Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:26][C:27]([NH2:29])=[O:28].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[NH:29][C:27](=[O:28])[N:26]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NC(N)=O
Reactant: CC(C)COc1ccccc1C(=O)CC(=O)c1ccc(F)c(C#N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)nc(=O)[nH]1
Temperature: 115 °C
Yield: 17.4 %

Procedure:
To a sealed vessel were added 2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxopropanoyl)benzonitrile (5.9 g, 17.4 mmol), urea (10 g) and a solution of 4 N HCl in dioxane (80 mL). The reaction mixture was heated at 115° C. for 4 h then cooled. More urea (10 g) and 4 N HCl in dioxane (50 mL) were added to the vessel and the reaction was again heated to 115° C. for 4 h. Upon cooling, a precipitate formed and the reaction mixture was filtered in vacuo. The filtrate was determined by LC/MS to contain the desired product and was concentrated in vacuo. The concentrated reaction mixture was dissolved in dichloromethane (100 mL) and was neutralized with a solution of saturated sodium bicarbonate and was then partitioned between dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo yielding 1.1 g crude 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzonitrile and was submitted to the next step with no further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxyindole (55 mg, 0.41 mmol) in DMF (1.5 ml) containing potassium carbonate (70 mg, 0.51 mmol) was heated at 100° C. for 2 hours. After cooling, water was added and the precipitate was collected by filtration, washed with water followed by ether, and dried under vacuum over phosphorus pentoxide to give 4-(indol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (90 mg, 64%).
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:10][C:2]1[O:18][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A 500-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a Claisen head with a condenser and a receiver connected to a cold trap and a vacuum controller was charged with 52.26 g of crude methyl 4-bromo-3-oxovalerate (ca. 0.250 mol) and 46.5 g of benzamide. A vacuum of 400 mbar was applied and the suspension was stirred at 90° C. for 18 h. After ca. 3 h the suspension had become a clear orange oil. After cooling to rt 300 ml of methanol and 1.0 g of p-toluenesulfonic acid monohydrate were added and the brown solution was stirred at reflux (ca. 73° C.) for 1 h. After this time 50 ml of methanol were distilled off, 50 ml of methanol were added and the mixture was heated at reflux for additional 30 min. After cooling and rotary evaporation (50° C., 8 mbar, 30 min), the residue was treated under argon with 150 ml of toluene and 125 ml of sat. aqueous sodium bicarbonate solution. The resulting suspension was stirred in an ice bath for 1 h, the precipitated benzamide was filtered off with suction and the filter cake was washed twice with a small amount of ice-cold toluene and water. The combined aqueous phases were extracted in a separatory funnel with 100 ml of toluene. Thereafter the combined organic phases were washed twice with 30 ml, a total of 60 ml of deionized water, dried (Na2SO4) and rotary evaporated (50° C., 8 mbar,1 h) to give 49.22 g of crude Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (theor. amount 57.81 g) as a yellow oil, which was used without purification in the next step.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](F)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]#[N:20])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH2:26][CH2:25][O:24][CH3:23])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]#[N:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c(C#N)cnc2cc(F)c(OC)cc12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Product: CCCCNc1c(C#N)cnc2cc(OCCOC)c(OC)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-butylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.55 mmol) and sodium hydride (55 mg, 2.29 mmol) in 1.7 mL of 2-methoxyethanol is heated at reflux for 30 minutes then cooled to room temperature. The reaction mixture is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 5% methanol in dichloromethane, followed by trituration with ethyl acetate, provides 135 mg of 4-butylamino-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 99-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[CH3:30][NH2:31].O.[OH-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][NH:31][CH3:30])[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CN
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCc1csc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) and KI (3 mg) in a 8M solution of methylamine in EtOH (1 mL) was stirred at 20° C. for 20 h. H2O (25 mL) was added and the pH of the mixture was set to 11 by addition of 2N NaOH. The precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) and the solid was isolated by filtration to give the title compound (49 mg) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:20])=[CH:17][CH:16]=3)=[CH:14][C:6]1=2
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 53 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (50 mg) was reacted with (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as in General Procedure 8 to give the title compound as a pale yellow solid (53% yield). M.p. 143-144° C., LCMS: m/z=518.30 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.48-1.58 (m, 1H), 1.87-2.15 (m, 4H), 2.17-2.22 (m, 3H), 2.55-2.64 (m, 4H), 2.83-2.89 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.50 (m, 2H), 3.60-3.64 (m, 2H), 4.40-4.49 (m, 3H), 5.07 (bs, 1H), 6.76 (s, 1H), 6.86-7.09 (m, 3H), 7.41 (d, J=8.1 Hz, 2H), 7.45-7.52 (m, 2H), 7.73 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].I[CH2:13][CH3:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: Fc1ccc(S)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in MeOH was stirred at 0° C. for 10 minutes. To this solution was added iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with addition ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (4.35 g, 18.50 mmol, 98% yield). It was used directly for the next reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][CH:5]([OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[CH3:26][CH2:27]O>B(F)(F)F.CCOCC>[CH3:1][C:2]1([CH3:25])[O:6][CH:5]([O:7][CH2:26][CH3:27])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC1(C)OC(O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: CCO
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC1OC(C)(C)C(c2ccc(S(C)(=O)=O)cc2)=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5,5-dimethyl-2-hydroxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran (Example 1, 500 mg, 1.38 mmol) in 5 mL of EtOH was added 3 drops of BF3.OEt2. The mixture was stirred at room temperature for 45 min, and the resulting precipitate was filtered and washed with EtOH to provide 497 mg of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[O:12]=[C:13]1[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH2:22][N:23]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(NCc2cnccc2NC(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2Cc3cnccc3NC2=O)CC1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
Trifluoroacetic acid (0.50 mL) was a add to a solution of the material from Step A (0.24 g, 0.63 mmol) in dichloromethane (5 mL). After stirring overnight, another 0.5 mL of trifluoroacetic acid was added. After an additional 2 h, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.31 g, 1.89 mmol) was added at room temperature. After 2 h, the acetonitrile was evaporated in vacuo, the residue partitioned between 1N NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 10 to 15% methanol in methylene chloride gradient elution), which gave the title compound (0.089 g). MS 305.3.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][Cl:35]>>[ClH:35].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: COc1cccc(CCl)c1
Agent: Cl
Product: COc1cccc(CN2CN(c3ccccc3)C3(CCN(C4CCCCCCCCC4)CC3)C2=O)c1

Procedure:
The title compound, white solid, m. p. 175° C. and MS: m/e=490.4 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-methoxybenzylchloride.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(S[C:15]1[S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[N+:19]=1[CH2:20][CH3:21])C.[C:26]([CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[S:38])([O:28][CH2:29][CH3:30])=[O:27]>C(N(CC)CC)C>[C:26]([CH2:31][N:32]1[C:36](=[O:37])[C:35](=[S:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[N:19]([CH2:20][CH3:21])[CH2:15]2)[S:34][C:33]1=[S:38])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCSc1sc2ccccc2[n+]1CC
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)C(=S2CN(CC)c3ccccc32)SC1=S

Procedure:
To 30 ml of an ethanol solution of 13.0 g of the intermediate product obtained in Preparative Example 2, viz., 2-ethylmercapto-3-ethylbenzothiazolium p-toluenesulfonate, was added 4.4 g of 3-carboethoxymethylrhodanine, while stirring the mixture at room temperature (about 20° C.), 6.1 g of triethylamine was added dropwise to the solution over a 3 minute period, and thereafter the resultant mixture was refluxed for 10 minutes. After cooling the reaction mixture, precipitates formed were recovered by filtration and recrystallized from a mixture of chloroform and ethanol to provide 1.1 g of 3-carboethoxymethyl-5-(3-ethylbenzothiazolylidene)rhodanine (melting point 250° to 252° C.).
Reaction SMILES: CS([S:5][CH2:6][CH2:7][S:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=O)=O.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:19][C:10]1[C:9]2[S:8][CH2:7][CH2:6][S:5][C:18]=2[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(SCCSS(C)(=O)=O)c1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1C)SCCS2
Temperature: 25 °C

Procedure:
49.2 g (0.154 mol) of methyl 3-(2-methylsulfonylthio-ethylthio)-2-methylbenzoate were dissolved in 500 ml of methylene chloride, 80.2 g (0.308 mol) of tin tetrachloride were added and the mixture was heated under reflux for three hours and stirred at room temperature for another ten hours. The mixture was then washed with water and saturated sodium bicarbonate solution and the organic phase was separated off, dried and concentrated. The oil that remained was chromatographed over silica gel using ethyl acetate/cyclohexane=1/10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([O:13]CC)(=[O:12])[CH:10]=[CH2:11].C(O)(=O)C.[OH-].[Na+]>>[Br:8][C:4]1[N:3]=[C:2]([NH:1][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CCNc1cccc(Br)n1
Temperature: 130 °C
Yield: 68 %

Procedure:
2-Amino-6-bromopyridine (25.0 g) was added to a mixture of ethyl acrylate (17.39 g) (1.2 eq) and acetic acid (4.55 g, 0.52 eq). The reaction mixture was heated at 130° C. for 70 hours and then cooled to room temperature. An aqueous NaOH solution (6N, 60 mL, 2.50 eq) was added and the resulting mixture was heated at reflux for one (1) hour and then cooled to room temperature. The solution was washed twice with ether and then acidified to pH 4-5 with concentrated HCl. The precipitate was collected by filtration to give the title compound as a tan solid (68% yield). M.p. 108-109° C., LCMS: m/z=245.06 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.33-3.40 (m, 4H), 6.46 (d, J=8.2 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 7.02 (t, J=5.4 Hz, 1H), 7.27 (dd, J=8.2 and 7.3 Hz, 1H), 12.22 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
To 110 ml of carbon tetrachloride, were added 10.5 g of 4'-methyl-2-cyanobiphenyl, 9.79 g of N-bromosuccinimide and 120 mg of 2,2'-azodiisobutylonitrile, followed by heating under reflux for 2 hours. After hot filtration of the insoluble matter, the filtrate was allowed to cool to room temperature. Crystals so precipitated were collected by filtration, whereby 6.6 g of the title compound was obtained.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH2:6][S:5][CH2:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(I)cc1F
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(Nc2ccc(I)cc2F)CSC1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J Org. Chem 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid. The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7 g, 42%). 1H NMR (d6-DMSO): 9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24 (t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccnc3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cccnc3)nc2c1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (123 μl, 0.970 mmol) and triethylamine (135 μl, 0.970 mmol) were added to a dimethyl sulfoxide (6 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(pyridin-3-yl)-1,3-benzoxazole-4-carbonitrile (I-209) (213 mg, 0.647 mmol), followed by stirring in an oil bath at 95° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml), then washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the residue was purified by silica gel column chromatography (eluent, chloroform/methanol=10:1), and the eluate was recrystallized from isopropanol to obtain the entitled compound (190 mg, 69.4%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][CH:6]=1.[C:9]([CH:11]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:10]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH:7]=[CH:11][C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CC=Cc1ccc(Cl)s1
Yield: 85.5 %

Procedure:
A solution of 2-chloro-5-formylthiophene (5.68 g., 40 mM) and cyanomethylenetriphenylphosphorane (12.04 g., 40 mM) in chloroform (100 ml.) was heated under reflux for 20 min., and was evaporated to an oily solid. This was triturated with ether (20 ml.) and colourless needles of triphenylphosphine oxide (m.p. 156°-157°) were filtered off, and were washed with ether (10 ml.). The combined filtrates were evaporated, and the residue was distilled under reduced pressure to give 3-(5-chlorothien-2-yl)acrylonitrile (5.62 g., 83%) as a colourless oil, b.p. 100°-104°/0.6mm., which crystallised in needles, m.p. 41°-43° [Found: C, 49.1; H, 2.5; C1, 21.1; N, 8.3; S, 19.1; C7H4ClNS (169.6) requires C, 49.6; H, 2.4; Cl, 20.9; N, 8.3; S, 18.9%]λmax. 315 nm (ε 21,120).
Reaction SMILES: C1(C2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][O:17][C:18]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[O:8]2)C=CC=CC=1.[ClH:26]>C(OCC)C>[ClH:26].[C:12]([NH:11][CH2:10][CH:9]([OH:8])[CH2:16][O:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1CC(COc2ncccc2C#N)OC1c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1ncccc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To S -2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred 4 hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform exrract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, S -2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of S -2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.