Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: O=C(c1ccccc1)N1CCCC1c1cccc(O)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Reaction time: 22 h
Yield: 60 %

Procedure:
To a solution of 3-[1-benzoyl-2-pyrrolidinyl]phenol (0.69 g) in dry tetrahydrofuran (35 ml) was added methyl isocyanate (0.16 ml) followed by milled potassium carbonate (0.46 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 22 hrs, at which time it was filtered through a pad of celite, and the solids washed with ethyl acetate. The combined filtrates were concentrated. Recrystallization of the residue from ethyl acetate afforded 0.50 g (60%) of product, mp 117°-121° C.
Reaction SMILES: [C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4](Cl)[CH:5]([CH3:7])[CH3:6].[C:13]([OH:19])(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.O>CCOCC>[C:1](=[O:12])([S:9][CH2:10][CH3:11])[O:2][O:3][CH:4]([O:19][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)O
Reactant: CCSC(=O)OOC(Cl)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: O
Product: CCSC(=O)OOC(OC(=O)C(C)(C)C)C(C)C
Temperature: 75 °C
Reaction time: 96 h

Procedure:
A mixture of (44) (936 mg, 4.76 mmol), pivalic acid (2.43 g, 23.8 mmol) and N,N-diisopropylethylamine (2.40 g, 23.8 mmol) was stirred at 75° C. for four days, and the reaction was judged complete by 1H-NMR. The reaction mixture was cooled to room temperature and portioned between water and ether, the ether phase was washed successively with water, aqueous NaHCO3, and brine, then dried over anhydrous Na2SO4. After rotary evaporation, the crude O-(1-pivaloyloxyisobutoxy) S-ethyl thiocarbonate (45) was obtained in quantitative yield, and used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.96 (d, 6H), 1.21 (d, 9H), 1.30 (t, 3H), 2.03 (m, 1H), 6.65 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](C)[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[C:20]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:33]2[CH:34]=[CH:35][C:30]([C:20]3[C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[C:25]=4[CH:17]=[CH:18][CH:19]=3)=[CH:31][CH:32]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)CSCc1ccc(Br)cc1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A solution of 3-(4-bromophenylmethylsulfanyl)-2-methylpropanoic acid methyl ester (0.260 g, 0.82 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (0.236 g, 086 mmol) and Pd(PPh3)4 (0.052 g, 5 mol %) in toluene (10 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (280 mg, 67%) as an oil. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 3.79 (s, 2H), 3.71 (s, 3H), 2.73 (s, 2H), 1.27 (s, 6H). LCMS 504 (M++23).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH:27]5[CH2:31][CH2:30][O:29][C:28]5=[O:32])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.FC(F)(F)C([O-])=O>>[CH3:1][C:2]1([CH3:33])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH:27]([CH2:31][CH2:30][OH:29])[CH2:28][OH:32])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCC5CCOC5=O)CC4)n3)ccc21
Agent: O=C([O-])C(F)(F)F
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCC(CO)CCO)CC4)n3)ccc21

Procedure:
The reduction was carried out analogously starting from 77 mg of 3-(2-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazin-1-yl}-ethyl)dihydrofuran-2-one from step a. The product is in the form of the trifluoroacetate salt.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:9][CH:8]=[C:7]([CH:18]2[CH2:20][CH2:19]2)[N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[CH:18]1([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(C2CC2)cnc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid methyl ester (150 mg, 550 μmol) in THF (9 ml) and MeOH (1.8 ml) was cooled at 0° C. and treated with LiOH (1.66 ml, 1N aqueous solution). The ice bath was removed after 10 min and the reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was acidified with HCl (1.66 ml, 1N aqueous solution), diluted with water and extracted with dichloromethane. The combined organic layers were dried and concentrated in vacuo to yield a yellow solid. The aqueous phase was also concentrated in vacuo and the residue was triturated with ethyl acetate and sucked off to yield identical yellow solid (according to analytics). The solid material was combined to yield the product (75 mg, 52%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC2(C(=O)OC)CCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(CC2(C(=O)O)CCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of 10.85 g methyl (4-ethoxybenzyl)-tetrahydro-2-furancarboxylate in 200 ml of ethanol was added 50 ml of 5N sodium hydroxide solution, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dissolved in 500 ml of ethyl acetate and 100 ml of 5N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with diisopropyl ether, to give 8.74 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([NH:49][C:50]([C:52]1[N:53]=[C:54]([C:61]([F:64])([F:63])[F:62])[N:55]2[CH2:60][CH2:59][NH:58][CH2:57][C:56]=12)=[O:51])[CH3:48].C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH2:47]([NH:49][C:50]([C:52]1[N:53]=[C:54]([C:61]([F:63])([F:64])[F:62])[N:55]2[CH2:60][CH2:59][N:58]([C:4](=[O:5])[C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])[CH2:57][C:56]=12)=[O:51])[CH3:48]
Reactant: CCNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 43.9 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (250 mg, 0.84 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (480 mg, 1.26 mmol), crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (242 mg, 0.92 mmol) and N, N-diisopropylethylamine (0.3 mL, 1.68 mmol). After stirring for 12 hours, the reaction mixture was added with 50 mL of H2O, and extracted with dichloromethane (50 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 100 mL of ethyl acetate, washed successively with saturated sodium bicarbonate solution (40 mL), saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-ethyl-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 7 (200 mg, yield 43.9%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: O=C1CCCCC1
Product: C1CCC2(CC1)NCCO2

Procedure:
2-Hydroxyethylamine and cyclohexanone were reacted according to Method B4a, Step 1 to afford 4-aza-1-oxaspiro[4.5]decane. The oxazolidine was reduced according to method B4a, Step 2 to afford N-cyclohexyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclohexyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methyl-4-nitrophenylimino)-3-cyclohexyl-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([C:24]([O:26]CC)=[CH2:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].CC(C)=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:24]([C:22]1[CH:21]=[CH:20][C:3]([C:4]([NH:6][CH2:7][C:8]2[S:9][C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)=[O:5])=[C:2]([NH2:1])[N:23]=1)(=[O:26])[CH3:25]
Reactant: C=C(OCC)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 2-amino-6 (1-ethoxy vinyl)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide described in Preparation Example A+-14 (2.0 mg, 0.0051 mmol) and acetone (2 mL) were added water (1 mL) and concentrated sulfuric acid (0.2 mL), and the solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with an aqueous solution of saturated sodium bicarbonate, and ethyl acetate was added for extraction. The organic layer was washed with brine, the solvent was then evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (1.0 mg, 0.0027 mmol, 53%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([O:24][N:25]=[C:26]1[C:30]2([CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)[CH2:29][NH:28][CH2:27]1)[CH3:23].C(#N)C>C(N(CC)CC)C>[C:37]([O:36][C:34]([N:32]1[CH2:33][C:30]2([C:26](=[N:25][O:24][CH2:22][CH3:23])[CH2:27][N:28]([C:11]3[C:12]([F:14])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[C:9]([NH2:17])[C:10]=3[F:16])[CH2:29]2)[CH2:31]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCON=C1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid, 680 mg of t-butyl 8-(ethoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 2 g of AmberliteR IRA-420 were added to 15 ml of acetonitrile and thereto 1.5 ml of triethylamine was dropped and the resulting mixture was refluxed for 5 days and filtered. The filtrate was concentrated under the reduced pressure and to the resulting residue 10 ml of isopropanol was added and the resulting solution was stirred for 1 hour at room temperature. The precipitated solid was filtered and dried to give 380 mg of the titled compound (yield: 51.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C@@H:5]([C:6]([O:8]C(C)(C)C)=[O:7])[CH2:4][C@H:3]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O1CCOCC1>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([C@@H:3]1[CH2:4][C@H:5]([C:6]([OH:8])=[O:7])[C:2]1([CH3:23])[CH3:1])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)[C@@H](C(=O)O)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
To a solution of (1R,3S)-1-benzyl 3-tert-butyl 2,2-dimethylcyclobutane-1,3-dicarboxylate (step 3, 1.0 g) dioxane-HCl (10 ml) was added at about 0° C. under nitrogen atmosphere. The reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give crude product, which upon column chromatography to afford the title compound (800 mg, 97.2% Yield). 1H NMR (300 MHz, CDCl3): δ 7.35 (5H, s), 5.12 (2H, d, J=2.7 Hz), 2.84 (2H, m), 2.63 (1H, m), 2.0 (1H, m), 1.35 (3H, s), 0.99 (3H, s); Mass: [M+H]+ 263.1 (20%), 285.1 [M+Na]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:10]([OH:19])=N[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=O)[CH3:2].[CH3:24]OCCOC(/N=N/C(OCCOC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3][C:4]1[C:5]([C:6]2[O:19][C:10]3[CH:24]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=3[N:8]=2)=[CH:20][CH:21]=[CH:22][N:23]=1)[CH3:2]
Reactant: CCSc1ncccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Reactant: COCCOC(=O)/N=N/C(=O)OCCOC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1ncccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 0.69 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl) nicotinamide, 0.75 g of DMEAD, 0.79 g of triphenylphosphine and 7 ml of THF was stirred at 50° C. for 4 hours. A saturated aqueous ammonium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.45 g of 2-(2-ethylsulfanylpyridin-3-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as Compound of Present Invention 34).
Reaction SMILES: FC1C=CC(O)=CC=1.FC1C=CC(OCCC#N)=CC=1.C(#N)C=C.[F:25][C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1.Cl.S(=O)(=O)(O)O>>[F:25][C:26]1[CH:27]=[C:28]2[C:29](=[CH:36][CH:37]=1)[O:30][CH2:31][CH2:32][C:33]2=[O:35]
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: Cl
Agent: N#CCCOc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: C=CC#N
Product: O=C1CCOc2ccc(F)cc21

Procedure:
Later developments in the overall method of production then finally gave a process for producing sorbinil which involved the following steps, viz., (1) p-fluorophenol was first converted to β-(p-fluorophenoxy)propionitrile by treatment with acrylonitrile in the presence of Triton B; (2) the nitrile intermediate was then converted to β-(p-fluorophenoxy)propionic acid by means of hydrochloric acid; (3) β-(p-fluorophenoxy)propionic acid was then condensed in the presence of concentrated sulfuric acid at 50° C. to afford 6-fluoro-4-chromanone; (4) the latter compound was thereafter condensed with potassium cyanide and ammonium carbonate in ethanol under standard Bucherer-Berg conditions to give the racemic precursor of sorbinil, which is called dl-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione; (5) the latter racemic spiro-hydantoin was then hydrolyzed with aqueous sodium hydroxide to the corresponding spiro-amino acid, which is called 4-amino-6-fluorochroman-4-carboxylic acid; (6) the latter acid, which can not be conveniently isolated in the process, was then treated in situ with sodium or potassium cyanate (after first adjusting the pH of the aqueous solution) in order to convert the amino acid to the corresponding hydantoic acid, which is called 6-fluoro-4-ureidochroman-4-carboxylic acid; (7) the latter hydantoic acid was then resolved according to the method described by B. W. Cue, Jr. et al. U.S. Pat. No. 4,435,578 by treatment with l-(-)-ephedrine in aqueous methanol to form the l-(-)-ephedrine salt of (4S)-6-fluoro-4-ureidochroman-4-carboxylic acid; and (8) the latter crystalline salt was thereafter converted to sorbinil by heating the diastereoisomer in glacial acetic acid to effect conversion to the desired (4S)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=C)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].C1COCC1.[OH2:37].I([O-])(=O)(=O)=O.[Na+].[OH2:44]>[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=[O:44])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S@:14](=[O:37])[CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1cc2ccccc2c2c1[S@](=O)CCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Temperature: 25 °C

Procedure:
To a solution of 2-[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]-1-oxo-1,2,3,4-tetrahydronaphtho[1,2-f][1,4]thiazepine-6-carbonitrile (Example 1, 225 mg, 0.50 mmol) in 3:1 THF/water (10 mL) under nitrogen at 0° C. was added osmium tetroxide (4% in water, 32.5 μL, 0.01 mmol) followed in 10 min by portion wise addition of sodium periodate over 5 min. The reaction mixture was allowed to warm to ambient temperature over 3 h and clarified by the addition of water. The products were extracted into ether and organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and evaporated to 230 mg of an oil which was chromatographed on silica gel in 10% MeOH/CHCl3 to give 40 mg of intermediate 78a, 22 mg of Intermediate 78b and 11 mg of Intermediate 78c.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[N:21]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:23]=3)[C:20](=[O:36])[NH:19][C:18]=2[C:37](=O)[NH2:38])=[CH:9]1)(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[N:21]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:23]=3)[C:20](=[O:36])[NH:19][C:18]=2[C:37]#[N:38])=[CH:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1cc(-n2c(-c3cn(CCCOC(C)=O)c4ccccc34)c(C(N)=O)[nH]c2=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)n1cc(-n2c(-c3cn(CCCOC(C)=O)c4ccccc34)c(C#N)[nH]c2=O)c2ccccc21
Yield: 82.7 %

Procedure:
A solution of 0.14 g (0.26 mmole) of the product of step b) in 7 ml of TMS-polyphosphate was heated to 50° C. for 4 hours. The mixture was diluted to 20 ml with CH2Cl2 and washed with water and brine. The organic phase was and evaporated and the residue purified by chromatography on silica (CH2Cl2:MeOH 98:2), to give 0.11 g (82%) of the sub-title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1Cl.[ClH:11].C1C(O)=CC=CC=1C.[N:20]#[C:21][NH2:22].[OH-].[Na+]>CCOCC>[ClH:9].[Cl:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[N:2]([CH3:1])[C:21]([NH2:22])=[NH:20]
Reactant: CNc1c(Cl)cccc1Cl
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: CN(C(=N)N)c1c(Cl)cccc1Cl

Procedure:
To 55.4 g (0.315 mole) of N-methyl-2,6-dichloroaniline is added 0.4 moles of ethereal HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2×1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dichlorophenyl)-1-methylguanidine hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:22][O:21][CH:19]1[CH2:20][N:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18]1
Reactant: COC1CN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)C1
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(c2ccc3c(c2)CNC3)C1

Procedure:
Prepared in analogy to Example A2(c) from 5-(3-methoxy-azetidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl Ester and trifluoroacetic acid. Brown foam. MS (m/e): 205.1 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([O:32][CH2:33][CH2:34]O)[CH3:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:31][CH2:30][O:32][CH2:33][CH3:34])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOCCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-[15-(trifluoromethyl)-pentadecylamino]benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.