Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:27])[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:27])[CH2:14]1)=[O:11]
Reactant: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 0.1 mL (1.15 mmol) of oxalyl chloride in 2 mL of CH2Cl2 cooled in a −78° C. bath, 0.1 mL (1.41 mmol) of dry DMSO was added. After 0.5 hr, a solution of 0.26 g (0.59 mmol) of 2(S)-(3-(R)-hydroxymethyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-ethylvaleric acid, 4-methoxybenzyl ester (step D) in 2.5 mL of CH2Cl2 was added. After 0.5 hr, 0.5 mL (3.57 mmol) of triethylamine was added to the reaction and the cold bath was removed. After stirring for 2 hr, the reaction was partitioned between water and CH2Cl2. The organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 20-30% EtOAc in hexane to isolate 0.23 g of the title compound. 1H NMR (CDCl3) 0.86 (m, 6H), 1.2-1.8 (m, 5H), 2.82 (m, 2H), 3.05 (t, 1H), 3.18 (m, 2H), 3.32 (d, 1H), 3.52 (m, 1H), 3.83 (s, 3H), 5.13 (s, 2H), 6.9-7.4 (m, 8H), 9.64 (d, 1H).
Reaction SMILES: [O:1]([CH:9]1[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Mg+2].[Br-].[Br-].[H-].[Al+3].[Li+].[H-].[H-].[H-].COC(C)(C)C>C1(C)C=CC=CC=1>[Si:2]([O:1][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: [Al+3]
Agent: [Br-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: -25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0 g, 9.42 mmol) in anhydrous toluene (15 mL) under an atmosphere of argon is treated with MgBr2 (3.5 g, 19.0 mol). The mixture is cooled to -25° C. and treated with lithium aluminum hydride (178 mg, 4.69 mmol) in one portion, followed by addition of anhydrous tert-butyl methyl ether (3.0 mL). The reaction is stirred at -20° C. for 2 hours and then overnight at room temperature. Additional lithium aluminum hydride (178 mg, 4.69 mmol) is added at room temperature and the reaction is stirred for 2 hours. The reaction is then quenched by slow addition of 1N NaOH (5 mL) followed by filtration through diatomaceous earth. The filtrate is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.3 g); cis/trans/1-2 +1-4 addition, 90/3/7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(OC)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.2 g, 0.015mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The dipropylamine (3.04 g, 0.03 mole) was added and the reaction mixture was allowed to stir at room temperature overnight, then heated at reflux for 8 hrs. The reaction mixture was filtered and the filtrate ws evaporated to dryness, then placed under high vacuum over the weekend. The residue was treated with water and the solid was collected by filtration, washed with water, and dried under high vacuum. The solid was dissolved in 100 ml of isopropyl alcohol, filtered, and the filtrate concentrated to 50 ml. The filtrate was diluted with water, seeded, and placed in a freezer overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight to give 1.8 g (33%) of title compound, mp 127°-29° C. Analysis: Calculated for C21H26N4O2 : C, 68.83; H, 7.15; N, 14.29; Found : C, 68.74; H, 7.15; N, 15.18.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[C:10]([OH:19])=[CH:9][C:8]=2[C:20](O)([CH3:22])[CH3:21])=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33](S(O)(=O)=O)=[CH:32][CH:31]=1>C(OC)(C)(C)C>[CH3:18][O:17][C:12]1[C:11]2[C:10]([OH:19])=[CH:9][C:8]3[C:20]([CH3:22])([CH3:21])[C:32]4[CH:31]=[C:30]([C:40]5[CH:15]=[CH:16][CH:7]=[CH:8][CH:9]=5)[CH:35]=[CH:34][C:33]=4[C:7]=3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc2c(-c3ccc(-c4ccccc4)cc3)c(C(C)(C)O)cc(O)c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)C
Product: COc1cccc2c3c(cc(O)c12)C(C)(C)c1cc(-c2ccccc2)ccc1-3
Temperature: 25 °C
Yield: 569.6 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere and equipped with a Dean-Stark trap, the product of Step 5 (20 g) was stirred in xylenes (300 mL). To this was added p-toluenesulfonic acid (990 mg). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. It was transferred to a separatory funnel and washed with saturated aqueous solution of sodium bicarbonate (300 mL), dried over sodium sulfate and then concentrated by rotary evaporation to yield a solid. The solid was slurried in a minimal amount of methyl tert-butyl ether and collected by vacuum filtration yielding 12 g of 4-methoxy-7,7-dimethyl-9-phenyl-7H-benzo[C]fluoren-5-ol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:49].Cl>>[ClH:49].[ClH:49].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:13][C:12]3=[O:25])[CH:9]=2)[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][C:3]1=2
Reactant: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CCNC2
Yield: 95 %

Procedure:
tert-Butyl 9-methyl-7-(2-oxo-4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (180 mg, 0.368 mmol) was deprotected and converted to the dihydrochloride salt according to Example 2 (step g) to provide the title compound (162 mg, 95%) as an off-white solid: 265° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 12.8-12.0 (br s, 1H), 9.76 (s, 2H), 8.68 (d, J=4.9 Hz, 1H), 8.12-8.06 (m, 1H), 7.69-7.64 (m, 1H), 7.59-7.55 (m, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.01-7.00 (dd, J=8.3, 1.7 Hz, 1H), 4.44 (s, 2H), 4.07 (s, 2H), 4.05-4.01 (m, 2H), 3.78-3.72 (m, 2H), 3.71-3.62 (m, 5H), 3.51-3.45 (m, 2H), 3.47-3.43 (m, 2H), 2.95 (t, J=5.7 Hz, 2H); ESI MS m/z 390 [M+H]+; HPLC (Method B) 99% (AUC), tR=7.9 min.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].C(ON=O)(C)(C)C>C(O)(=O)C>[F:8][C:6]1[CH:5]=[C:4]2[C:3]([S:9](=[O:11])(=[O:10])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:2][CH:7]=1
Reactant: Nc1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(F)ccc21
Temperature: 10 °C
Yield: 2.4 %

Procedure:
2-Amino-4-fluoro-N-quinolin-8-yl-benzenesulfonamide (Example Compound 31) (315 mg, 0.99 mmol) was suspended in acetic acid (4 ml) and cooled to 10° C. Tert-butylnitrite (177 μl, 1.49 mmol) was added and the reaction was warmed to room temperature over 10 min. The reaction was quenched water (5 ml) and the resulting solution was concentrated in vacuo. The crude residue was dissolved in acetic acid (2 ml) and irradiated at 120° C. for 10 mins in the microwave. After cooling, the reaction was concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic conditions) to give the title compound (7 mg, 2%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH3:10][NH:11][S:12]([C:15]1[CH:16]=[C:17]([C:25](Cl)=[O:26])[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=1)(=[O:14])=[O:13]>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:25]([C:17]1[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=[C:15]([S:12](=[O:14])(=[O:13])[NH:11][CH3:10])[CH:16]=1)=[O:26])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 62 %

Procedure:
In a similar manner to that of the above example, 82 g of levorotatory 1-ethyl-2-aminomethyl-pyrrolidine was reacted with 195 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride to give 151 g of levorotatory-N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide (M.P.: 136°-137° C.; yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH:17]([C:23]([CH3:25])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH:17]([C:23](=[O:24])[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(Cl)c(Cl)c1)C(C)=O
Yield: 67.8 %

Procedure:
13.0 g (80 mmol) of 3,4-dichlorophenol and 12.2 g (88 mmol) of potassium carbonate were refluxed for 30 minutes in 400 ml of acetone. 15.8 g (96 mmol) of ethyl 2-chloroacetoacetate were subsequently added dropwise, the mixture was refluxed for 8 hours and evaporated in vacuo, and water was added to the residue. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and evaporated. Column chromatography of the residue gave 15.8 g (68% of theory) of ethyl 2-(3,4-dichlorophenoxy)-3-ketobutanate as an oil.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl>C(O)C>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1ncc[nH]1
Reactant: Nc1ccccc1CCl
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1CSc1ncc[nH]1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 1.5 g (15 mmol) of 2-mercaptoimidazole in 15 ml of ethanol was added at room temperature 2.66 g (15 mmol) of 2-aminobenzyl chloride hydrochloride. The mixture was then stirred for one hr. at room temperature. The obtained homogeneous solution was placed under reduced pressure at a temperature below 40° C. to distill off the solvent. To the residue were successively added water and saturated aqueous sodium hydrogencarbonate to precipitate a crystalline product. The product was collected by filtration, washed twice with water, and dried to give 2.5 g of the desired compound as a pale gray crystalline product, yield 80.9%.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[C:12]3[CH2:28][CH:29]=[CH:30][CH:31]=[C:11]23)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=CC=1C1C2C=CC=CC=2CNC2C=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>C(#N)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]2=3)=[O:9])=[CH:32][CH:33]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2C(c2ccccc2Cl)=C2CC=CC=C21
Agent: Clc1ccccc1C1c2ccccc2CNc2ccccc21
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2C(c2ccccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
preferred method of synthesis of N-(4′-nitrobenzoyl)-11-(2′-chlorophenyl)-5,6-dihydro-1H-dibenz[b,e]azepine (Compound 28) is as follows: A mixture of 0.2 g (0.00065 mole) of 11-(2′-chlorophenyl)-5,6-dihydro-11H-dibenz[b,e]azepine, 0.179 g (0.0013 mole) of potassium carbonate and 0.133 g (0.00072 mole) of 4-nitrobenzoyl chloride in 10 mL of acetonitrile, was stirred at room temperature for 12 hours. The mixture was stirred with 15 mL of water for 10 minutes. The reaction mixture was extracted with ethyl acetate (2×15 mL). The organic layer was dried over magnesium sulfate. Evaporation gave the crude product as a sticky solid. Trituration of the crude product with ethanol and washing the obtained solid with hexane gave 0.148 g (50% yield) of a white solid having a melting point of 178-181° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[O:11])=[C:4]([I:12])[CH:3]=1.[CH2:13]([SiH](CC)CC)C.CO.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[C:5]([CH2:10][O:11][CH3:13])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1nc(Cl)cc(I)c1C=O
Reactant: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCc1c(I)cc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a mixture of 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde (1.07 g, 3.60 mmol), triethylsilane (0.86 mL, 5.40 mmol) and methanol (0.43 mL, 10.6 mmol) at 0° C. was added trifluoroacetic acid (2.2 mL, 28.6 mmol), and the resulting solution was stirred at 25° C. for 14 h. After dilution with ether (30 mL), saturated NaHCO3 was added until the aqueous phase was rendered basic. The aqueous layer was extracted with ether (10 mL), and the combined ether layers were washed with water (10 mL) and brine (10 mL), and dried (Na2SO4). Concentration gave the crude product which was purified by radial PLC (silica gel, 5% ethyl acetate/hexanes) to afford 2-chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine as a white solid (1.05 g, 93%): mp 69°-72° C. Recrystallization from hexanes provided an analytical sample: mp 74°-75° C. 1H NMR (300 MHz, CDCl3) δ7.40 (S, 1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.42 (s, 3H); IR (nujol) 1550, 1300, 1115, 1090, 1020, 940, 905, 830, 720 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11]1[S:10][CH2:16][C:14](=[O:15])[N:13]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccccc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 10.4 %

Procedure:
To a suspension of 2-chloro-benzylamine (7.88 g, 55 mmol) and Rhodanine (6.65 g, 50 mmol) in acetonitrile (150 mL) was added DIPEA (19.15 mL, 110 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (13.5 g, 50 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (1 L) and methanol (500 mL). The combined solvents were removed under the vacuum and the crude residue was diluted with water (150 mL) and ethyl acetate (150 mL). After shaking, lot of solids formed which was collected by filtration to obtain 1.25 g of the desired product. Then, the two layers were separated and the ethyl acetate layer was washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the ethyl acetate solution was removed partially and the remaining solution was stored in the refrigerator. Then, the precipitated solids were collected by filtration to afford 2.67 g of the desired product. Then, the aqueous layer was again extracted with dichloromethane (2×150 mL). The combined dichloromethane extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to obtain 4.2 g (total product 8.12 g, 67.5% yield) of 2-(2-chloro-benzylamino)-thiazol-4-one as a white amorphous solid: EI-HRMS m/e calcd for C10H9ClN2OS (M+) 240.0124, found 240.0122.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: C=CCCBr
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: C=CCCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and 4-bromo-1-butene, colorless oily N-[2-(3-but-3-enyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1([CH2:31][O:32]C2CCCCO2)[N:13]([CH2:14][C:15]#[N:16])[C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)[C:10]1=[O:30].Cl.O>CO.C(Cl)Cl>[OH:32][CH2:31][C:9]1([CH2:8][OH:7])[N:13]([CH2:14][C:15]#[N:16])[C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=2)[C:10]1=[O:30]
Reactant: N#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC1CCCCO1)COC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)CO
Temperature: 0 °C
Yield: 70.4 %

Procedure:
4.68 g of the product obtained in Stage 1 above in solution in 50 ml of methanol and 8.8 ml of hydrochloric acid are introduced and the whole is taken to reflux for 30 minutes. 60 ml of ice-cooled water is added, extraction is carried out with ether, the ethereal phase is washed with a saturated solution of sodium chloride and dried. After purification on silica, eluting with methylene chloride-acetone: 85-15 then 8-2, the crystals obtained are taken up in 10 ml of methylene chloride, separated out and dried. In this way 2.26 g of expected product (white crystals) is obtained. M.p.=157-158° C.
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:11][C:9]1[C:8]([O:12][CH2:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:7][N:6]=[C:5]([CH:4]=[O:20])[CH:10]=1
Reactant: CON(C)C(=O)c1cc(C)c(OCC(F)(F)C(F)F)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C=O)ncc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (1.20 g, yellow solid) from N-methoxy-N,4-dimethyl-5-(2,2,3,3-tetrafluoropropoxy)picolinamide (1.36 g, 4.38 mmol, Step-4) and lithium aluminum hydride (83 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.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.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 25.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (105 mg, 0.24 mmol), 3-tributylstannanyl-pyridine (133 mg, 0.36 mmol), and PdCl2(PPh3)2 (34 mg, 0.048 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under N2 atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 24 mg of the title compound. MS: (+) m/z 388.33 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:20]Br)[CH2:17][C:18]#[N:19]>CC(C)=O>[O:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:20][CH:16]1[CH2:17][C:18]#[N:19]
Reactant: Oc1ccccc1S
Reactant: N#CCC(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCC1CSc2ccccc2O1

Procedure:
To the refluxing solution of 75 g of 2-hydroxythiophenol [J. Pharm. Sci. 61, 2 (1972)] in 660 ml of acetone is added 42 g of potassium carbonate, followed by the dropwise addition of the solution of 33.5 g of 3,4-dibromobutyronitrile in 50 ml of acetone while stirring. After 30 minutes refluxing, a second, third, and fourth addition of 42 g potassium carbonate and 33.5 g of 3,4-dibromobutyronitrile is made. The whole mixture is refluxed for 20 hours, cooled and filtered. The filtrate is evaporated and the residue distilled in a bulb to bulb apparatus at 185° and 0.5 mmHg, to yield the 2-(1,4-benzoxathian-2-yl)-acetonitrile.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1C=CC=CC=1.ClC1[N:36]=[C:35]([Cl:37])[CH:34]=[C:33]([CH3:38])[N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:35]1[N:36]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[N:32]=[C:33]([CH3:38])[CH:34]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Ic1ccccc1
Product: Cc1cc(Cl)nc(-n2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2=O)n1

Procedure:
4-{3-[1-(6-Chloro-4-methyl-pyrimidin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,4-dichloro-6-methylprimidine for the iodobenzene in Step 3.