 3H), 6.9-6.7 (m, 3H), 5.55 (s, 2H), and 4.15 (s, 3H). IR (CDCl3, cm−1) 3200 (br), 1684, 1598, 1442, 1428, 1331, 1285, and 1267. MS (ES) m/e 364, 366, 368.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][C:20](OCC)=[O:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[NH2:9][C:8]1[C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[NH:1][C:20](=[O:21])[C:19]=1[C:11]1[NH:10][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Cn1ncc(C#N)c1N
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N)c(-c3nc4ccccc4[nH]3)c(=O)[nH]c21
Reaction time: 18 h

Procedure:
5-Amino-1-methyl-1H-pyrazole-4-carbonitrile (1.0 eq) and ethyl 1H-benzimidazol-2-ylacetate (1.0 eq) were dissolved in THF and dried over sieves. LiHMDS (3 eq) was added dropwise and the mixture stirred for 18 hours. The mixture was filtered and diluted with EtOAc, then washed with an aqueous saturated NH4Cl solution. The aqueous layer was washed with EtOAc (3×), and the organic layers combined, dried over MgSO4, and concentrated yielding pure product. LC/MS m/z 281.0 (MH+), Rt 1.41 minutes.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1N1CCNCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1N1CCNCC1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
In 30 ml of methanol was dissolved 3.13 g (0.015 mole) of 1-(3-nitro-2-pyridyl)piperazine, and 2 g of 5% palladium carbon was added thereto. While stirring the mixture at room temperature, hydrogen gas was passed through for one hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 2.56 g of 1-(3-amino-2-pyridyl)piperazine as pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Br>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrCc1ccccc1Br
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCc2ccccc2Br)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromo-2-bromomethyl-benzene using the conditions described in Example 10C to provide 4-(2-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]3[S:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[N:19]=3)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(N(C(C)C)CC)(C)C>[CH3:14][C:13]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[N:10]=[C:11]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:19]=2)[N:12]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole (100 mg, 0.22 mmol) in diisopropylethylamine (10 mL) was added 1-methylpiperazine (2 mL, 2.2 mmol). The mixture was stirred at 80° C. for 16 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to give the title compound as an oil; MS (ES+) C24H24F3N7OS requires: 515. found: 516. [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=5.1 Hz, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.58 (s, 1H), 7.29 (d, J=8.1 Hz, 2H), 6.43 (d, J=5.2 Hz, 1H), 6.40 (s, 1H), 5.34 (s, 2H), 3.61-3.49 (m, 4H), 2.57-2.44 (m, 7H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:10][CH:12]1[CH2:13][O:14]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: ClCC1CO1
Product: Fc1ccc(OCC2CO2)cc1F

Procedure:
The title compound was prepared from 3,4-difluoro-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]1[C:10](C(O)=O)=[C:9]([F:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C2C(=CC=CC=2)C=CC=1>[Cu]>[F:1][C:2]1[CH:10]=[C:9]([F:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(C(=O)O)c1F
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C

Procedure:
A mixture of 2.20 g (0.01 mole) of 2,4,5-trifluoroisophthalic acid (dried under high vacuum). 1.0 ml of quinoline and 0.23 g of copper powder was heated on an oil bath at 200° C. After a while, the mixture liquefied and released a gas (ca. 280 ml by top purging). After the gas had been completely released, the liquefied mixture was cooled to room temperature, followed by addition of 15 ml of a mixture (1:1 by weight) of conc. HCl and water.