Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[C:7]([CH3:13])[C:6]=1[Cl:14].[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([N:30]=[C:31]=[O:32])=[O:29]>C1(C)C=CC=CC=1.CCCCCC>[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[C:28]([NH:30][C:31]([NH:9][C:8]1[CH:10]=[C:11]([CH3:12])[C:5]([O:4][C:3]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:18][C:2]=2[Cl:1])=[C:6]([Cl:14])[C:7]=1[CH3:13])=[O:32])=[O:29]
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C

Procedure:
To a solution containing 1.61 grams (0.004 moles) of 4-(2-chloro-4-phenylphenoxy)-2,5-dimethyl-3-chloroaniline prepared in Part B and 3 milliliters of toluene, which solution was warmed to 40° C.-50° C. and placed under an atmosphere of nitrogen, was added a solution containing 0.98 grams (0.005 moles) of 2-chlorobenzoyl isocyanate and 0.05 milliliters of toluene. The resulting mixture was then heated to a temperature of 60° C.-70° C, for a period of 0.5-1.0 hours. After cooling to ambient temperature, the reaction mixture was diluted with 4 milliliters of toluene and 2 milliliters of hexane. This mixture was then filtred to give a solid material. The solid material was washed once with a toluene-hexane mixture (1:2 volume ratio) and finally once with hexane and then dried overnight in a vaccum oven at 50° C. This afforded a tan powder material having a melting point of 198° C.-199° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].Cl.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(O)(=O)C.Cl>C(O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:10][C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:29]2)=[CH:24][CH:23]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccc(Br)cc2)c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (3.8 g, 13.3 mmol) prepared in Step 3 of Preparation 14, 4-bromophenylhydrazine hydrochloride (3.3 g, 13.5 mmol), acetic acid (15.0 mL) and conc. hydrochloric acid (20.0 mL) were added to ethanol (35.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 5.4 g of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[F:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)c(F)c(F)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to conc. H2SO4 (50 ml) at 0-5° C. Then the reaction mixture was slowly treated with conc. HNO3 (3.39 ml, 48.44 mmol, 90%) while maintaining the internal temperature below 20° C. The reaction mixture was stirred at room temperature for 16 h and poured onto ice (300 g) and the oily layer was extracted with CH2Cl2 (2×125 ml). The organic layer was washed with water (2×200 ml), brine (200 ml) and dried (MgSO4) and evaporated to obtain the crude product which was purified over flash silica gel chromatography to obtain the title product (6.5 g, 85%). 1H-NMR (300 MHz, CDCl3): δ 6.96 (septet, 1H), 2.39 (s, 3H). 19FNMR (CDCl3): δ −128.18, −141.50, −159.05.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[S:45](Cl)([CH3:48])(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:45]([CH3:48])(=[O:47])=[O:46])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in DCM (5 mL), Et3N (0.06 g, 0.596 mmol) and mesyl chloride (0.046 g, 0.403 mmol) were added at 0° C. and stirred it at room temperature for 2 h. After completion, reaction was quenched with ice-water. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound. LCMS: 582.30 (M+1)+; HPLC: 92.74% (@ 254 nm) (Rt; 5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.86 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.34 (s, 1H), 7.90 (s, 1H), 6.93 (s, 1H), 5.90 (s, 1H), 5.23-5.20 (m, 1H), 4.39 (d, 2H, J=4.4 Hz), 4.08 (bs, 2H), 3.80 (bs, 2H), 3.72 (d, 2H, J=11.60 Hz), 3.30 (bs, 2H), 3.15 (d, 2H, J=15.60 Hz), 2.93 (s, 3H), 2.84-2.76 (m, 2H), 2.27 (m, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 1.81-1.73 (m, 2H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([CH2:13][CH3:14])[C:3]=12.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:13]([C:12]1[C:3]2[C:4](=[C:5]([N:10]3[CH2:11][CH2:12][CH2:3][CH2:4][CH2:9]3)[N:6]=[N:7][C:2]=2[N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:9]=[N:10][C:11]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: C1CCNCC1
Reactant: CCc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12
Product: CCc1c(-c2ccccc2)ncc2c(N3CCCCC3)nnc(N3CCCCC3)c12

Procedure:
3.0 g. of 1,4-dichloro-8-ethyl-7-phenylpyrido[3,4-d]-pyridazine was heated together with 15 g. of piperidine at 120° C for 1.5 hours, after which time the excess piperidine was distilled off. To the residue was added 60 ml. of water and the resultant crystals were recovered by filtration and were chromatographed on a column packed with silica gel, followed by elution with a mixed solvent of acetone-benzene (1:8). The combined eluate is concentrated and the residue was dissolved in 100 ml. of ethanol. Following the addition of 5 ml. of water, the solution was concentrated to dryness. The concentrate was diluted with 100 ml. of water and stirred, whereupon 2.5 g. of 8-ethyl-7-phenyl-1,4-dipiperidinopyrido-[3,4-d]pyridazine was obtained. Melting point: 64°-65° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19](OCC)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[NH2:34][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:19]([C:3]1[C:4](=[O:18])[C:5]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])=[O:20])(=[O:32])=[O:33]
Reactant: CCCC1(CCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C(C(=O)Nc2ccccc2S(N)(=O)=O)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A suspension of the product of Example 1F (490 mg, 1.55 mmol) and 2-aminobenzenesulfonamide (Aldrich) (267 mg, 1.55 mmol) in toluene (25 mL) was stirred at reflux for 18 hours, cooled to 25° C. and concentrated in vacuo. The residue was recrystallized from ether-hexane solution to afford the title compound (410 mg, 60%). 1H NMR (300 MHz, CDCl3): δ 17.76 (d, J=12.13 Hz, 1 H), 12.67 (s, 1 H), 8.34 (m, 1 H), 8.09, (dd, J=8.09, 1.47 Hz, 1 H), 7.63 (m, 1 H), 7.38 (m, 3 H), 6.83 (m, 1 H), 5.57 (s, 2 H), 4.85 (s, 1 H), 2.32 (m, 2 H), 1.93 (m, 2 H), 0.97 (m, 2 H), 0.68 (m, 8 H).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C>C(#N)C>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: [O-][n+]1onc2ccccc21
Reactant: C1CCC2=NCCCN2CC1
Agent: N#CN
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a stirred mixture containing 1.000 kg (7.347 moles) of benzofuroxan and 2.237 kg (14.694 moles) of DBU was added a solution containing 618 g (14.694 moles) of cyanamide in 380 ml of acetonitrile while maintaining the temperature below 25° C. After stirring for 48 hours at 20-25° C. the reaction mixture was dilute with 6.620 liters of acetonitrile and cooled below 15° C. To the cooled mixture was added 882 g (14.694 moles) of acetic acid while maintaining the temperature below 15° C. After stirring overnight at 5-10° C. the precipitated product was collected by filtration and washed with acetonitrile (2×2 liters). The resulting solid was suspended in 2 liters of water, stirred about 30 minutes until a homogeneous suspension was obtained, and then filtered. The collected solid was resuspended in 2 liters of water, stirred for 20-30 minutes and filtered. The solid collected was dried to constant weight under vacuum at 50-55° C. to give 506.6 g of tirapazamine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1c(C(F)(F)F)ccnc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF(dry) (10 mL) was added MeI (0.317 ml). The mixture was stirred at room temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16].[OH-].[Na+]>Br.CO.O>[O:17]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]3=2)[CH2:12][CH2:13][C@@H:14]1[CH2:15][OH:16]
Reactant: OC[C@@H](O)CCc1ccc2ccccc2c1O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC[C@H]1CCc2ccc3ccccc3c2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 166.3 %

Procedure:
(2S)-4-(1-hydroxy-2-naphthyl)-1,2-butanediol (3.50 g, 15.1 mmol) is dissolved in hydrogen bromide (30 wt. % in acetic acid, 100 mL) and the reaction mixture is stirred at 0° C. for 2 h. The reaction mixture is quenched by the addition of water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts are washed with water (3×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude oil. The residue is dissolved in methanol (100 mL) and the resulting solution is slowly added to a solution of aqueous sodium hydroxide (2.5 M, 150 mL) in water (350 mL) and the reaction mixture is allowed to stir at 0° C. for 30 min. The reaction mixture is quenched by the addition of aqueous hydrogen chloride (1.0 M, 500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts are washed with water (2×200 mL), aqueous sodium chloride (300 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:1) provides 5.38 g (70%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol as a colorless oil. [α]D25=−51.23 (c 11.58 in chloroform, 50% ee); Rf=0.52 (silica, ethyl acetate:hexanes 1:1); Anal. Calcd. for C14H14O2.0.25H2O: C, 76.86; H, 6.68. Found: C, 76.47; H, 6.38.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>CCO>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]=[C:4]([CH3:11])[CH3:3])[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCC=C(C)C
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCC=C(C)C
Temperature: 25 °C
Yield: 43.9 %

Procedure:
Sodium hydride (0.465 g, 19.4 mmol) was added slowly to a NaCl ice bath containing EtOH (5.88 mL, 3.3 M) stirring under N2. 6-Methylhept-5-en-2-one (2.4412 g, 19.3 mmol) and diethyloxalate (2.63 mL, 19.4 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated, and purified by silica gel chromatography (Combiflash column, 70:30:3 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 1.9190 g (43.8%) of 49. 1H (CDCl3, 400 MHz): δ 14.44 (1H, broad s), 6.34 (1H, s), 5.06 (1H, t, J=7.3 Hz, 4.33 (2H, q, J=7.1 Hz), 2.49 (2H, t, J=7.3 Hz), 2.31 (2H, q, J=7.3 Hz), 1.66 (3H, s), 1.60 (3H, s), 1.35 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 202.83, 166.39, 162.08, 133.42, 121.90, 101.64, 62.40, 40.92, 25.59, 23.34, 17.61, 13.96 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 25.59, 17.62, 13.97; CH2 carbons: 62.40, 40.92, 23.34; CH carbons: 121.90, 101.64 ppm. HPLC: 11.007 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:34])[CH2:32][O:31][CH3:30])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: COCC(=O)Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)COC)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methoxyacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][C:4]=1[S:13][CH3:14].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:18])=[O:11])=[CH:5][C:4]=1[S:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CC(=O)O)cc1SC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Cl)cc1SC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxy-3-(methylthio)phenylacetic acid (10.2 g, 47.3 mmol) in THF (300 mL) was added oxalyl chloride (6.6 g, 52 mmol, 1.1 equivalent) followed by a catalytic amount of N,N-dimethylformamide (DMF) (~0.5 mL). The reaction mixture was stirred at ambient temperature for 3 h and then concentrated under reduced pressure to give the title compound as a yellow oil. The product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[C:6]=2[CH:17]=1.[Br-].[C:19](CCCC[Zn+])#N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:19])[CH2:13][CH2:14][C:15]#[N:16])[C:6]=2[CH:17]=1
Reactant: N#CCCCC[Zn+]
Reactant: N#CCCCc1cc(=O)oc2ccc(Cl)cc12
Agent: [Br-]
Product: CC(CCC#N)c1cc(=O)oc2ccc(Cl)cc12

Procedure:
Is prepared via the method used for 4-(6-Chloro-2-oxo-2H-1-benzopyran-4-yl)-butyronitrile except 4-cyanobutylzinc bromide is used instead of 3-cyanopropylzinc bromide.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>COC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 25.7 g of 9-bromophenanthrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 340 mL of dimethyl ether (DME) and 170 mL of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase which had been separated was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 25.0 g (yield: 89%) of 9-(2-formylphenyl)phenanthrene was obtained.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:7]CCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.C(=O)CC>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][C:23]2[C:24](=[O:26])[O:25][CH:1]([CH2:2][CH3:7])[C:27]=2[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCC=O
Solvent: C1CCOC1
Product: CCC1OC(=O)c2cnc(Cl)cc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (5 ml, 30 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50 C for 0.5 h. A solution of 6-chloro-nicotinic acid (1.58 g, 10 mmol) in THF (20 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 1.5 h and then cooled to −78° C. The reaction mixture is treated with propionaldehyde (4.2 ml, 58 mmol) dropwise at −50° C. The reaction is stirred at −78° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL) The aqueous solution is treated with aqueous 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. An oily residue separates from solution. Dichloromethane is added to the aqueous phase which dissolves the oily residue. Without extracting, the solution is poured into a separatory funnel and the organic phase is collected. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give the title compound (1.45 g, 73%) as a yellow oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[NH:11][C:12](=O)[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:6]([NH:9][C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[S:18][C:17](=[O:19])[N:16]([C@@H:20]3[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:37])[CH3:36])[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])[C:14]=2[N:15]=1)(=[O:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(Cl)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Phosphorus oxychloride (6.42 mL, 70.2 mmol) was added dropwise to a solution of 16 (3.40 g, 7.02 mmol), triethylamine (1.96 mL, 14.04 mmol), and chloroform (14 mL) over 30 minutes at room temperature under nitrogen. The reaction mixture was then heated to 70° C. for 30 h. The mixture was cooled to ambient temperature, added dropwise over 2 h to a 0° C. solution of saturated aq. NaHCO3 (500 mL), and stirred for an additional 1 h. The layers were separated, aqueous layer back extracted with methylene chloride (2×100 mL), combined organic layers were dried (MgSO4), filtered and concentrated to a yellow solid. Purification was achieved via flash chromatography (SiO2, 5% Acetone-CHCl3) to afford 81 (3.17 g, 90%) as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 11.08 (s, 1H), 6.09 (d, J=4.0 Hz, 1H), 5.99 (dd, J=6.0, 4.0 Hz, 1H), 5.76 (t, J=6.8 Hz, 1H), 4.41 (dd, J=11.2, 3.2 Hz, 1H), 4.32 (td, J=7.2, 3.2 Hz, 1H), 4.24 (dd, J=11.6, 6.8 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H); [M+H]+ 503.3.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9][CH2:10]Cl)=[O:8])=[CH:5][CH:4]=[C:3]([F:12])[CH:2]=1.[CH3:13][CH:14]1[NH:18][CH2:17][CH2:16][S:15]1.C([O-])(=O)C.[Na+]>C(O)C>[F:12][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:8])[CH2:9][CH2:10][N:18]2[CH2:17][CH2:16][S:15][CH:14]2[CH3:13])=[CH:1][CH:2]=1
Reactant: CC1NCCS1
Reactant: O=C(CCCl)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1SCCN1CCC(=O)c1ccc(F)cc1
Yield: 84.1 %

Procedure:
3.73 g (0.02 mol) of β-chloro-4-fluoropropiophenone are added in little portions at room temperature to a suspension containing 2.06 g (0.02 mol) of 2-methylthiazolidine and 1.64 g (0.02 mol) of anhydrous sodium acetate in 20 ml of ethanol over 30 minutes under stirring. After stirring for an additional 3 hours, the reaction mixture is evaporated, saturated sodium hydrogen carbonate solution is added to the oily yellow residue and it is extracted twice with 30 ml of ether each. After drying and evaporating the extract, the oily yellow residue is dissolved in acetone and acidified by 48% hydrobromic acid. Thus, 4.26 g of a white crystalline product are obtained and recrystallized twice from ethanol to give 2.00 g (29.9%) of hydrobromide of the title compound, m.p.: 151°-152° C.