Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:27][C:26]2[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=2)[C:20]([NH2:22])=[O:21])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cccc(-c2nc(CBr)sc2Br)c1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a solution of 5-Bromo-2-bromomethyl-4-(3-methoxy-phenyl)-thiazole (0.80 g, 2.20 mmol) in 5 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.38 g, 2.20 mmol) and potassium carbonate (1.06 g, 7.70 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.50 g, 49%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9](Cl)=[O:10]>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=1[F:6])[CH3:2]
Reactant: CCNCC
Reactant: O=C(Cl)c1cc(F)ccc1F
Product: CCN(CC)C(=O)c1cc(F)ccc1F
Yield: 93.8 %

Procedure:
Diethyl amine (15.4 g, 210 mmol) and 2,5-difluorobenzoyl chloride (17.6 g, 100 mmol) were reacted using General Method E1 to afford 20.0 g of N,N-diethyl-2,5-difluorobenzamide as a clear oil, a 94% yield.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[O:5]=[CH:6][CH:7]([CH3:12])[CH2:8][C:9]#[C:10][CH3:11].[Cl-].[NH4+]>O1CCCC1>[OH:5][CH:6]([CH:7]([CH3:12])[CH2:8][C:9]#[C:10][CH3:11])[C:1]#[CH:2]
Reactant: CC#CCC(C)C=O
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)CC#CC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 50 ml of 2M ethylmagnesium bromide in tetrahydrofuran at 0° C. was added a solution of 1-oxo-2-methylhex-4-yne in 20 ml of tetrahydrofuran. The mixture was stirred for 11/2 hour at 0° C., poured into saturated ammonium chloride solution, and extracted three times with diethyl ether. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane, to give 6.0 g of 3-hydroxy-4-methyloct-1,6-diyne, the compound of formula (LXV).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][C:25]([CH3:27])=[CH2:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28]O.[OH-].[Na+].O>C1COCC1>[CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][CH:25]([CH3:27])[CH2:26][OH:28])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=C(C)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (3.05 g, 8.1 mmol) in THF (50 mL) was added BH3 solution in THF (32 mL, 1 mol/L, 32.4 mmol), and the mixture was stirred at room temperature for 16 hrs. Then 30% H2O2 solution (30 mL) and 10% sodium hydroxide solution (50 mL) were added slowly to the mixture, and the mixture was stirred for another 2 hrs. The mixture was then treated with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by a standard method to give the product (1.97 g). LC-MS: m/z 394.5 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[Br:15][C:16]1[CH:17]=[C:18]([C:23]([C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=2)=O)[CH:19]=[C:20]([Br:22])[CH:21]=1>O1CCCC1.C(COC)OC>[Br:15][C:16]1[CH:17]=[C:18]([C:23]2([C:25]3[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([Br:32])[CH:26]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=[C:20]([Br:22])[CH:21]=1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1cc(Br)cc(Br)c1
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3ccccc32)c1

Procedure:
The corresponding Grignard compound is prepared from 144.5 g (620 mmol) of 2-bromobiphenyl and 15.3 g (580 mmol) of magnesium in a mixture of 500 ml of tetrahydrofuran and 250 ml of dimethoxyethane. A suspension of 224.0 g (450 mmol) of bis(3,5-dibromophenyl) ketone in 1000 ml of tetrahydrofuran is then added at room temperature, and the mixture is stirred for a further twelve hours. The solvent is removed in vacuo, 1000 ml of glacial acetic acid and 5 ml of hydrogen bromide are added to the residue, and the mixture is stirred for one hour. The suspension is heated under reflux for half an hour and stirred at room temperature for twelve hours. The solid is filtered off with suction, washed three times with 300 ml of ethanol and recrystallised twice from toluene. Yield: 183.2 g (289 mmol), 64.3%, purity about 99.8% (HPLC).
Reaction SMILES: [C:1]12([CH:11]([OH:44])[CH2:12][N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH2:41][CH3:42])[N:15]=[C:14]3[CH3:43])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]12([C:11](=[O:44])[CH2:12][N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:37][C:36](=[O:38])[O:35][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:39][CH2:40][CH2:41][CH3:42])[N:15]=[C:14]3[CH3:43])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCCCc1nc(C)n(CC(O)C23CC4CC(CC(C4)C2)C3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CCCCc1nc(C)n(CC(=O)C23CC4CC(CC(C4)C2)C3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 3-[2-(1-adamantyl)-2-hydroxyethyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.078 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.067 g) and methylene chloride (10 mL) was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture. The mixture was stirred at room temperature for 2 hr and extracted with chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.057 g, 73%).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:15]([S-:20])(=[S:19])OCC.[K+].O.Cl>CN(C=O)C>[C:9]([C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:15]([SH:20])[S:19][C:2]=2[CH:8]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1ccc2nc(S)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 2-fluoro-4-((trimethylsilyl)ethynyl)aniline (4.4 g, 21.2 mmol) from Step 1 of this Example in 20 mL of DMF was added potassium O-ethyl carbonodithioate (7.48 g, 46.8 mmol). The resulting mixture was heated under reflux for 4 h. After cooling to rt, the reaction mixture was treated with water (30 mL) and 1N HCl (100 mL). The mixture was stirred at rt for 2 h before the precipitates were collected by filtration and washed with water to give the crude 6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 99%) as a dark brown solid. LCMS (ESI) m/z 192 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.O1CCOCC1.C(N(C(C)C)CC)(C)C.[CH:53]1([S:56](Cl)(=[O:58])=[O:57])[CH2:55][CH2:54]1>CO.ClCCl>[CH:53]1([S:56]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:15]3[CH:19]=[C:18]([C:20]4[N:25]5[CH:26]=[CH:27][N:28]=[C:24]5[CH:23]=[C:22]([C:29]5[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=5)[N:21]=4)[CH:17]=[N:16]3)[CH2:7]2)(=[O:58])=[O:57])[CH2:55][CH2:54]1
Reactant: COc1ncc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ncc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C5CC5)C4)c3)n2)cn1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
tert-Butyl 3-(cyanomethyl)-3-(4-(7-(2-methoxypyrimidin-5-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (150 mg, 0.308 mmol) was dissolved in MeOH (5 ml) and a 4M HCl/dioxane solution (5 mL) was added. The resulting mixture was stirred for 20 minutes and then was concentrated to a solid. To the solid was added dichloromethane (15 mL) and diisopropyl ethylamine (787 μL, 4.52 mmol). After 10 minutes, the resulting mixture was cooled to −40° C. and cyclopropanesulfonyl chloride (43.3 mg, 0308 mmol) was added. The reaction mixture was allowed to come to ambient temperature overnight. The resulting mixture was concentrated to an oil and the oil was chromatographed to yield 70.8 mg (46.8%) of the title compound. MS (apci) m/z=509.0 (M+H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][C:5]=1[C:6]#[N:7].[BH4-].[Na+].S(OC)(OC)(=O)=O>O.CO>[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#CSc1ccc(N)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CO
Product: CSc1ccc(N)c(C#N)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium hydroxide (97%, 1.20 g (29.1 mmol)) was dissolved in a mixed solvent of water (4.0 ml) and methanol (20.0 ml). To this, 2-amino-5-thiocyanobenzonitrile (5.03 g (28.7 mmol) was added with stirring. To the resulting mixture, after 30 minutes' stirring under cooling with ice, sodium borohydride (90%, 0.60 g (14.3 mmol)) was added and further stirred for 30 minutes under cooling with ice. Then, dimethyl sulfate (95%, 3.0 ml (30.0 mmol)) was added dropwise. The resulting mixture was further stirred under cooling with ice for 30 minutes and at room temperature for 30 minutes, and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 4.73 g (100%) of 2-amino-5-methylthiobenzonitrile as yellow crystals.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](C(OCC)=O)[C:27]([O:29]CC)=[O:28].CC(C)=O>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][CH:15]=1)[CH2:11][O:13][C:26]([C:27]([OH:29])=[O:28])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(O)C1=C(c2ccccc2)c2cc(Br)ccc2CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.6 %

Procedure:
A mixture of 2-benzoyl-4-bromobenzoic acid (25 g, 82 mmol), potassium carbonate (12 g, 87 mmol), diethyl bromomalonate (22 g, 92 mmol), acetone (450 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The residue was crystallized from hexane and the crystals were collected by filtration. The obtained crystals were added to a mixture of acetic acid (235 mL) and concentrated hydrochloric acid (360 mL) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (17 g, 60%) as crystals.
Reaction SMILES: Cl[C:2](Cl)([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:2]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)([C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: COc1cccc(C(Cl)(Cl)c2cccc(OC)c2)c1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Product: CCOC(=O)c1ccc2c(c1)OC(c1cccc(OC)c1)(c1cccc(OC)c1)O2

Procedure:
This compound was prepared from dichloro-bis-(3-methoxyphenyl)-methane and ethyl 3,4-dihydroxybenzoate according to Example 269d; the crude product was used for the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.B(F)(F)F.[C:20](=O)(O)[O-].[Na+]>>[CH3:20][O:14][C:13]([C:3]1[C:2]([OH:1])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]2)=[CH:5][CH:4]=1)=[O:15]
Reactant: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)c1ccc2ccc(C)nc2c1O

Procedure:
8-Hydroxy-2-methyl-7-quinolinecarboxylic acid (as reported by Meek, W. H. et al., in J. Chem. Eng. Data 1969, 14(3), 388-91) is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent such as isooctane to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][O:1][C@@H:2]1[C@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@H:5]2[C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](O)[C@H]2OC(C)(C)O[C@H]21
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta-[d][1,3]dioxol-4-yl)carbamate (7.0 g, 25.6 mmol) in dry DMF (70 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.3 g, 30.7 mmol). After stirring for 30 min at 0° C., 2-(tert-butoxy)ethyl 4-methylbenzenesulfonate (7.0 g, 25.6 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (70 mL). To the mixture was extracted 3×100 mL of n-hexane. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIId was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[N:13]=1.[ClH:31]>C(#N)C.[Cu]Cl>[Cl:31][C:9]1[S:10][C:11]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[N:13]=1
Reactant: Cl
Reactant: CCOC(=O)c1sc(N)nc1OCc1ccccc1C(F)(F)F
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
Copper(I) chloride (0.342 g, 3.45 mmol) and t-butyl nitrite (0.52 mL, 4.37 mmol) were stirred in 20 mL of acetonitrile. Ethyl 2-amino-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate (1.00 g, 2.88 mmol) was added, and the reaction was stirred for 1.5 hours. The reaction was heated to 65° C. with an oil bath for an hour and cooled to room temperature. The reaction mixture was slowly pipeted onto 40 mL of 6N HCl stirring at 0° C. The ice bath was removed, and the mixture was warmed to room temperature, where it stirred for 30 minutes. The mixture was poured into ethyl acetate and water, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide 0.537 g (51%) of ethyl 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.73 (m, 3H), 7.60 (m, 1H), 5.63 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[S:11])[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: NCC(N)=O
Product: NC(=O)CNC(=S)Nc1c(Cl)cccc1Cl

Procedure:
2-[3-(2,6-Dichlorophenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 40.8 g of 2,6-dichlorophenyl-isothiocyanate and 29.6 g of glycinamide. The product was obtained (54 g) as a solid, m.p. 189°-191° C. Mass spectrum (+FAB, [M+H]+) m/z 278/280/282. This intermediate was used in the next paragraph without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:17][C:18]3[N:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][C:22](C#N)=[C:21]4[O:30][CH:31]([CH3:33])[CH3:32])[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C(O[Na])(C)=O.C(OC1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)(C)C>CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[S:12][C:13](=[CH:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[C:21]([O:30][CH:31]([CH3:33])[CH3:32])[CH:22]=[CH:23][N:24]=4)[N:19]=3)[C:14](=[O:16])[N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCCc4cccc(F)c4)=NC3=O)nc12
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a mixture of 2-[2-(3-fluoro-phenyl)-ethylamino]-thiazol-4-one (38.1 mg, 0.16 mmol) (see Example 7), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 4 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-[2-(3-fluoro-phenyl)-ethylamino]-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a light green solid (45.9 mg, 65.8%). HR-ES (+) m/e calcd for C23H21FN4O2S (M+H)+ 437.1442. found 437.1443.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:20][CH2:21][F:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:20][CH2:21][F:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2cc(F)c(F)cc2c1=O
Yield: 70 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), 1-bromo-2-fluoroethane (25.1 g, 197.5 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylformamide (200 ml) and heated to 90° for 20 hours. The reaction mixture was poured into cold water (1.5 l), and the copious precipitate was filtered. The precipitate was washed with cold water and recrystallized from ethyl acetate to provide the title product as light brown needles, m.p. 178°-180° (8.22 g, 27.5 mmol, 70% yield).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:15])[CH2:7][NH:8][C:9]2[CH2:13][S:12][C:11](=[O:14])[N:10]=2)[CH2:2]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:13]2/[C:9]([NH:8][CH2:7][C:6]([NH:5][CH:3]3[CH2:4][O:1][CH2:2]3)=[O:15])=[N:10][C:11](=[O:14])[S:12]/2)[CH2:23][CH2:22]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C(CNC1=NC(=O)SC1)NC1COC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C(CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)NC1COC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 52.4 %

Procedure:
To a solution of N-oxetan-3-yl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (2 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.47 g) in 2-propanol (20 mL) was added piperidinium acetate (1.06 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated under reduced pressure. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane/water to give the title compound (2.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C(O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:23][O:22][C:20](=[O:21])[C:17]1[CH:18]=[CH:19][C:14]([C:13]2[S:28][C:9]([C:8]3[CH:25]=[CH:26][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=3)=[N:11][N:12]=2)=[CH:15][CH:16]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1
Yield: 60 %

Procedure:
1,2-di(4-Carbomethoxybenzoyl)hydrazine (A), prepared as in Example 1, in pyridine was refluxed with phosphorus pentasulfide for 15 hours. The mixture was cooled and poured into 20% ethanol. After the solution was neutralized with sodium bicarbonate, the product, dimethyl-4,4'-(1,3,4-thiadiazol-2,5-diyl)dibenzoate (D), was obtained by filtration (m.p. 268°-270°, yield 60%). Then II was obtained by reacting D in a similar manner as in Example 1.