Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:14]CCl.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:14])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C=Cc1ccc(Cl)cc1
Yield: 95 %

Procedure:
The synthesis method of Example 7-(1) was applied. 4-Chlorocinnamic acid (10.0 g), 1,2-dichloroethane (50 methanol (9.0 ml) and concentrated sulfuric acid (0.4 ml) were used as reagents to give 10.2 g of a white solid (yield 95%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]1([CH:15]=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O1CCCC1>[C:5]1([CH:15]([OH:16])[CH2:1][CH3:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCOC1
Product: CCC(O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a flame-dried flask containing 8.0 mL of dry tetrahydrofuran under an argon atmosphere cooled to -78° C. Is added 4.0 mL (3.0 M) of a solution of ethylmagnesium bromide in tetrahydrofuran. The stirrable mixture is treated with a solution of 1.36 g of commercially available 1-naphthaldehyde in 4.0 mL of tetrahydrofuran with a 2 mL rinse. The reaction is stirred at -78° C. for 5 minutes then warmed to room temperature. After 1 hour the mixture is re-cooled to 0° C., carefully quenched with saturated ammonium chloride, and diluted with diethyl ether. The layers are separated; organic phase washed with brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue is flash column chromatographed using 25% ethyl acetate in hexane to give 1.76 g of the title product as a pale pink oil.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:41])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:41])[C@H:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc1F)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A mixture of sodium borohydride (0.049 g, 1.30 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.738 g, 1.30 mmol in 10 mL of ethanol) was added with a 5 mL ethanol rinse. The reaction was stirred at ambient temperature overnight. The white precipitate which formed was collected by filtration to afford 0.335 g (45%) of (1R*,2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which had: NMR δ7.63 (s, 4 H), 7.07 (dd, J=2, 11.5 Hz, 1 H), 6.98-6.84 (m, 2 H), 5.13 (s, 1 H), 4.20 (d, J=9.5 Hz, 1 H), 3.06 (sym m, 1 H), 2.81-2.71 (m, 1 H), 2.70-2.50 (m, 3 H), 2.15 (sym m, 2 H), 1.81 (distorted d, J=14 Hz, 2 H), 1.59 (s, 1 H), 1.33-1.19 (m, 3 H), 1.08 (d, J=7 Hz, 18 H), 0.81 (d, J=6.5 Hz, 3 H). The product also contained about 7% of the erythro diastereomer but was suitable for use without additional purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH3:20])=[CH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:7][C:8]([CH3:20])=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C=C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)=Cc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a suspension of isopropyltriphenylphosphonium iodide (9.5 g) in tetrahydrofuran (90 mL) was added n-butyllithium (1.5 mol/L hexane solution, 15 mL) at 0° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added a solution of methyl terephthalaldehydate (3.3 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=3/1) and then by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=10/1) to give methyl 4-(2-methylprop-1-en-1-yl)benzoate (3.4 g). To a suspension of lithium aluminum hydride (0.68 g) in diethyl ether (120 mL) was added a solution of methyl 4-(2-methylprop-1-en-1-yl)benzoate (3.4 g) in diethyl ether (30 mL) at 0° C., and the mixture was heated under reflux for 50 minutes. After the reaction mixture was cooled to 0° C., water (0.69 mL), 15% aqueous sodium hydroxide solution (0.69 mL) and water (2 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Insoluble materials were removed by filtrate, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1-2/1) to give 4-(2-methylprop-1-en-1-yl)benzyl alcohol (2.8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][NH:21][CH:22]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][O:33][CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.CNCCCCO>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:21]([CH:22]3[C:30]4[C:25](=[C:26]([O:31][CH2:32][O:33][CH3:34])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)[CH3:20])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNC1CCc2c(OCOC)cccc21
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CNCCCCO
Product: COCOc1cccc2c1CCC2N(C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and 1-methylamino-4-(methoxymethoxy)indane was use in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nnn1-c1ccc(Br)cc1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCn1nnn(-c2ccc(Br)cc2)c1=O
Yield: 81 %

Procedure:
Compound 14a (5.00 g, 20.7 mmol) was treated with SEMCl using the reaction conditions described in Example 10, Step C to obtain compound 14b as a white solid (6.90 g, 81% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C13H19BrN4O2Si: 371.0 (M+H). Found 371.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[C:11][Si](C)(C)C)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[CH:11])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1cnc(N)c(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.3 grams (0.006 mole) of 2-amino-3-cyano-5-(trimethylsilylethynyl)pyrazine and 0.9 gram (0.006 mole) of potassium carbonate in 50 mL of methanol is stirred at ambient temperature for one hour. The reaction mixture is then concentrated under reduced pressure to a residue. The residue is taken up in about 75 mL of water, and the solution is extracted with two 200 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2-amino-3-cyano-5-ethynylpyrazine. This reaction is repeated several times.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@@H:12]2[CH2:14][NH:15]C(=O)OC(C)(C)C)=[N:3]1.[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[ClH:23].[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:13][C@@H:12]2[CH2:14][NH2:15])=[N:3]1
Reactant: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)cccc2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1cc2c([C@H]3C[C@@H]3CN)cccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of tert-butyl {[(1S,2S)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (2.68 g, 8.89 mmol) in ethyl acetate (50 mL) was added 4 M hydrochloric acid/ethyl acetate (50 mL) solution, and the mixture was stirred at room temperature for 3 hr. The solvent was concentrated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (2.40 g, yield 98%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N.C[OH:30]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:30])[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(NCCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Reactant: CO
Agent: Cl
Agent: N
Product: Nc1nc(NCCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Yield: 77 %

Procedure:
6-Amino-9-benzyl-2-benzylmethylamino-8-bromopurine (85 mg, 0.20 mmol) in concentrated hydrochloric acid (30 ml) and methanol (20 ml) were refluxed for 5 hours under heating. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered, washed with water and dried to give the subject compound (56 mg, yield 77%).
Reaction SMILES: N[C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:17]>>[Cl:17][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCc1ncccc1N
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NCCCCc1ncccc1Cl

Procedure:
(a) Reaction of 3-amino-2-(4-aminobutyl)pyridine with sodium nitrite/hydrochloric acid and treatment of the resultant diazonium salt with cuprous chloride yields 3-chloro-2-(4-aminobutyl)pyridine. By a similar procedure employing cuprous bromide and hydrobromic acid 3-bromo-2-(4-aminobutyl)pyridine may be produced and when the diazonium salt is treated with sulphuric acid the product is 3-hydroxy-2-(4-aminobutyl)pyridine.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[C:35](Cl)=[O:36]>>[Cl:29][C:30]1[CH:34]=[CH:33][S:32][C:31]=1[C:35]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1sccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3sccc3Cl)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chloro-2-thiophenecarbonyl chloride: ESMS m/e: 524.2 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([CH3:15])=[N:13][N:14]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([C:21](=[O:22])[C:20]4[CH:31]=[CH:32][C:17]([Cl:16])=[CH:18][CH:19]=4)=[CH:30][CH:29]=3)[C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2cnn(C(C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (10 ml) was dissolved 5-t-butyl-3-methyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (516 mg) followed by addition of 4-(4-chlorobenzoyl)benzyl bromide (1.2 g) and potassium carbonate (525 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate-THF and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1), washed with n-hexane-diethyl ether, and dried. White powder, 527 g.
Reaction SMILES: C1[C:6](=[O:7])[CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:3]=2C1.BrC1C=CC(CC(O)=O)=CC=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[Br:12][C:10]1[CH:9]=[CH:8][C:4]([CH2:5][C:6]([Cl:27])=[O:7])=[CH:3][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: O=C(O)Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Br)cc1

Procedure:
The synthesis of 6-bromo-β-tetralone is accomplished by dissolving 4-bromophenylacetic acid in methylene chloride and dimethyl formamide, under nitrogen. Oxalyl chloride is added and the mixture is stirred under a positive nitrogen atmosphere to produce the 4-bromophenylacetyl chloride, at a yield which typically is better than 99%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[C:33](O)(=O)[CH2:34]CC(O)=O>C(Cl)(Cl)Cl>[CH3:33][CH2:34][O:29][C:28]1[CH:30]=[CH:31][C:25]([C:24]2[NH:32][C:19]3[CH:18]=[C:17]([C:15]4[NH:16][C:10]5[CH:9]=[C:8]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:13]=[CH:12][C:11]=5[N:14]=4)[CH:22]=[CH:21][C:20]=3[N:23]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)CCC(=O)O
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc3ccc(-c4nc5ccc(N6CCN(C)CC6)cc5[nH]4)cc3[nH]2)cc1
Yield: 80 %

Procedure:
In this step, synthesis of an active ester of a binding enhancer is described, which can then be easily conjugated to both the photoreactive ligand and the linker. A solution of bisbenzimidazole (6 g, 0.01 mol) dicyclohexylcarbodiimide (0.05 mol) and succinic acid (0.01 mol) in 100 mL of chloroform is stirred overnight ( 18-24 hrs). During this time, a white precipitate is formed. The precipitate is filtered of and washed with chloroform (2×50 mL). The combined chloroform is concentrated under vacuum in a rotary evaporator and the residue purified by flash column chromatography. The fractions containing the product is combined and concentrated under vacuum in a rotary evaporate to afford bisbenzimide succinnate ester (80%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][C:26]=1[F:36].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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.C(OCC)(=O)C>[F:36][C:26]1[CH:27]=[C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[CH:29]=[CH:30][C:25]=1[CH2:24][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cc(-n2cccn2)ccc1CCl
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.51 g), 1-(4-(chloromethyl)-3-fluorophenyl)-1H-pyrazole (0.35 g) and sodium carbonate (0.35 g) in 1,2-dimethoxyethane (7.80 mL)-water (2.60 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.10 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.54 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:18]3)=[CH:13][CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][F:36]>CN(C)C=O.C(OCC)(=O)C>[F:36][CH2:35][CH2:34][N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11](/[CH:10]=[CH:9]/[C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)[CH:20]=2)[C:15](=[O:26])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17]1
Reactant: CCOC(=O)c1c[nH]c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(CCF)c2cc(/C=C/c3nc(C(C)C)cs3)ccc2c1=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
Ethyl 7-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate (368 mg, 1.00 mmol) was dissolved in dimethylformamide (6 ml), added with potassium carbonate (276 mg, 2.00 mmol) and 1-bromo-2-fluoroethane (0.223 ml, 3.00 mmol), and then the mixture was stirred overnight at 65° C. The reaction mixture was left stand for cooling and then diluted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1) to obtain the title compound (254 mg, 61%) as colorless transparent oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:20][CH2:21][OH:22])[CH2:8][CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:20][CH2:21][O:22][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:8]1)=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To an ice-cold stirred mixture of (2-hydroxyethyl)-[2-hydroxy-2-(4-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester (5.50 g, 16.8 mmol) and triphenylphosphine (5.17 g, (19.7 mmol) in toluene (80 mL) was added triethylamine (6.15 mL, 4.46 g, 44.2 mmol) followed a solution of di-tert-butylazodicarboxylate (3.10 mL, 19.7 mmol) in toluene (30 mL) dropwise. The reaction mixture was stirred for 18 h at room temperature, washed with water (50 mL), and the aqueous layer was back extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane, the obtained product was triturated with diisopropyl ether and collected. The title compound (3.56 g, 11.5 mmol, 68%) was obtained as a white solid. ESMS m/z 253 (M+H-tBu)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (d, J=8.3 Hz, 2H) 7.57 (d, J=8.3 Hz, 2H) 4.53 (d, J=10.3 Hz, 1H) 4.20 (br. s., 1H) 4.06 (d, J=11.3 Hz, 1H) 3.94 (br. s., 1H) 3.66-3.75 (m, 1H) 3.06 (br. s., 1H) 2.76 (br. s., 1H) 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH3:47])[C:4](=[O:48])[CH:3]=1.[CH3:49][CH2:50][O:51][C:52]([CH2:54][SH:55])=[O:53].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([O:51][C:52]([CH2:54][S:55][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH3:47])[C:4](=[O:48])[CH:3]=1)=[O:53])[CH3:49]
Reactant: CCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CSc1cc(=O)n(CC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 33 %

Procedure:
A mixture of 6-chloro-3-ethyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), ethyl thioglycollate (0.13 ml) and potassium carbonate (0.19 g) in acetonitrile (10 ml) was heated under reflux for 10 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and 1N hydrochloric acid (1.5 ml), followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.15 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)c(Cl)cc1F
Reactant: COC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (794.5 mg, 3.49 mmol) in dichloromethane (7.3 mL) was added drop-wise to a mixture of methyl 4-aminobenzoate (528.0 mg, 3.49 mmol), pyridine (847.6 μL, 10.48 mmol) and dichloromethane (11.0 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction, water (10 mL) was added. The solid was isolated by filtration, washed with water (2×10 mL) and hexane (2×10 mL) to yield methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (955 mg, 80%) as a light pink solid. ESI-MS m/z calc. 341.00. found 342.2 (M+1)+; Retention time: 1.75 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.03 (d, J=6.7 Hz, 1H), 8.02-7.95 (m, 2H), 7.93 (d, J=9.4 Hz, 1H), 7.88-7.76 (m, 2H), 3.84 (s, 3H) ppm.