Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[CH:9]=[C:10]([S:12][CH3:13])[S:11][C:6]=2[CH:5]=1)(O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[OH:2][CH2:1][C:4]1[CH:16]=[CH:15][C:7]2[C:8](=[O:14])[CH:9]=[C:10]([S:12][CH3:13])[S:11][C:6]=2[CH:5]=1
Reactant: CSc1cc(=O)c2ccc(C(=O)O)cc2s1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cc(=O)c2ccc(CO)cc2s1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
7-Carboxy-2-methylthio-4-oxo-4H-1-benzothiopyran (1.48 g, 5.87 mmol) was suspended in tetrahydrofuran (30 ml), added with triethylamine (1 ml, 7.17 mmol) and cooled to −10° C. Then, the reaction mixture was added dropwise with ethyl chlorocarbonate (0.6 ml, 5.94 mmol) and stirred at 0-5° C. for 0.5 hour. The reaction mixture was filtered and the insoluble matter was further washed with tetrahydrofuran (10 ml×2 times). The washing liquid was mixed with the previous tetrahydrofuran solution. Sodium borohidride (568 mg, 15 mmol) was suspended in water (8 ml) and added dropwise with the previously obtained tetrahydrofuran solution over 45 minutes under ice-water cooling. The reaction mixture was acidified with 2N hydrochloric acid and extracted by ethyl acetate (300 ml), washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was washed with ether to obtain 800mg (yield: 57%) of substaintially pure 7-hydroxymethyl-2-methylthio-4-oxo-4H-1-benzothiopyran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:15][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc2cc(OCC(=O)OCC)c(Cl)c(Cl)c2s1
Reaction time: 72 h
Yield: 58.9 %

Procedure:
A mixture of 11.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, 8.82 g of ethyl bromoacetate, 7.52 g of potassium carbonate, 135 ml of 2-butanone and 9 ml of dimethylformamide is stirred for 3 days. The reaction mixture is filtered and 100 ml of water and 100 ml of ether are added. The layers are separated and the aqueous layer is extracted 2 times with 100-ml portions of ether. The combined organic layers are dried, filtered and the filtrate is evaporated to give an oil which crystallizes from hexane. Recrystallization from ether-hexane gives 9 g of ethyl [(6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetate, mp 62°-63°.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][OH:11])[CH2:5]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].C(#N)C1C=CC=CC=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH2:10][CH:6]2[CH2:7][CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]2)[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: CN1CCCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCCC(COc2cccc(F)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.2 %

Procedure:
Sodium hydride (60%; 316 mg; 7.9 mmol) was suspended in DMF and cooled to 0° C. 1-Methylpiperidin-3-ylmethanol (998 mg; 7.5 mmol) was added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1.1 g; 7.9 mmol) in DMF was cooled to 0° C. and the alcohol mixture was added dropwise to the benzonitrile solution and allowed to warm to room temperature overnight. The solution was poured into water and extracted with dichloromethane and solvent removed. Purification by column chromatography (10% ethyl acetate/hexane) to yield 79 milligrams of 2-fluoro-6-(1-methylpiperidin-3-ylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:8]1[CH:7]=[CH:6]2.[OH-].[Na+].C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:8]1[CH:7]=[CH:6]2
Reactant: CCOC(=O)c1cn2c(ccc3cc(OC)ccc32)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(ccc3nc(C(=O)O)cn32)c1

Procedure:
840 mg of ethyl 7-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate were suspended in a mixture of 100 ml of water and 150 ml of ethanol and 3.5 ml of N sodium hydroxide solution were added. The mixture was heated on a steam bath for 30 minutes and the resulting solution was decolorized with charcoal, filtered and acidified with 3.7 ml of N hydrochloric acid. The mixture was cooled in ice to obtain colorless crystals of 7-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 265°-266° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Ic1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccccc1
Yield: 90 %

Procedure:
Following General Procedure A (90° C., 30 hours), diethyl malonate (240 mg, 1.5 mmol) is coupled with iodobenzene (112 μL, 1.0 mmol) to give 90% diethylphenylmalonate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1.C1(C[C@@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1cnccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 96 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-aminopyrazine (95 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate/hexanes) 350 mg (96%)of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C21H24N4O2 (M+) 364.1899, found 364.1908.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=2[OH:11])[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(C)sc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C)sc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-methyl-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (21 g), potassium carbonate (12.2 g) and dry dimethylformamide (750 ml) was stirred at ambient temperature and iodomethane (6 ml) added. The mixture was stirred at ambient temperature for approximately 3.5 hours, then at 60° for 2 hours. The solvent was removed under reduced pressure to give a residue which on treatment with water (300 ml) gave the novel compound ethyl 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate, m.p. 143°-144°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[Mg].[Br-].[Li+].[F:12][C@H:13]1[CH2:30][C@@:28]2([CH3:29])[C@@H:24]([CH2:25][CH2:26][C:27]2=[O:31])[C@H:23]2[C@H:14]1[C@@H:15]1[C:20]([CH:21]=[CH:22]2)=[CH:19][C:18](=[O:32])[CH2:17][CH2:16]1>C1COCC1.CN1CCCN(C)C1=O.C[Si](C)(C)Cl.[Cu]I.C(O)(=O)C>[Cl:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:22]1[CH2:21][C:20]2[C@H:15]([CH2:16][CH2:17][C:18](=[O:32])[CH:19]=2)[C@@H:14]2[C@@H:23]1[C@H:24]1[C@@:28]([CH2:30][C@@H:13]2[F:12])([CH3:29])[C:27](=[O:31])[CH2:26][CH2:25]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: ClCCCCCCBr
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
First 30 ml of a solution that consists of 41 ml of 1-bromo-6-chlorohexane in 270 ml of THF is added to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction starts, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pynrmidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -40° C. Then, it is stirred for 30 more minutes at -30° C. and mixed drop by drop at -50° C. with a solution of 23.5 g of 11β-fluoro-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -40° C. It is stirred for 1 hour cold, then 32 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 25.2 g of 7α-(6-chlorohexyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[C:18]([N:20]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:11][CH:10]=1>CCOCC>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2[CH2:18][N:20]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1
Reactant: CCCN(CCc1ccccc1)C(=O)C1CCc2ccc(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCc1ccccc1)CC1CCc2ccc(OC)cc21
Reaction time: 5 h

Procedure:
To a suspension of 1 g of lithium aluminium hydride in 15 milliliters of anhydrous ether was added a solution of 5 g of the residue of 6-methoxy-N-propyl-N-(2-phenylethyl)-1-indanamide in 15 milliliters of anhydrous ether at a rate which maintained gentle reflux of the reaction mixture. Reflux and stirring were continued for 5 hours. The reaction mixture was then stirred overnight without heating. Destruction of the excess lithium aluminium hydride was completed by cautious dropwise addition of 1 milliliter of water followed by dropwise addition of 1 milliliter of 14% sodium hydroxide solution and subsequent addition of 5 milliliters of water. Stirring was continued for 30 minutes. Filtration yielded a clear ether solution which was dried (MgSO4) and evaporated, yielding 4 grams of an oil, which was used directly in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:8]([C:10]2[N:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[CH:26]=3)[C:20]([O:22]C)=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1>O.C1COCC1>[N:4]1([C:8]([C:10]2[N:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:34])[CH2:29][O:30][CH:31]([F:32])[F:33])[CH:26]=3)[C:20]([OH:22])=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
Lithium hydroxide monohydrate (48 mg, 1.13 mmol) in water (5 mL) was added to a solution of methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoate (0.33 g, 0.75 mmol) in THF (10 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a white foam (0.26 g). m/z 424 (M+H)+
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]=1.C(N(CC)[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[CH3:33])C.[ClH:37].[NH4+].[OH-]>O1CCCC1.O>[ClH:37].[CH:21]1[C:22]2[CH:13]3[N:14]([C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=4[CH2:33]3)[CH2:15][CH2:16][C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CCN(CC)C(=O)c1cccnc1C
Reactant: C1=NCCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2cccnc2CC2c3ccccc3CCN12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
Diisopropylamine (28 ml) and 150 ml of tetrahydrofuran were cooled to -65° C. and 125 mL of 1.6M n-butyllithium was added. To the resulting solution was added a solution of 16.2 g of 3,4-dihydroisoquinoline and 38.4 g of 2-methylnicotinic acid diethylamide in tetrahydrofuran. The mixture was allowed to warm to -20° C. and 600 ml of 3N hydrochloric acid was then added followed by 200 ml of water. The mixture was basified with NH4OH and extracted twice with ether. The ether extracts were combined, dried over anhydrous magnesium sulfate and evaporated to a residue, which was dissolved in methanol and acidified with anhydrous HCl in ether. Acetone (50 ml) was added and the mixture was allowed to stand overnight. The crystalline product was collected by filtration, yielding 34 g of (±)-5,6,13,13a-tetrahydroisoquino[2,1-g][1,6]naphthyridine-8-one hydrochloride, m.p. 220°-222° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[CH:6][CH:5]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][CH:6]=1)[CH3:11])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: CNc1ccc(C(=O)OC)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N(C)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
4-Methylamino-benzoic acid methyl ester (0.41 g) were suspended in chloroform (20 ml). Isobutyryl chloride (0.79 g) in chloroform (10 ml) was added dropwise for 30 minutes and then dropwise triethylamine (1 ml) dissolved in chloroform (5 ml). The reaction mixture was stirred for 3 hours and the solvent was evaporated. 1M NaOII(aq) (40 ml) was added and the mixture stirred overnight. The solution was filtered to remove unsolved material and then acidified with 2M HCl(aq). Filtration and drying in vacuum yielded 0.48 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[N:7]=[CH:11][CH:10]=[C:12]2[CH3:14]
Reactant: C=CC(C)=O
Reactant: COc1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1ccc2nccc(C)c2c1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a stirred solution of 4-methoxyaniline (1 g. 8.1 mmol.) in acetic acid (10 ml), activated silferc (1.3 g., ferric chloride 8.1 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.62 g, 8.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.1 g. 8.1 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 58%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C(=O)N([Cl:23])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[C:10]([Cl:23])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(NC2CCC2)c2cc[nH]c2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1nc(NC2CCC2)c2c(Cl)c[nH]c2n1
Yield: 19.4 %

Procedure:
To a suspension of 2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (102 mg, 0.460 mmol) in CH2Cl2 (5 mL) at room temperature, NCS (68 mg, 0.51 mmol) was added. The mixture was stirred at reflux for 18 h. After being concentrated in vacuo, the residue was purified by HPLC to give 2,5-dichloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (23 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.C(OCC)(=O)C>[CH3:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ncccc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 33.3 %

Procedure:
Preparation of example 14 from the title compound of Example 7 (15 mg, 0.054 mmol), 2-methyl-nicotinic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (ethyl acetate), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.018 mmol) as a yellow powder in 33% yield.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[I-].[Na+].[CH2:18]([N:20]([CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])[CH3:19]>CC(C)=O.C(=O)([O-])O.[Na+].O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2([C:3]3[N:27]=[C:25]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:28][CH3:29])[S:26][CH:2]=3)[CH2:8][CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: O=C(CCl)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCN(CC)CCCNC(N)=S
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)CCCNc1nc(C2(c3ccc(Cl)cc3)CCC2)cs1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-1-[1-(4-chlorophenyl)cyclobutyl]ethanone (120 mg, 0.494 mmol) and sodium iodide (74 mg, 0.494 mmol) in acetone (2.5 mL) was stirred at room temperature for 5 minutes. Next (3-diethylaminopropyl)thiourea (94 mg, 0.494 mmol) was added. The resulting mixture was heated at 50° C. for 1 h. After the mixture was allowed to cool to room temperature, it was diluted with 5% sodium hydrogen carbonate in water and then extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil. The oil was purified by column chromatography on silica gel using dichloromethane/2 N ammonia in ethanol (90:10) to give 162 mg of N′-{4-[1-(4-chlorophenyl)cyclobutyl]thiazol-2-yl}-N,N-diethylpropane-1,3-diamine, 19, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 1.02 (t, 6H, J=7.2 Hz); 1.71–1.80 (m, 2H); 1.82–1.91 (m, 1H); 2.08–2.20 (m, 1H); 2.48–2.59 (m, 8H); 2.67–2.76 (m, 2H); 3.27 (t, 2H, J=6.3 Hz); 5.91 s (s, 1H); 6.17 (bs, 1H); 7.25 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 11.8, 16.9, 26.2, 34.3, 45.8, 47.1, 49.1, 51.9, 100.3, 128.2, 128.3, 131.5, 147.1, 159.8, 169.9.
Reaction SMILES: [C:1]1(Br)[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3].C([Li:17])CCC>>[C:1]1([Li:17])[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: [Li]CCCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F

Procedure:
The reaction mixture may also be reacted directly without isolation of the C6F5Br with butyl lithium to produce C6F5Li which,in turn, is reacted with BCl3 or BF3 to produce (C6 F5)3B.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.CN(C)C=O.Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:10][N:9]=1
Reactant: BrCCOC1CCCCO1
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(OCCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add cesium carbonate (3 Eq, 53.05 mmoles; 17.2 g) to a solution of 2-fluoro-5-hydroxypyridine (2.0 g, 1.00 Eq, 17.68 mmoles) in dimethylformamide (0.3 M; 762.37 mmoles; 59.0 mL), followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (17.7 mmoles, 3.7 g) and stir at room temperature overnight. Transfer to a separatory funnel and add EtOAc (500 mL). Wash organic layer, wash with water (300 mL) followed by brine (200 mL). Dry over Na2SO4, filter and concentrate. Purify the crude mixture by HPLC eluting with hexanes/EtOAc 7/3 to give 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine as a pale yellow oil (3.9 g, 16.2 mmoles; 91% yield). LCMS (Low) rt=1.8 min., M+1=242.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22](O)=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.[Cl-].[NH4+].N.Cl>O1CCCC1.CO.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]([NH2:29])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC(=O)O)c3c2)c1=O
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC(N)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetic acid (0.960 g, 0.00250 mol) and 1,1'-carbonyldiimidazole (0.420 g, 0.00259 mol) in tetrahydrofuran is stirred at room temperature for 4.5 hours, treated with ammonium chloride (0.230 g, 0.00430 mol), stirred overnight at room temperature, treated with concentrated ammonia (1.00 mL), stirred for 5 minutes, acidified with 10% hydrochloric acid, and concentrated in vacuo to obtain a residue. The residue is diluted with a 5% methanol in methylene chloride solution and the resultant mixture is stirred for three hours and filtered to obtain a solid. The solid is washed with a 5% methanol in methylene chloride solution, slurried in water, filtered, and dried to give the title product as a white solid which is identified by NMR spectral analysis.