Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:25]=1[CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:25]=1[CH2:26][N:3]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)[CH2:1][CH3:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCNc1ccc(C(=O)OC)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of methyl 6-ethylaminonicotinoate (15.2 g, 84.4 mmol) in DMF (50 ml) was cooled to 0° C. and treated with sodium hydride (60%, 75 mmol). The reaction was stirred for 1 hour and a solution of 2-benzyloxy-5-bromobenzylbromide (25 g, 70.2 mmol) in DMF (50 ml) added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction was quenched with water and extracted with ethyl acetate (three times). The organic layers were combined, washed with water and brine twice, dried (MgSO4) and evaporated to give a white solid. Recrystallisation from ethyl/acetate/hexane gave methyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridine-5-carboxylate (22.7 g, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[C:19]2[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=2[N:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:12](=[O:31])[N:11]1[CH3:32])[C:5]#[N:6].[C:33]([O-:36])(=[O:35])C.[Na+].[C]=O.[CH3:40]O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:40][O:36][C:33](=[O:35])[C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:19]2[C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:14]=2[N:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:12](=[O:31])[N:11]1[CH3:32]
Reactant: CO
Reactant: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Br
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Product: COC(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C

Procedure:
3-Bromo-4-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile (INTERMEDIATE 23, 10.5 g, 20.8 mmol), 1.1-bis(diphenylphosphino)-ferrocen (1.15 g, 2.08 mmol), palladium acetate (233 mg, 1.04 mmol) and sodium acetate (5.12 g, 62.5 mmol) are suspended in methanol (180 mL) and treated with carbon monoxide at 5 bar and 100° C. for 40 h. The product begins to crystallize from the reaction mixture. Diisopropylether and dichloromethane are added and further crystals are collected. Further purification is performed by recrystallization from methanol and by flash chromatography on silica (dichloromethane/methanol 99:1). Yield: 1.7 g. ESI mass spectrum: [M+H]+=484; Retention time HPLC: 0.68 min (X012_S02).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C(#N)C>[C:13]([CH2:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[NH2:15]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NC(=O)CBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)COC(=O)c1ccc(O)cc1
Yield: 59.4 %

Procedure:
10 g of p-hydroxybenzoic acid and 10 g of α-bromoacetamide were dissolved in 150 ml of acetonitrile, and 7 g of triethylamine was added to the solution. The resulting mixture was refluxed for 7 hours followed by concentrating under reduced pressure. Water was then added to the residue to obtain 8.4 g of crystals of the above-titled compound having a melting point of 250°-255° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 235a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.59-1.83 (m, 2H) 2.02 (s, 3H) 2.75 (s, 3H) 3.97 (t, J=6.43 Hz, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.04-7.18 (m, 4H) 7.25-7.45 (m, J=8.64, 3.86 Hz, 3H) 7.77 (d, J=8.46 Hz, 1H) 8.35 (d, J=7.35 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H) 9.96 (s, 1H) 10.99 (s, 1H) 14.31 (s, 1H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[O:32][CH2:33][CH3:34])(=[O:3])[CH3:2].Cl[C:36]1[CH:45]=[C:44]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]2)[C:37]=1[C:46]([O:48][CH3:49])=[O:47].Cl>BrCCBr.C1COCC1.Cl[Si](C)(C)C.[Zn]>[CH2:33]([O:32][C:25]1[CH:26]=[CH:27][C:28]([CH2:30][C:36]2[CH:45]=[C:44]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]3)[C:37]=2[C:46]([O:48][CH3:49])=[O:47])=[CH:29][C:24]=1[C@H:6]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7]1)[CH3:34]
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
Reactant: CCOc1ccc(CBr)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)OC)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Two drops of 1,2-dibromoethane was added to a suspension of zinc powder (0.17 g) in THF (5.0 ml) in an argon atmosphere and the mixture was refluxed with heating for five minutes. After cooling to room temperature, two drops of chlorotrimethylsilane was added to the reaction mixture. The mixture was stirred for 15 minutes. Next, (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol (1.4 g) was added to the reaction mixture and the mixture was refluxed with heating for one hour. After cooling to room temperature, tetrakistriphenylphosphine palladium (0) (0.27 g) and methyl 2-chloroazulene-1-carboxylate (0.28 g) were added to the reaction mixture. The mixture was refluxed with heating for six hours. After cooling to room temperature, the reaction mixture was poured into 10% aqueous solution of hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.58 g).
Reaction SMILES: O=C[C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])O)O.C1([NH:18][N:19]=C[C@@H]([C@H]([C@H](C)O)O)O)C=CC=CC=1.[NH2:28][C:29]1[N:34]=[C:33]([NH2:35])[C:32]([NH2:36])=[C:31]([OH:37])[N:30]=1>>[NH2:18][NH2:19].[CH3:11][C@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[NH:36][C:32]2[C:31]([N:30]=[C:29]([NH2:28])[NH:34][C:33]=2[NH:35][CH2:3]1)=[O:37]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)C=NNc1ccccc1
Reactant: Nc1nc(N)c(N)c(O)n1
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Product: C[C@H](O)[C@H](O)[C@H]1CNc2[nH]c(N)nc(=O)c2N1
Product: NN

Procedure:
1',2'-diacyl-L-biopterin of the general formula (III) can be prepared by converting L-rhamnose to an acyl derivative of 5-deoxy-L-arabinose-phenylhydrazone through a 1,1-dialkylsulfonyl-L-rhamnose, reacting the obtained acyl derivative with 2,4,5-triamino-6-hydroxy-pyrimidine to obtain a hydrazine derivative of tetrahydro-L-biopterin and oxidizing the hydrazine derivative, without isolating the intermediate products in the course of reaction from the 1,1-dialkylsufonyl-L-rhamnose to the 1',2'-diacyl-L-biopterin.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>O1CCCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)[C@H](N)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of (S)-(−)-2-amino-3-methyl-1-butanol (2.50 g, 24.2 mmol) in tetrahydrofuran (35 mL) was slowly added 1,3-propane sultone (2.89 g, 23.0 mmol). The mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was suspended in 80% acetone/ethanol (75 mL). The suspension was stirred at reflux for 30 secondes. The solid product was collected by filtration, and dried in a vacuum oven (50° C.), to afford compound EP (2.9 g, 56%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (dd, 1H), 3.62 (dd, 1H), 3.13 (m, 2H), 2.90 (m, 1H), 2.88 (t, 3H), 1.90 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 64.74, 57.24, 48.20, 44.44, 26.98, 21.49, 18.53, 17.00. [OC]D=+4.1° (c=0.0017 in water), ES-MS 224 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:16][CH3:17])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4](F)[C:3]=1[F:20].[H-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=3)[C:14](=[O:15])[N:16]([CH3:17])[C:4]=2[C:3]=1[F:20]
Reactant: CNC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.5 %

Procedure:
To a solution of 4-(4-bromo-2,3-difluorophenyl)-N,2-dimethylnicotinamide (600 mg, 1.76 mmol) in tetrahydrofuran (20 mL) at 0° C. was added NaH (176 mg, 4.40 mmol) and the reaction mixture was brought to room temperature gradually. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford 8-bromo-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (400 mg, 1.24 mmol, 71% yield) as yellow solid. LC/MS (ESI) m/e 322.8 [(M+2H)+, calcd for C14H12BrFN2O 322.9]; LC/MS retention time (method G): tR=2.21 min.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[Cl:15][C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[OH:24]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[C:20]([S:22][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:19]=[C:18]([Cl:23])[C:17]=1[OH:24]
Reactant: C=CC(=O)N(C)CCc1ccccn1
Reactant: Oc1c(Cl)cc(S)cc1Cl
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(Cl)c(O)c(Cl)c1

Procedure:
The title compound was prepared according to the method of Example 4, from N-methyl-N-[2-(2-pyridinyl)-ethyl]-2-propenamide (2.5 g. 0.013 mole), 2,6 dichloro-4-mercaptophenol (2.56 g, 0.013 mole) and triethylamine (5 ml), m.p. about 120°-123° C. Analysis calc. for C17H18N2O2Cl2S (385.31): Calc.: C, 52.97; H, 4.71; N, 7.27; Cl, 18.40; S, 8.32. Found: C, 53.18; H, 4.89; N, 7 34; Cl, 18.59; S, 8 05.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[CH3:10][S-:11].[Na+]>O1CCCC1>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:11][CH3:10])[N:3]=1)#[N:9]
Reactant: N#Cc1cccc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cccc(C#N)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
A mixture of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol), sodium thiomethoxide (0.39 g, 5.5 mmol) and tetrahydrofuran (50 ml) was stirred at 90° C. for 18 hrs. The reaction mixture was concentrated under reduced pressure, combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give the titled compound as an oil (0.76 g, 98%).
Reaction SMILES: [O:1]=[C:2]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:5](O)=[O:6].O[C:26](C(F)(F)F)=O.[NH2:32][CH:33]([CH3:44])[CH:34]([C:36]1[O:37][C:38]([CH2:41][O:42][CH3:43])=[N:39][N:40]=1)[OH:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[OH:35][CH:34]([C:36]1[O:37][C:38]([CH2:41][O:42][CH3:43])=[N:39][N:40]=1)[CH:33]([NH:32][C:5](=[O:6])[CH:4]([CH2:8][S:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10])[CH2:3][C:2](=[O:1])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:44][CH3:26]
Reactant: O=C(O)C(CC(=O)N1CCCCC1)CS(=O)(=O)Cc1ccccc1
Reactant: COCc1nnc(C(O)C(C)N)o1
Reactant: O=C(O)C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(NC(=O)C(CC(=O)N1CCCCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nnc(COC)o1
Reaction time: 14 h
Yield: 37.3 %

Procedure:
To a stirred mixture of 4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyric acid (229 mg, 0.65 mmol), 2-amino-1-(5-methoxymethyl-1,3,4-oxadiazole-2-yl)-1-propanol TFA salt (204 mg), prepared as in reference 15, and HOBt (119 mg, 0.78 mmol) in MeCl2 (5 ml), was added EDC (187 mg, 0.98 mmol) and N-methylmorpholine (0.35 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 130 mg of N-{1-[hydroxy-(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-methyl]-propyl}-4-oxo-2-benzylsulfonylmethyl-4-piperidin-1-yl-butyramide; MS: 535.4(M−1), 537.7(M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH2:40])=[S:39])([CH3:29])[CH3:28].[C:41]([O-])(=[O:43])C.[Na+]>>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:31]=1[NH:37][C:38]([NH:40][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=1)=[O:43])=[S:39])([CH3:29])[CH3:28]
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(2-isopropyl-5-methylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.118 g, 35%): 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 10.05 (s, 1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.03-7.93 (m, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (dt, J=7.8, 1.4 Hz, 1H), 7.21 (dd, J=4.9, 3.0 Hz, 2H), 7.15-7.03 (m, 2H), 3.18 (q, J=6.5 Hz, 2H), 2.95 (hept, J=6.7 Hz, 1H), 2.73 (t, J=7.7 Hz, 2H), 2.25 (s, 3H), 1.90-1.76 (m, 2H), 1.13 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 597 ([M+H]+), 595 ([M−H]−).
Reaction SMILES: [O:1]1[CH:12]([C:13]([O:15]C2CCCCC2)=[O:14])[CH:2]1[C:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[OH-].[K+:23]>CN(C)C=O>[O:1]1[CH:12]([C:13]([OH:15])=[O:14])[CH:2]1[C:3]([OH:5])=[O:4].[CH:6]1([K:23])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(OC1CCCCC1)C1OC1C(=O)OC1CCCCC1
Reactant: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)C1OC1C(=O)O
Product: [K]C1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.0 g (0.0034 mole) of dicyclohexyl epoxysuccinate dissolved in 30 ml of dimethylformamide, 2 ml of aqueous 1 N potassium hydroxide solution was added dropwise while being stirred and cooled at 0° C. After 10 min., the mixture was filtered. Then, to the solution, 400 ml of acetone was added and the mixture was allowed to stand for a while. The resulting crystals were recrystallized from water-acetone to give cyclohexyl potassium epoxysuccinate (EP-2) as colorless needles. Yield 0.74 g (74%), m.p. 188°-190° C.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.[Li]CCCC.[CH:22]([O:25][C:26]1[CH:33]=[CH:32]C(C#N)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[CH:22]([O:25][C:26]1[CH:33]=[CH:32][C:16]([C:15]2[NH:3][C:4](=[O:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[CH:28][CH:27]=1)([CH3:24])[CH3:23]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CC(C)Oc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(=O)[nH]c(-c3ccc(OC(C)C)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a stirred solution of N,N-diethyl-4-methoxy-2-methylbenzamide (3.5 g, 15.82 mmol) in THF (35 ml) was added n-BuLi (2.82 ml, 4.52 mmol, in hexane) at −78° C. and stirred for 1 h. 4-isopropoxy benzonitrile (2.55 g, 15.82 mmol) was added at same temperature and allowed to warm to room temperature and continued the stirring for another 1 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (2*100 ml). The organic phase was washed with brine then dried on Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (3.5 g, 71.5%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.21(s, 1H), 8.09-8.07 (d, J=8 Hz, 1H), 7.71-7.69 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 1H), 7.03-7.01 (d, J=8 Hz, 3H), 6.76 (s, 1H), 4.71 (m, 1H), 3.88 (s, 3H), 1.30 (m, 6H); MS: MS m/z 310.7 (M++1).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]3=[N:17][NH:18][C:19](=[O:24])[C:20]4[CH:21]=[CH:22][CH:23]=[C:14]([C:15]=43)[NH:13][CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:14]3[NH:13][CH:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:11]([C:8]4[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=4)[C:16]([C:15]=23)=[N:17][NH:18]1
Reactant: CCOC(OCC)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A mixture of 9-(4-(diethoxymethyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7 H)-one (270 mg, 0.61 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature for 3 hr. The mixture was then adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (140 mg, yield: 69%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.CN(C)C=O.Cl>O.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>[C:28]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][C:12]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:30])[CH3:29]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-[4-(benzyloxy)-2-bromophenyl]prop-2-enoate (950 mg, 2.63 mmol, 1.00 equiv), tributyl(1-ethoxyethenyl)stannane (1.434 g, 3.97 mmol, 1.51 equiv), Pd(PPh3)2Cl2 (184.8 mg, 0.26 mmol, 0.1 equiv), N,N-dimethylformamide (15 mL). The resulting solution was stirred overnight at 90° C. in an oil bath. The mixture was cooled to 0° C. before 2N hydrogen chloride (10 mL) was carefully added dropwise. The resulting solution was stirred for an additional 1.0 h at 15° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The solution was then diluted with 10 mL of H2O. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The combined extracts were washed with 1×20 mL of water and 1×20 mL of aqueous saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 800 mg (89%) of ethyl (2E)-3-[2-acetyl-4-(benzyloxy)phenyl]prop-2-enoate as light yellow oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@@H:3]1[C:20]2[C@:15]([CH3:22])([CH:16]=[CH:17][C:18](=[O:21])[CH:19]=2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1.S(Cl)([Cl:29])(=O)=O>N1C=CC=CC=1>[Cl:29][C:19]1[C:18](=[O:21])[CH:17]=[CH:16][C@@:15]2([CH3:22])[C:20]=1[C@@H:3]([C:2]([F:24])([F:25])[F:1])[CH2:4][C@@H:5]1[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]1[CH2:7][CH2:8][C:9]2=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](C(F)(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C(Cl)=C1[C@@H](C(F)(F)F)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 6α-trifluoromethyl-androsta-1,4-diene-3,17-dione (3.524 g, 10 mmol) in pyridine (35 ml) was added dropwise sulfurylchloride (2.699 g, 20 mmol) at about +5° C. in 20 min. The reaction mixture was stirred further 1 h at +5° C. and then poured onto water. The precipitate was filtered off and the residue purified by trituration in ethylacetate and dichloromethane. Thus almost pure title compound was obtained in about 60% yield (2.32 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[N:19]1[N:20]=[C:21]([SH:28])[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12.BrC1C=CC2N(C(SC3C=CC4N(C=C(NC(C5CC5)=O)N=4)N=3)=NN=2)C=1>>[N:19]1[N:20]=[C:21]([S:28][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:10]=3)[N:7]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12
Reactant: Sc1nnc2ccccn12
Reactant: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Agent: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Product: CC(C)(C)OC(=O)Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1

Procedure:
The title compound was prepared from tert-butyl 6-iodoimidazo[1,2-b]pyridazin-2-ylcarbamate and [1,2,4]triazolo[4,3-a]pyridine-3-thiol following the procedure for the synthesis of compound 4.