Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([C:20]2[C:21]3[CH:33]=[CH:32][C:31]([CH2:34]OS(C)(=O)=O)=[CH:30][C:22]=3[S:23][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[CH:15]=[CH:16][CH:17]=1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([C:20]2[C:21]3[CH:33]=[CH:32][C:31]([CH2:34][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:30][C:22]=3[S:23][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc2cc(COS(C)(=O)=O)ccc2c1S(=O)c1cccc(OC)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(COc3cccnc3)ccc2c1S(=O)c1cccc(OC)c1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
3-Hydroxypyridine (57 mg, 0.6 mmol) was added to a stirred suspension of sodium hydride (24 mg of 60% dispersion in mineral oil, 0.6 mmol) in anhydrous dimethylformamide (2 ml), under a nitrogen atmosphere. After 30 minutes, ethyl 3-[(3-methoxyphenyl)sulfinyl]-6-[(methylsulfonyloxy)methyl]benzo[b]thiophene-2-carboxylate (Preparation 18, 234 mg, 0.5 mmol) was added to the mixture, and the mixture was stirred for 3 hours. The reaction was partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 2% ethanol in dichloromethane as eluant The semi-pure product was re-chromatographed on silica gel using ethyl acetate, and then crystallised from diethyl ether, to give the title compound as a colourless solid (110 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[CH:23]=2)=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.O=S(Cl)Cl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]3[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:24]=3[C:23]=2[C:6]([C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)O)cc1C#N
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC)c(C#N)c2)cc1
Yield: 107.5 %

Procedure:
1.8 g of the title compound was prepared from 3.9 g (3.9 mmol) of 3-cyano-4-methoxybenzoic acid (converted to the acid chloride with 30 mL of SOCl2 and three drops of DMF), 6 g (22 mmol) of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene, and 14.7 g (110 mmol) of AlCl3 in a manner similar to that in Preparation 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](=[O:34])[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: O=C(CC1CCCCN1)c1cc2ccccc2o1
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)c2cc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid and (RS)-1-benzofuran-2-yl-2-piperidin-2-yl-ethanone, D37 according to a procedure similar to that for Description 35.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[K].[O:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].[I-].[Na+].O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][O:17][C:18]3=[O:23])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: ClCCCCCc1cccc2nccn12
Reactant: O=C1COC(=O)N1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC(=O)N1CCCCCc1cccc2nccn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 15.59 g (70 mmol) of 5-(5-chloropentyl)imidazo[1,2-a]pyridine and 9.74 g (70 mmol) of oxazolidine-2,4-dione potassium salt in 300 ml of N,N-dimethylformamide, 10.49 g (70 mmol) of sodium iodide was added, followed by stirring at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate→ethyl acetate/ethanol=10/1) to yield 11.90 g (59.2%, light orange crystal) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:31]3[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=3)=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN)c(C)c3)nc2c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCNC(=O)c4ccc(C)cc4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
A mixture of compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.060 g, 0.16 mmol), p-toluoyl chloride (0.028 mL, 0.21 mmol), and PS-DIEA (0.057 g, 0.21 mmol) in CH2Cl2 (4.0 mL) was stirred at room temperature for 16 h. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel to yield N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide (0.037 g, 51%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.80-11.00 (s, 1H), 8.69 (t, J=5.43 Hz, 1H), 7.88 (s, 2H), 7.79 (d, J=8.19 Hz, 2H), 7.28 (d, J=8.00 Hz, 2H), 6.73 (d, J=2.31 Hz, 1H), 6.51 (d, J=2.31 Hz, 1H), 3.94 (t, J=5.59 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72-3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m/z 488 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCc2c[nH]cn2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(C(=CCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxy-3-phenylpropyl]-1H-imidazole (2,5 g, 6,6 mmol) is dissolved in methylene chloride (50 ml) and thionyl chloride (3,2 g, 26,9 mmol) is added to the solution. The mixture is refluxed for two hours. The solvents are evaporated. 2M sodium hydroxide is added to the residue and the product is extracted into ethyl acetate and dried. The product is convened to its HCl salt with dry hydrogen chloride gas and the solvent is evaporated. Yield 2,14 g, 91%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2COCCO2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30 mL) was treated with sodium hydride (60%, 245 mg) at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The resulting mixture was stirred at room temperature for 2 hours and another portion of sodium hydride (60%, 245 mg) was added. The reaction mixture was stirred overnight and quenched with ice water (3 mL). The cloudy mixture was filtered and the filtrate was concentrated. The residue was triturated with methanol to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of fluoride 48 (103 mg, 0.22 mmol) and morpholine (2 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 50 (83 mg, 71%) as a white powder: mp (EtOAc) 208-210° C.; 1H NMR δ 9.23 (s, 1 H, CONH), 8.57 (br s, 1 H, H-2′), 8.47 (br d, J=4.5Hz, 1 H, H-6′), 8.00 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.91 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.8Hz, 1 H, H-4′), 7.54 (d, J=9.0Hz, 2 H, H-3″, H-5″), 7.37 (dd, J=7.8, 4.7Hz, 1 H, H-5′), 7.05 (d, J=9.0Hz, 2 H, H-2″, H-6″), 4.49-4.54 (m, 4 H, CH2SO2, CH2N), 3.72 (br t, J=4.8Hz, 4 H, 2×CH2O), 3.27 (br t, J=4.8Hz, 4 H, 2×CH2N), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 157.8, 154.2, 149.7, 148.8, 148.0, 135.3, 135.1, 134.8, 129.7 (2), 128.8, 128.0 (2), 126.4, 126.0, 125.4 (2), 123.4, 113.3 (2), 65.6 (2), 53.2, 46.7 (2), 40.4, 9.6; MS m/z 533.7 (MH+, 100%). Anal. calcd for C28H28N4O5S: C, 63.14; H, 5.30; N, 10.52. Found: C, 62.94; H, 5.18; N, 10.51%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: CCOC(=O)C(F)Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)C(=O)OCC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of ethyl 3-(4-aminophenyl)-2-fluoropropanoate (400 mg, 1.89 mmol) and 4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde (434 mg, 1.45 mmol) in toluene (25 mL) were added molecular sieves (0.4 nm, beads, 1.6 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (20 mL) and ethanol (20 mL), 10% palladium-carbon (50% water-containing product, 0.40 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% hexane/ethyl acetate) to give the title compound (320 mg, yield 45%) as a colorless oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH-].[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]>>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:8][N+:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)C(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: CC(C)C(=O)[O-]

Procedure:
To a 20 L, round bottom flask was added isobutyric acid (1300 mL, 14 mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L, 14 mol). The water was removed under reduced pressure, and azeotroped with toluene (2×2 L) to leave the product (1b) as an amber liquid, which was used without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=12.[C:15]([O-])(=[O:17])C.[Na+].C=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[OH:17][CH2:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2=[N:1][CH:2]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cccn2ccnc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cccn2c(CO)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
A mixture of ethyl imidazo[1,2-a]pyridine-8-carboxylate (1 g, 5.26 mmol), sodium acetate (1.725 g, 21.03 mmol), formaldehyde (36.5% wt. in water, 2.5 mL, 33.1 mmol) and acetic acid (1.145 mL, 20 mmol) was stirred at room temperature for 3 hours. The reaction mixture was then heated at reflux for a further 4 hours and then cooled and diluted with water (50 mL). The pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution (ca. 10 mL) and the solution was extracted successively with ethyl acetate (3×50 mL) and 3:1 chloroform:isopropanol (100 mL). The organic extracts were combined, washed successively with saturated sodium bicarbonate (50 mL) and brine (50 mL) and dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane and purified on a silica cartridge (100 g) using a 0-30% methanol (+1% Et3N)-DCM gradient over 60 mins. The product containing fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (1.007 g)
Reaction SMILES: [CH3:1][N:2]1[CH2:11][C@@H:10]2[C@H:4]([CH2:5][NH:6][C:7](=[O:24])[C:8]3[CH:15]=[C:14]([CH:16]=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:13]=[CH:12][C:9]=32)[CH2:3]1>[Pd].CO>[CH3:1][N:2]1[CH2:11][C@@H:10]2[C@H:4]([CH2:5][NH:6][C:7](=[O:24])[C:8]3[CH:15]=[C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:13]=[CH:12][C:9]=32)[CH2:3]1
Reactant: CN1C[C@H]2CNC(=O)c3cc(C=Cc4ccccc4)ccc3[C@@H]2C1
Agent: [Pd]
Solvent: CO
Product: CN1C[C@H]2CNC(=O)c3cc(CCc4ccccc4)ccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 50 mL pressure bottle was added a mixture of Example 85 (31.8 mg, 0.100 mmol), 5% palladium on carbon, wet (7.95 mg, 0.075 mmol) and methanol (10 mL). This was stirred for 5 hours under an atmosphere of hydrogen (30 psi) at room temperature. The reaction was complete as indicated by LC/MS. The mixture was filtered through a nylon membrane, concentrated, and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (0-20%) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.90 (t, J=3.6, 1H), 7.71 (d, J=1.9, 1H), 7.32-7.12 (m, 6H), 7.06 (d, J=7.8, 1H), 3.27-3.13 (m, 2H), 3.07 (dt, J=9.2, 18.4, 2H), 2.92-2.82 (m, 5H), 2.65-2.56 (m, 2H), 2.35 (d, J=3.9, 3H), 2.20-2.06 (m, 1H); MS (ESI+) m/z 321.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[S:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(C[C:34]2[S:35][C:36]([C:39](OC)=O)=[CH:37][CH:38]=2)C(C=O)=CN=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[S:15][CH:14]=2)[C:7](/[CH:10]=[C:16](\[CH2:39][C:36]2[S:35][CH:34]=[CH:38][CH:37]=2)/[C:18]([OH:20])=[O:19])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)s1
Reactant: CCCCc1ncc(C=O)n1Cc1csc(C(=O)OC)c1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1csc(C(=O)O)c1

Procedure:
The title compound was prepared following the procedures described in Example 1 (v-vi) using 2-n-butyl-1-[(5-carbomethoxy-3-thienyl)methyl]imidazol-5-carboxaldehyde (prepared by the methods described in Example 2 (i-iii)) in place of 2-n-butyl-1-[(5-carbomethoxy-2-thienyl)methyl]-imidazol-5-carboxaldehyde; mp 133°-135° C. (d).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6](O)=[O:7])=[C:4]([Cl:12])[CH:3]=1.S(Cl)([Cl:15])=O>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([Cl:15])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cc(Br)cc1Cl
Solvent: ClCCl
Product: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 103.1 %

Procedure:
A solution of 4-bromo-2,6-dichlorobenzoic acid (2 g, 7.4 mmol), and thionyl chloride (5.5 mL, 74 mmol) in dichloromethane (30 mL) was heated under refluxed for 5 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting mass was taken up in dichloromethane (20 mL) and concentrated under vacuum. The process was repeated 2-3 times to remove excess thionyl chloride. 4-Bromo-2,6-dichlorobenzoyl chloride (2.2 g, 100%) thus formed was used as such for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=O)[N:11]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:10]=2[CH:22]=1)=O.C([SiH](CC)CC)C.B(F)(F)F>ClCCCl.CC#N>[Br:1][C:2]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:3]=1[CH2:4][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][CH2:12][N:11]([C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[C:10]=2[CH:22]=1
Reactant: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)C(=O)CO2)c1cc(I)ccc1Br
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(N1CCOc2ccc(Cc3cc(I)ccc3Br)cc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a stirred solution of 6-(2-bromo-5-iodo-benzoyl)-4-(2,2,2-trifluoro-acetyl)-4H-benzo[1,4]oxazin-3-one (16.0 g, 29.252 mmol) in 1,2-dichloroethane/MeCN (1:2 mixture, 60 mL) was added triethylsilane (9.9 mL, 62.43 mmol) and borontrifluoride diethyletherate complex (4.9 mL, 38.51 mmol) simultaneously at −10° C. After stirring overnight at room temperature, the reaction was heated at 50° C. for 3 h. The reaction was quenched by the addition of aq. sodium bicarbonate (50 mL). Volatiles were evaporated under reduced pressure, and the resulting residue was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with water and brine, then dried over sodium sulfate and concentrated to a residue which was purified by silica gel column chromatography to furnish 1-[6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (12.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)C=CCO2
Yield: 58.3 %

Procedure:
6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acid (1 g) were dissolved in toluene and refluxed over-night with subsequent water removal. The mixture was then cooled and washed with NaHCO3 (aq) and purified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) of pure 6-fluoro-2H-chromene.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:24]2[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]([F:48])([S:44](F)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]>CN(C)C=O>[F:38][C:39]([F:48])([S:44]([O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:9]3[CH:8]=[C:7]([N:24]4[CH:29]=[CH:28][C:27](=[O:30])[NH:26][C:25]4=[O:31])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=3[O:11][CH3:12])[CH:14]=2)[CH:19]=1)(=[O:46])=[O:45])[C:40]([F:43])([F:42])[F:41]
Reactant: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(-c2ccc3cc(OS(=O)(=O)C(F)(F)C(F)(F)F)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.0 g of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (23.5 mmol, 1.0 equivalent) in 100 mL of N,N-dimethylformamide was added 6.5 g of 325-mesh potassium carbonate (47 mmol, 2.0 equivalents). 1,1,2,2,2-pentafluoroethanesulfonyl fluoride (4 g, 20 mmol, 0.85 equivalents) was bubbled sub-surface into the reaction mixture over 3 hours, and the mixture was stirred for 0.5 hours. The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with 5 mL of N,N-dimethylformamide. The solution was diluted with 24 mL of water and 150 mL of ethyl acetate and the resultant solution was washed four times with 50 mL portions of 10 wt % aqueous sodium chloride, followed by 25 mL of saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, the drying agent was filtered off and the organic solution was concentrated in vacuo. The resultant solid was purified by chromatography over silica gel with gradient elution (40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes). The desired product was dissolved in 10 mL of ethyl acetate and 200 mL of heptanes was added over 60 minutes. The product crystallized and was isolated by filtration. The wet cake was washed with 40 mL of heptanes and dried in vacuo with heating at 50° C. The title compound was isolated as a white solid (9.4 g, 67% yield). 1H NMR (600 MHz, CDCl3) δ ppm 8.60 (d, J=0.5 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.42 (dd, J=9.0, 2.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.27-7.26 (m, 2H), 5.82 (dd, J=8.0, 2.3 Hz, 1H), 3.30 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz, CDCl3) δ ppm 162.6 (C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.23 (C), 132.18 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 61.0 (CH3), 35.8 (C), 30.8 (CH3). 19F NMR (564 MHz, CDCl3) δ ppm −79.1 (3F), −113.4 (2F). LC-MS m/z 599.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:11][CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CC(Br)c1ccc(C#N)cn1
Temperature: 25 °C

Procedure:
A solution of 6-ethyl-nicotinonitrile (synthesis described in WO2008/71404, 1000 mg, 7.57 mmol), N-bromosuccinimide (1632 mg, 9.08 mmol) and 2,2′-azo-bis(isobutyronitrile) (62 mg, 0.38 mmol) in chloroform (12 mL) is heated at reflux for 7 min. After cooling to room temperature, the reaction mixture is filtered and the volatiles are removed under reduced pressure (260 mbar, 55° C.) to yield the product which was used without further purification. Yield: 1597 mg (quant.); ESI mass spectrum: [M+H]+=211 (Br pattern); Retention time HPLC: 0.92 min (Z018_S04).