Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.CN(C)C(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=[C:2]([Br:1])[N:3]=3)=[CH:29][CH:30]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (12.5 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12) (13.1 mmol), potassium carbonate (25 mmol), acetonitrile (50 mL) and N,N-dimethylacetamide (20 mL) is heated at 65° C. for 16 hrs. The mixture is cooled to room temperature, treated water (100 mL), and extracted with ethyl acetate (3×80 mL). The extracts are washed with water (3×60 mL) and brine (1×60 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is chromatographed over silica gel, eluting with ethyl acetate, to give 4-[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (13) as a light brown foam.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].CO.O>CN1CCCC1=O>[OH:2][C:1]1[NH:24][C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[N:13]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(O)nc2c1
Temperature: 100 °C

Procedure:
The solution of 5.9 g of carbonyldiimidazole in 10 ml of N-methylpyrrolidone is added dropwise to the solution of 5 g of methyl 3,4-diaminobenzoate in 10 ml of N-methylpyrrolidone, and the mixture is heated to 100° C. for 2 hours. After cooling to 60° C., 5 ml of methanol were added dropwise and then the mixture was stirred at room temperature with 150 ml of water, and the precipitate was filtered off with suction, washed with isopropanol and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3Cl)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-chloro-phenylboronic acid (51 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [P:1]([O-:26])([O:22][CH2:23][CH2:24]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[S:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[P:1]([O-:26])([O:22][CH2:23][CH2:24][C:28]1[S:27][CH:31]=[CH:30][NH+:29]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Product: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCc1[nH+]ccs1
Temperature: 60 °C
Yield: 30.8 %

Procedure:
3,6-Dioxaoctadecyl 2-bromoethyl phosphate (2.5 g) and thiazole (5.0 g) are mixed and heated at 60° C. The excess thiazole is removed under reduced pressure, silver carbonate and methanol are added to the residue, and the mixture is heated under reflux. The insolubles are filtered off, the filtrate is concentrated to dryness, and the residue is purified twice by silica gel column chromatography (developing solvent: methanol; chloroform-methanol-water). There is obtained 0.78 g of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH2:14][CH:15]([CH3:49])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[OH:13][CH2:14][CH:15]([CH3:49])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.36 g), sodium hydrogen carbonate (2.18 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.64 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.20 g, 27%).
Reaction SMILES: F[C:2]1[C:15]2[C:14](=O)[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.[CH3:57][NH:58][NH2:59]>N1C=CC=CC=1>[CH3:57][N:58]1[C:2]2[CH:3]=[CH:4][C:5]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[C:6]3[C:7](=[O:17])[C:8]4[CH:9]=[CH:10][N:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:59]1
Reactant: CNN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3C)-c3cnccc3C(=O)c24)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 1:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy) benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione, of Preparative Example 10a, (0.041 g) is dissolved in dry pyridine (2 mL) and a freshly prepared 1M solution of N-methyhydrazine in pyridine (0.183 mL) is added. After stirring for three hours at room temperature the reaction mixture is concentrated to dryness and added with water (5 mL), with NaH2PO4 saturated solution (5 mL) and extracted several times with methylene chloride (50 mL). The combined organic solutions are dried ever anhydrous sodium sulfate and the solvent is removed at reduced pressure. The obtained residue is purified by silica-gel column chromatography (eluant: methylene chloride/ethyl acetate 90/10 v/v (50 mL), then 75/25 (50 mL), then 60/40 (50 mL) and finally 40/60 (50 mL) to give 2-methyl-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)[C:2]1C=CC=CC=1.C1C[O:51]CC1>CO.[C].[Pd]>[C:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=[CH:12]2)(=[O:51])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)C(O)(c1ccc2cc(OCc3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Reaction time: 5 h

Procedure:
1-(6-Benzyloxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (2.4 g) was dissolved in a mixed solution of THF and methanol (1:1, 160 ml). To the solution was added 10% palladium carbon (0.8 g). The mixture was stirred for 5 h under hydrogen atmosphere. The catalyst was filtered off, and filtrate was concentrated. The residue was crystallized from THF-ethyl acetate to give the titled compound (1.20 g) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C[Si](C)(C)N[Si](C)(C)C>O1CCOCC1>[N:16]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: O=C1CONC(=O)N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: O=C1N=C(N2CCNCC2)CON1
Yield: 42 %

Procedure:
A solution of 1.16 g (0.010 of 6H-1,2,4-oxadiazin-3,5-(2H,4H)-dione, 5 mg of ammonium sulfate, 2.49 g (0.029 mole) of piperazine and 20 ml of hexamethyldisilazane in 40 ml of dry freshly distilled dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield 0.78 g (42 percent) of 5-(1-piperazinyl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH3:21])[C:10]=1[C:11](O)=[O:12]>CN(C=O)C>[ClH:3].[Br:5][C:6]1[N:7]=[CH:8][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH3:21])[C:10]=1[C:11]([Cl:3])=[O:12]
Reactant: Cc1ccc(-n2cnc(Br)c2C(=O)O)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cnc(Br)c2C(=O)Cl)c(C)c1
Product: Cl
Temperature: 75 °C

Procedure:
To 8 mL of thionyl chloride was added 1.2 g (3.9 mmol) of 4-bromo-1-(2,4-dimethylphenyl)-1H-imidazole-5-carboxylic acid and 2 drops of DMF. The solution was heated to 75° C. for 4 h. The resulting slurry was cooled to room temperature and the white precipitate was collected by filtration. The precipitate was then slurried in ethyl acetate, collected by filtration and dried to give 0.81 g of the title compound as a white solid. The original filtrate was also concentrated and slurried in ethyl acetate to give an additional 0.21 g of the title compound. The overall yield of the title compound was 1.02 g (74%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[NH:9][N:8]=2)[CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:9]([C:30]([C:28]3[S:29][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[CH:26][CH:27]=3)=[O:31])[N:8]=2)[CH:2]=1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccn2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (1.01 g, 4.22 mmol) and 5-pyridin-2-ylthiophene-2-carboxylic acid (0.886 g, 4.32 mmol) in DCM (50 mL) was added EDCI (0.970 g, 5.10 mmol). The reaction mixture was allowed to stir at rt overnight. The solution was filtered and the resulting precipitate was washed with DCM to give a light tan solid. The filtrate was concentrated and the resulting residue was purified by column chromatography to give a yellow solid. The two batches of product were combined to give 2-{3-pyridin-3-yl-1-[(5-pyridin-2-yl-2-thienyl)carbonyl]4,5-dihydro-1H-pyrazol-5-yl}phenol (I-76) (1.293 g, 72%) as a tan solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.71-9.84 (bs, 1H), 9.11-9.16 (m, 1H), 8.72-8.77 (m, 1H), 8.60-8.65 (m, 1H), 8.35-8.42 (m, 1H), 8.06 (d, 1H), 8.01-8.04 (m, 1H), 7.84-7.94 (m, 2H), 7.66-7.73 (m, 1H), 7.34-7.41 (m, 1H), 7.04-7.12 (m, 1H), 6.93-6.99 (m, 1H), 6.82-6.87 (m, 1H), 6.73 (t, 1H), 5.87 (dd, 1H), 3.92 (dd, 1H), and 3.22 (dd, 1H). LCMS: (FA) ES+ 427.5, ES-425.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[C:38](O)=[O:39].CCN(CC)CC.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:35][C:38](=[O:39])[C:37]([CH3:36])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC(=O)C(C)(C)c2ccccc2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-aminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.405 mmol) and α,α-dimethylphenylacetic acid (101 mg, 0.608 mmol) in CH2Cl2 (3 mL) is subsequently added Et3N (0.085 mL, 0.608 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.608 mmol; commercially available from ABCR, AV24631) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide HCl (118 mg, 0.608 mmol). Stirring is continued overnight at room temperature, the mixture is then diluted with CH2Cl2, and the organic layer is subsequently washed with 2N HCl, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Purification by RP-HPLC on a PrepC18 OBD column (dimensions: 30×100 mm; 5 μM particle size, SunFire Ltd) and using a 95-5% gradient of MeCN/H2O 5:95 (containing 0.1% TFA) to MeCN/H2O 95:5 (containing 0.1% TFA) over 20 min gives the title compound as colorless oil. MS [M]+=640.2. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.2 min.
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:14]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1.[C-]#N.[Na+]>>[O:24]1[C:16]2[CH:15]=[CH:14][C:19]([C@@H:20]3[O:21][CH:13]=[N:12][C@@H:11]3[S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])=[CH:18][C:17]=2[O:22][CH2:23]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@H]2c2ccc3c(c2)OCO3)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.23 g, 1.20 mmol), piperonal (0.19 g, 1.26 mmol) and NaCN (5.9 mg, 0.12 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 346.5 (M+H+).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([C:21](=[O:23])[CH3:22])[C:12]=1[OH:24])(=O)C.[OH-].[Na+].C(OCC)(=O)C.C(Cl)(Cl)Cl.COC1C=CC(C=O)=CC=1>CO>[C:21]([C:13]1[C:12]([OH:24])=[C:11]([C@@H:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]2[OH:4])[C:16]([O:17][CH3:18])=[CH:15][C:14]=1[O:19][CH3:20])(=[O:23])[CH3:22]
Reactant: COc1cc(OC)c([C@@H]2CCCC[C@H]2OC(C)=O)c(O)c1C(C)=O
Agent: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(OC)c([C@@H]2CCCC[C@H]2O)c(O)c1C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a suspension of trans-2-(3-acetyl-4,6,-dimethoxy-2-hydroxyphenyl)cyclohexyl acetate (IV; 43 g; 0.128 mol) in methanol (460 ml) was added a solution of sodium hydroxide (20%; 154 ml) using the addition funnel and allowed to stir at room temperature for 15 min. The reaction mixture was then heated to 60° C. and the progress of the reaction monitored by TLC (tlc system 10% ethyl acetate-chloroform; anisaldehyde spray; pdt. Rf value 0.3). Complete consumption of the starting material was seen after stirring at 60° C. for 3 hours. The reaction mixture was then cooled in an ice bath and neutralized with 2N HCl. The precipitated solid was filtered and dried at high vacuum (dry solid 32 g). The filtrate was concentrated in-vacuo to remove methanol and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulphate. It was concentrated and chromatographed over silica gel (eluent 3% ethyl acetate-chloroform) to get 3 g of the title compound. In total, 35 g of the title compound was isolated (yield 93%; mp. 162-64° C.).
Reaction SMILES: C(SC[C:11]1[C:12](=[O:48])[C:13]([CH2:38][S:39][C:40](=O)C2C=CC=CC=2)=[C:14](CSC(=O)C2C=CC=CC=2)[C:15](=[O:27])[C:16]=1[CH2:17][S:18][C:19](=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+].O>C(O)CO>[CH:38]1[S:39][CH:40]=[C:14]2[C:15](=[O:27])[C:16]3[C:11]([C:12](=[O:48])[C:13]=12)=[CH:19][S:18][CH:17]=3
Reactant: O=C1C(CSC(=O)c2ccccc2)=C(CSC(=O)c2ccccc2)C(=O)C(CSC(=O)c2ccccc2)=C1CSC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C1c2cscc2C(=O)c2cscc21
Reaction time: 5 h
Yield: 72.9 %

Procedure:
48.5 g (68.5 millimoles) of 2,3,5,6-tetra-(benzoylthiomethyl)-p-benzoquinone were suspended in 450 ml of ethylene glycol, and 32.8 g (411 millimoles) of 50% strength sodium hydroxide solution were added, while stirring thoroughly. A strong jet of compressed air was then passed through the reaction mixture, and the latter was slowly heated up. At an internal temperature of 70° C., the dark mixture became homogeneous. The internal temperature was increased to 90°-100° C., and thorough stirring was continued at this temperature for 5 hours, while compressed air was continuously passed through. The mixture was cooled, 700 ml of water were added and stirring was continued for a further 0.5 hour, while cooling with ice. The solid material was filtered off under suction and washed with a large amount of water. 11.0 g (73%) of 4,8-dihydrobenzo[1,2-c:4,5-c']dithiophene-4,8-dione of melting point 340° C. were isolated.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:30])[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:23]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2ccc(OC)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(6-methoxy-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.14 mmol), β-alanine (726 mg, 8.2 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 53 mg of the title compound as a light yellow solid. MS: (+) m/z 551.39 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:10]([Al](CC)CC)[CH3:11]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([CH2:10][CH3:11])[C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: CC[Al](CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1nc(Cl)ccc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a solution of 3-amino-2,6-dichloropyridine (8.1 g, 50 mmol, purchased from TCI) in 1,4-dioxane (248 ml) was added tetrakis(triphenylphosphine)palladium(0) (920 mg, 0.80 mmol) and triethylaluminum (52 mmol, 0.94 M in hexane) at room temperature, and the mixture was stirred for 3 hours at 100° C. The mixture was quenched with 2 M HCl aqueous solution after cooling, and then it was separated between the aqueous and organic phases. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography, eluting with hexane/EtOAc (2:1), to give the title compound (2.73 g, 35%).