Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[S:12][C:11]=2[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O.C(OCC)(=O)C>[CH2:34]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]3=[O:25])[S:12][C:11]=2[CH:27]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To an N,N-dimethylformamide (3 mL) solution of 2-(6-hydroxy-benzo[b]thiophen-2-ylmethyl)-isoindole-1,3-dione (121 mg, 0.391 mmol) were added potassium carbonate (162 mg, 1.17 mmol) and benzyl bromide (70 μL, 0.587 mmol). The mixture was stirred at 100° C. for 30 minutes. The reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with water followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 4:1 and then 1:1) to obtain the title compound (144 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[C:5]([F:10])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:3]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:25](=[O:26])[C@H:24]([CH2:23][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[C:5]([F:10])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CN1CCN(c2nc(Cl)nc(NN)c2F)CC1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Yield: 46.1 %

Procedure:
A mixture of 2-chloro-5-fluoro-4-hydrazino-6-(4-methyl-1-piperazinyl)pyrimidine (31 mg, 0.12 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (36 mg, 0.12 mmol), HOAt (20 mg, 0.144 mmol), EDC (28 mg, 0.144 mmol) and NMM (26 uL, 0.144 mmol) in DMF (2 mL) was stirred until the reaction was complete (2 h). The reaction mixture was then purified via RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (30 mg, 46%). LCMS: (M+H)+: 542.3; (M+Na)+: 564.3.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.BrBr>C(Cl)(Cl)(Cl)Cl>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:2][CH:7]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: C1=C(c2ccccn2)c2ccccc2OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 10 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 0.12 ml of bromine were added. The mixture was stirred at room temperature for 1 hour, then at 35° C. for 1 hour and finally at 65° C. for 1 hour. After cooling the mixture was washed with sodium bicarbonate solution, the aqueous washings were extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 230 mg of 6-bromo-3,4-dihydro-2,2-dimethyl)-4-(2-pyridyl)-2H-1-benzopyran of melting point 134-136° C.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2cnccc12
Product: Brc1cccc(Nc2ncnc3cnccc23)c1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (75 mg, 0.42 mmol) (see previous experimental), and 3-bromoaniline (1 mL) is heated to 100° C. under N2 for 2 h. The reaction mixture is then chromatographed on silica using MPLC and eluting with a gradient system (CHCl3 to 5% MeOH in CHCl3) The fractions are concentrated under reduced pressure, and the resulting solid is recrystallized from Et2O to yield 4-(3-bromoanilino)pyrido[3,4-d]pyrimidine (66 mg, 52.7%) as a light brown solid. 1H NMR (DMSO) δ 10.15 (1H, s), 9.21 (1H, s), 8.80 (1H, s), 8.76 (1H, d, J=5.8 Hz), 8.44 (1H, d, J=5.6 Hz), 8.25 (1H, s), 7.93 (1H, d, J=7.7 Hz), 7.45-7.37 (2H, m).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1.CN(C=O)C>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 124.3 %

Procedure:
To a 2 L 3-neck round bottom flask outfitted with an addition funnel and thermometer were added anhydrous THF (700 mL) and NaH (60 wt %, 3.90 g, 97.5 mmol). The suspension was cooled in an isopropanol/dry ice bath until the internal temperature was about −20° C. (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (20.0 g, 92.9 mmol) dissolved in anhydrous THF (300 mL) was added dropwise via the addition funnel maintaining the internal temperature between −20° C. to −15° C. Once the addition was complete, the reaction was stirred for 45 minutes at a temperature between 0° C. to 10° C. The reaction was then cooled to −70° C. and a solution of 2,6-dinitrobenzonitrile (19.9 g, 103 mmol) in anhydrous DMF (200 mL) was added dropwise via the addition funnel. The reaction was allowed to warm up gradually to room temperature overnight and THF was removed under reduced pressure. The remaining solution was cooled in an ice bath and treated with a cooled saturated NH4Cl solution (200 mL). The resulting mixture was diluted with EtOAc and successively washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude (S)-tert-butyl 3-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (41.74 g) as an orange solid. MS 262 (MH+-Boc). This material was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][NH:14][C:15]([NH:17][CH2:18][C:19]#[CH:20])=[O:16].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:12][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:20]#[C:19][CH2:18][NH:17][C:15]([NH:14][CH3:13])=[O:16])=[CH:10][C:2]=1[Cl:1]
Reactant: C#CCNC(=O)NC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CNC(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (500 mg, 1.68 mmol) and N-methyl-N′-prop-2-yn-1-ylurea (226 mg, 2.02 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (118 mg, 10 mol %) followed by copper(I) iodide (32 mg, 10 mol %) and diisopropylamine (339 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred 3 hr. then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N′-methylurea (177 mg, 37%) as an colourless solid; NMR Spectrum:(DMSOd6) 2.55 (d, 3), 4.00 (d, 2H), 5.52 (s, 2H), 5.84 (q, 1H), 6.05 (s, 2H), 6.27 (t, 1H), 6.78 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[N:8]/[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:19][CH:18]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of diphenylmethanamine (3.00 g, 16.4 mmol) in methanol (80 mL) was added 4-methoxybenzaldehyde (2.45 g, 18.0 mmol) and sodium carbonate (2.60 g, 24.6 mmol). The reaction mixture was stirred at room temperature for 16 h prior to removal of all solvents under vacuum. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 39 as a white solid (3.62 g, 73%). LRMS (ESI): (calc.) 301.4 (found) 302.4 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[S:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[S:15][C:14]([C:12]2[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:28]4[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1
Product: Nc1ncc(-c2cccc(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example B.3) (0.31 g, 0.74 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.81 mmol) according to the general procedure III. Obtained as a light yellow solid (0.075 g, 23%). MS (ISP) 434.2 [(M+H)+]; mp 228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[C:16]([C:17](O)=[O:18])[N:12]3[C@:11]([CH3:32])([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[C:10]2=[O:33])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[C:49]([O:53][C:54](=[O:57])[CH2:55][NH2:56])([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl.CN(C=O)C>[C:49]([O:53][C:54](=[O:57])[CH2:55][NH:56][C:17]([C:16]1[N:12]2[C@:11]([CH3:32])([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=3)[C:10](=[O:33])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]2=[N:14][CH:15]=1)=[O:18])([CH3:52])([CH3:51])[CH3:50]
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)O)n21
Reactant: CC(C)(C)OC(=O)CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1cnc2n1[C@](C)(Cc1ccc(OC(F)(F)F)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
To a solution of (R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.500 g, 1.0 mmol) in CH2Cl2 (15 mL) was added oxalyl chloride (0.194 mL, 2.2 mmol), followed by slow addition of DMF (0.05 mL). The reaction was stirred for 90 min. The volatiles were removed in vacuo, and the residue dissolved in THF (15 mL). To this cloudy solution was added diisopropylethylamine (0.88 mL, 5.0 mmol) followed by glycine tert-butyl ester (0.30 mL, 2.2 mmol). The reaction was stirred for another 14 h. The volatiles were removed in vacuo at 40° C. The reaction mixture was diluted with ethyl acetate and washed with 1 N aqueous HCl (×2), 10% aqueous Na2CO3 (×2) and brine (×2). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford {[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-acetic acid tert-butyl ester (0.483 g) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@@H:20](O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:20]([C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[F:12])[CH3:21])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Br)cc1O
Reactant: C[C@H](O)c1cc(F)ccc1F
Product: C[C@@H](Oc1cc(Br)cnc1[N+](=O)[O-])c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
The title compound was prepared by a similar method to that of preparation 18 using commercially available 5-bromo-3-hydroxy-2-nitro-pyridine and (S)-1-(2,5-difluoro-phenyl)-ethanol except the reaction time was 1 hr and crude reaction purified by chromatography on silica gel eluting with ethyl acetate in heptane (50:50) to give a yellow oil (21.0 g, 93%).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](/[CH:19]=[CH:20]\[CH3:21])=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=O)(C)(C)C.[ClH:29]>CCOCC.O>[ClH:29].[CH:19](/[C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:26])[N:11]3[CH2:27][CH2:28][NH:8][CH2:9][C@H:10]32)=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)=[CH:20]/[CH3:21]
Reactant: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (40 mg, 0.1 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 24 mg of a white solid. MS (ESI) 297 (M−Cl).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=1>CN(C)C=O>[OH:15][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:8][CH:9]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(O)cc1
Reaction time: 2 h

Procedure:
In a reactor, 50 ml of dimethylformamide and 21.6 g (0.22 moles) of maleic anhydride were placed, to which were gradually added 21.8 g (0.20 moles) of p-aminophenol at 20° C. with thorough stirring. After completion of the addition, the reaction was allowed to proceed at 20° C. for 2 hours to yield N-(p-hydroxyphenyl)maleamic acid. To the reaction mixture, a previously formed solution containing 70 ml of dimethylformamide, 11.4 g (0.0803 moles) of phosphorus pentoxide and 5 g (0.049 moles) of sulfuric acid, was added dropwise with the use of a dropping funnel. Thereafter, the reaction was continued at 70° C. for 2 hours. After cooling to room temperature, the resulting reaction mixture was poured into 400 ml of ice water to precipitate N-(p-hydroxyphenyl)maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 31.3 g (0.165 moles) of N-(p-hydroxyphenyl)maleimide (yield 82.5%).
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[SH:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].[CH3:25]N1CCN(C)C1=O>C(OCC)(=O)C>[CH3:25][S:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12]
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Reactant: Nc1ccccc1S
Reactant: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: CSc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 46.4 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 27.8 g of 2-mercaptoaniline and 120 ml of 1.3-dimethyl-2-imidazolidinone under ice-cooling conditions, followed by agitation for 20 minutes. About 200 ml of ethyl acetate was added to the reaction mixture, and the resultant crystals were collected by filtration, washed with hexane and dried to give 61 g of 1-(2-methylmercaptophenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1>C(O)C>[F:18][CH:2]([F:1])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:7]([NH:11][CH3:10])=[N:6][C:5]#[N:4])[N:11]=1
Reactant: NCCSCc1csc(NC(N)=NCC(F)F)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1csc(NC(N)=NCC(F)F)n1
Reaction time: 16 h
Yield: 115.1 %

Procedure:
Dimethyl (cyanoimido)dithiocarbonate (0.07 g.) and 2-[2-(2,2-difluoroethyl)guanidino]-4-[(2-aminoethyl)-thiomethyl]thiazole (0.15 g.) were dissolved in ethanol (3 ml.) and heated under reflux for 20 minutes. The solvent was evaporated and the residual gum was dissolved in ethanolic methylamine (33% w/v, 3 ml.) and allowed to stand at room temperature for 16 hours. The solvent was evaporated and the residual gum purified by preparative thin layer chromatography using ethyl acetate/methanol/ammonia 6:1:1 v/v/v as developing solvent. The appropriate zone of the chromatogram was isolated and extracted with methanol/ammonia 10:1 v/v. The solvent was evaporated and the residue was dissolved in ethyl acetate, filtered and added to a solution of maleic acid (0.1 g.) in ethyl acetate. The precipitate was filtered to give 2-[2-(2,2-difluoroethyl)guanidino]4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (0.11 g.), m.p. 108°-112° (decomp.) containing 1.25 molar equivalents of maleic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[ClH:20].[H][H]>O.[Pd]>[NH2:1][CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH3:19])[NH:11][C:10](=[O:16])[CH:9]([CH3:17])[CH2:8]3.[ClH:20]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(CN)O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C(C)C3)OC(CN)C2C
Yield: 59.3 %

Procedure:
The trans compound obtained in Example 297 (380 mg, 1.29 mmol) was dissolved in water (30 ml). To the solution, 10% palladium-on-carbon (400 mg) was added. The mixture was stirred at 80° C. for 2 days in the stream of hydrogen. After removing the catalyst by filtration, the filtrate was distilled off under reduced pressure, and the residue was subjected to recrystallization from methanol-ether to obtain 227 mg of the title compound in a trans form as colorless crystals (59%). By a similar procedure using the cis compound obtained in Example 297 (165 mg, 0.56 mmol), 85 mg of the title compound in a cis form was obtained as colorless crystals (51%).
Reaction SMILES: Cl[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C[Si]([O:29][Si](C)(C)C)(C)C.[K].[Si](O[K])(C)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:3]2[C:2](=[O:29])[NH:7][N:6]3[C:8](=[O:11])[NH:9][N:10]=[C:5]3[C:4]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: C[Si](C)(C)O[K]
Agent: [K]
Solvent: C1CCOC1
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 22 %

Procedure:
To the solution of 6-chloro-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (28 mg, 0.078 mmol), prepared as described in Example 8B, in THF (3 ml) was added potassium trimethylsilyloxide, TMSOK, (36 mg, 0.28 mmol). The reaction mixture was refluxed for 1 hour. After this time, the solution was cooled to RT. The solution was concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (8 mg, 22%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=4[F:1])=[O:6])[CH2:26][CH2:27]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Yield: 95.8 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (399 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (381 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 160, the title compound (668.5 mg) was obtained.
Reaction SMILES: CC([C:5]1[C:25](=[O:26])[C:24](C(C)(C)C)=[CH:23][C:7](=[C:8]2[CH:14]=[C:13](C(C)(C)C)[C:11](=[O:12])[C:10](C(C)(C)C)=[CH:9]2)[CH:6]=1)(C)C.FC(F)(F)S(O)(=O)=O>C(C1C=CC=CC=1)C>[C:11]1([OH:12])[CH:10]=[CH:9][C:8]([C:7]2[CH:23]=[CH:24][C:25]([OH:26])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)C1=CC(=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)C=C(C(C)(C)C)C1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCc1ccccc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 0.75 h
Yield: 87.7 %

Procedure:
10 g (24.5 mmole) of 3,3',5,5'-tetra-tert-butyl-diphenoquinone in 40 ml ethylbenzene was hydrogenated as in Example 9. The filtrate was transferred to a popbottle containing 1.5 g (10 mmol) trifluoromethane sulfonic acid and a magnetic stirring bar. The reaction mixture was kept at 120° C. for 45 minutes. 4 g of 4,4'-biphenol was obtained as white material after recrystallization from acetone (88% yield). The filtrate contained 13.8 g (85.2 mmol) of p- and m-tert-butyl-ethyl-benzene (86.9% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([O:20][CH3:21])[C:14]=1[N+:22]([O-:24])=[O:23].CCN(CC)CC>C(Cl)Cl>[CH:12]([C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([O:20][CH3:21])[C:14]=1[N+:22]([O-:24])=[O:23])=[O:11]
Reactant: COc1nc(C)cc(CO)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc(C)cc(C=O)c1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a −70° C. solution of oxalyl chloride (2.0 mL, 22 =mol) in 50 mL of DCM was added 3.4 mL (44 mmol) of DMSO in 10 mL of DCM by dropping funnel. After 2 min, the reaction mixture was treated with 3.99 g (20 mmol) of the alcohol from step C in 20 mL of DCM. The solution was stirred for an additional 15 min at −70° C., treated with 14 mL (50 mmol) of Et3N and warned to ambient temperature over 90 min. The reaction was quenched with 100 mL of water and the two phases were separated. The aqueous phase was extracted with 100 mL of DCM and the combined organic extracts were washed with 50 mL of brine and dried over MgSO4. The yellow solution was concentrated and chromatographed (2:3 EtOAc/Hexane) to afford the aldehyde as a yellow solid.