Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35](F)[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]>CS(C)=O.O>[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCCO
Temperature: 90 °C

Procedure:
0.9 g of potassium carbonate and 3.3 ml of 3-amino-1-propanol are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 1 and a half hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (70/30 by volume), so as to give 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)-amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH2:25]=O>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:25][N:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:18])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=O
Reactant: O=C1COc2cc(O)ccc21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (3.00 g, 20.0 mmol) in ethanol (20 mL) was added with 1-tert-butoxycarbonylpiperazine (3.73 g, 20.0 mmol), and 37% aqueous formaldehyde (1.62 g, 20.0 mmol) at room temperature. The mixture was stirred overnight at room temperature, and then subjected to suction filtration, and the filtrate was concentrated. Crude product obtained by silica gel column chromatography (hexane/ethyl acetate) was recrystallized from ethyl acetate to obtain the objective tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (3.51 g, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH2:12]1N2CN3CN(C2)CN1C3.[OH2:22]>CS(O)(=O)=O>[CH:11]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7])=[O:22]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: CS(=O)(=O)O
Product: Cc1cc(C(=O)O)cc(C=O)c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
The 4-hydroxy-3-methylbenzoic acid (10.1 g, 66.38 mmole) was suspended in methanesulfonic acid (50 mL) and cooled to 0° C. (ice bath). Hexamethylenetetramine (18.6 g, 132.75 mmole) was added portionwise over 1 hour. The reaction was warmed to room temperature followed by heating to 90° C. (oil bath) for 5 hours. The reaction was allowed to cool to room temperature and stired for 18 hours. The contents were poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid (9.0 g, 75%). 1H NMR (DMSO/400 MHz) 12.84 (brs, 1H), 11.40 (s, 1H), 10.09 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1ccncc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.45 g (1.79 mmol) 4-bromomethyl-pyridine and 0.68 g (4.89 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[C:29](=O)[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]4=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[CH2:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:29]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Yield: 57 %

Procedure:
By using 2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 57%. Melting point: 113-114° C. (Hexane)
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].O>C(O)C>[CH:12]([C:11]1[C:3]([CH2:2][S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc2c(cc1CSCC(=O)O)OCO2
Yield: 58.8 %

Procedure:
A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) in 10 ml of ethanol was added to a liquid mixture comprising 2.1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanol and 25 ml of water to carry out the reaction at 80° C. for 40 minutes. The reaction mixture was concentrated, followed by the addition of water. The obtained mixture was washed with ethyl acetate. Concentrated hydrochloric acid was added to the mixture to acidify the aqueous layer, followed by the extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by column chromatography to obtain 2.45 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2].[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1.O>CC(N(C)C)=O>[C:12]([Si:16]([O:10][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[F:11])([CH3:19])[CH3:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(F)c(O)c1
Agent: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of 75.5 g 5-ethoxy-2-fluoro-phenol described in example 1.1 in 250 ml DMA were added 80.2 g t-butyl dimethylchlorsilane and 36.2 g imidazole at 0° C. The reaction mixture was warmed to r.t. After 4 hrs, 400 ml water were added. The mixture was extracted with hexane. The organic layer was washed with water, 10% Na2CO3 solution, water and brine, dried over MgSO4, filtrated and concentrated to give 127.0 g tert-butyl-(5-ethoxy-2-fluoro-phenoxy)-dimethyl-silane as light brown liquid which was used in the next step without further purification.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[CH:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[C:24]([CH:4]=[O:5])[CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: CC1=CCOc2cc(OCc3ccccc3)ccc21
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=C(C=O)COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DMF (1 mL) was added dropwise POCl3 (0.25 mL) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 7-(benzyloxy)-4-methyl 2H-chromene (280 mg) in DCM (1 mL), followed by stirring at room temperature for 3 hours. The reaction liquid was poured into ice-water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=85:15 to 70:30) to obtain 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (234 mg) as a pale yellow powder.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1>>[O:29]1[C:33]2([CH2:38][CH2:37][N:36]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:35][CH2:34]2)[O:32][CH2:31][CH2:30]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC7(CC6)OCCO7)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Yield: 72.34 %

Procedure:
2α,3α-Epoxy-17β-hydroxy-16β-(4-methyl-1-piperazinyl)-5α-androstane is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to give the title compound in a yield of 72.34%, m.p.: 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Br:16])=[CH:13][CH:12]=1)([OH:10])=[O:9]>CC(C)=O>[Br-:16].[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Clc1ccncc1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C[n+]2ccc(Cl)cc2)cc1
Product: [Br-]

Procedure:
The starting material was prepared by reaction of 4-chloropyridine with 4-carboxybenzyl bromide in acetone to give 4-chloro-1-(4-carboxybenzyl)pyridinium bromide. n.m.r. in d6DMSO:-5.9(s, 2H); 7.55(d, 2H); 7.9(d, 2H); 8.35(d, 2H); 9.2(d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:10]Br>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccccc1N
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1N
Reaction time: 1 h
Yield: 57 %

Procedure:
At room temperature, 3.4 ml (30 mmol, 1.25 eq) of 2-methoxyaniline is diluted in 10 ml of acetic acid. Over approximately 1 hour, 1.2 ml (24 mmol, 0.8 eq) of bromine dissolved in 10 ml of acetic acid is added dropwise. A purple precipitate is formed. When all the bromine has been added, the hydrobromide is filtered on a Buchner funnel and rinsed with acetic acid. Take up the solid in a H2O/CH2Cl2 mixture. A slight excess of KOH pellets is added, the aqueous phase is extracted with CH2Cl2 and the organic phase is dried on MgSO4. Concentration under reduced pressure gives a brown oil which is purified by column chromatography (eluent CH2Cl2). The expected product (3.46 g) is a colorless oil (yield: 57%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@@H:5]([NH:14]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)#[N:2].Cl>C(Cl)Cl.O1CCOCC1.CCOCC>[ClH:12].[NH2:14][C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)[CH2:4][CH2:3][C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CCC[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 12 h
Yield: 104.6 %

Procedure:
To a stirred solution of 368 (534 mg, 1.62 mmol) in DCM (5 mL) was added 4M HCl (811 μL, 3.24 mmol) in dioxane and stirring was continued for 12 h. The mixture was diluted with ether, filtered and dried to afford 225 mgs (52%) of (R)-4-amino-4-(3,4-dichlorophenyl)butanenitrile hydrochloride (370) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[O:17])[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([N:14]([CH2:15][CH:16]=[O:17])[C:9]([NH:8][C:6]1[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CCCNCC=O
Reactant: CSc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CCCN(CC=O)C(=O)Nc1nnc(SC)s1

Procedure:
A mixture of 5-methylthio-1,3,4-thiadiazol-2-yl-isocyanate dimer (0.05 mole), the dimethyl acetal of 2-propylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido] acetaldehyde.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C.Cl>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([B:27]([OH:28])[OH:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(CCOCc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(CCOCc2ccccc2)cc1
Reaction time: 3 h
Yield: 64 %

Procedure:
3.8 g (13.0 mmol) of 4-(2-benzyloxyethyl) phenylbromide and 30 ml of dry THF were cooled to -80° C., and 9.4 ml of n-butyllithium (1.65M) was dripped to it. Stirring at the foregoing temperature was performed for 3 hours, and then mixture solution of 5.68 g (30.2 mmol) of triisopropoxyboron and 15 ml of dry THF was dripped, and stirring at room temperature was performed for 13 hours. After the reactions had been completed, 15 ml of 10% hydrochloric acid was added, and extraction with ethyl acetate was performed. After the extracted solution was dried, the solvent was removed by filtration. Then, refining was performed with a silica gel column chromatography (developing solvent: toluene/ethyl acetate=20/1) so that 3.21 g of 4-(2-benzyloxyethyl) phenyl boronic acid was obtained (yield 64%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([CH3:23])[CH3:22]>>[CH3:23][C:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1)([CH3:20])[CH3:22]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Product: CC(C)(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-[(2-methylpropan-2-yl)oxy]benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-[(2-methylpropan-2-yl)oxy]phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)C=C.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21](O)([CH3:23])[CH3:22]>>[CH2:23]([C:10]1[C:9](=[O:11])[C:8]2[CH:13]=[CH:14][C:15]3[C:20]([C:7]=2[C:6](=[O:12])[C:5]=1[OH:4])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH2:22]
Reactant: C=Cc1ccccc1
Reactant: C=CCOC1=CC(=O)C=CC1=O
Reactant: CC(C)O
Product: C=CCC1=C(O)C(=O)c2c(ccc3ccccc23)C1=O
Temperature: 25 °C

Procedure:
2-Allyloxy-1,4-benzoquinone (10 g, 61 mM) and Styrene (19.8 g, 183 mM) were dissolved in 100 ml of isopropanol and refluxed for 48 hours. The reaction solution was cooled to room temperature, was concentrated by distillation under reduced pressure. 100 ml of toluene added to concentrated solution and toluene was dissolved, and refluxed for 12 hours, and was then purified by chromatography on silica gel to give to 3.4 g (12.9 mM) of 2-Allyl-3-hydroxy-1,4-phenanthrenequinone.
Reaction SMILES: Cl.[CH2:2]([C:9]1[O:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]=1[C:14]1[CH:38]=[CH:37][C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:36])[CH2:25][CH:26]3C(=O)OC(C)(C)[O:28][C:27]3=[O:35])=[CH:20][CH:19]=2)=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[CH2:2]([C:9]1[O:10][C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:36])[CH2:25][CH2:26][C:27]([OH:35])=[O:28])=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
2N Hydrochloric acid (1 mL) was added to a stirred solution of 5-{2-[4′-(2-benzyl-benzofuran-3-yl)-biphen-4-yl]-2-oxoethyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione (200 mg, 0.36 mmol) in THF (10 mL), and the resultant solution was heated at 70° C. for 6 hrs and then cooled to room temperature and concentrated in vacuo. The resulting solid was redissolved in DMSO (10 mL), and heated to 150° C. for 3 hrs before being cooled to room temperature, and diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water (2×10 mL), brine (3×10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by trituration and filtration from MeOH afforded the title compound as a white solid (105 mg, 62%). Rf: 0.20 (5% methanol in dichloromethane); 1H-NMR (CDCl3, 300 MHz): δ 8.10 (2H, d, J=8 Hz, Ar-H), 7.80 (5H, m, Ar-H), 7.62 (1H, d, J=8 Hz, Ar-H), 7.48 (1H, d, J=8 Hz, Ar-H), 7.29 (6H, m, Ar-H), 4.26 (2H, s, PhCH2), 3.86 (2H, t, J=6 Hz), 2.86 (2H, t, J=6 Hz); ESI-LCMS e/z calcd for C31H24O4: 460.527, found 461 (M+H)+.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[CH3:9].[C:16]([OH:22])(=O)[CH2:17][C:18]([OH:20])=O>C(O)(=O)C>[CH2:8]([N:10]1[C:16](=[O:22])[CH2:17][C:18](=[O:20])[N:13]([CH2:14][CH3:15])[C:11]1=[O:12])[CH3:9]
Reactant: O=C(O)CC(=O)O
Reactant: CCNC(=O)NCC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCN1C(=O)CC(=O)N(CC)C1=O
Temperature: 90 °C

Procedure:
Acetic anhydride (16 ml, 0.15 mole) was added dropwise over two hours to a solution of 1,3-diethylurea (5.3 g, 0.05 mole) and malonic acid (5.2 g, 0.05 mole) in acetic acid (40 ml) at 65° C. After the addition was complete, the temperature was raised to 90° C. and maintained there for three hours. The solvent was evaporated under reduced pressure and the residue boiled with ethanol for fifteen minutes. After some time, 1,3-diethyl-2,4,6-(1H,3H,5H)- pyrimidinetrione crystallized in cubic crystals, m.p. 52° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][N:7]=1.[OH-].[Na+].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH3:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[NH:2][C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:19]
Reactant: S=C=Nc1ccccc1
Reactant: Cn1ccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cn1ccnc1NC(=S)Nc1ccccc1

Procedure:
A 4.8 g (0.036 mole) sample of 2-amino-1-methylimidazole hydrochloride is suspended in 20 ml of methylene chloride and stirred with 10 ml of 50% NaOH. The organic layer is separated and the aqueous layer is extracted twice with 20 ml portions of fresh methylene chloride. The combined organic extracts are dried over K2CO3 and filtered. The filtrate is treated with 4.86 g (0.036 mole) of phenyl isothiocyanate. The solution is heated under reflux for 4 hr. Evaporation of the solvent in vacuo followed by recrystallization of the residue from acetone-ether (1:1) and MeOH-ether (1:1) gives the product, N-(1-methylimidazol-2-yl)-N'-phenylthiourea; m.p. 170°-172° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)O1>C1COCC1.C(OCC)(=O)C.O>[N:27]1([C:24]2[N:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (2.50 g, 9.96 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]morpholine (2.89 g, 9.96 mmol) were combined in THF (40 ml). Tetrakis(triphenylphoshine)palladium(0) (0.58 g, 0.50 mmol) was added and the reaction mixture was heated to reflux overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 ml) and water (500 ml). A red solid crashed out. The mixture was filtered and the solid was washed with ethyl acetate to yield the title compound as a red solid.