Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH:7]2[O:11][C:10](=[O:12])[N:9]=[N:8]2)[CH2:6][CH2:5]1.[Cl:13][C:14]1[CH:15]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=[C:18]([Cl:21])[C:19]=1Cl.O>CN(C)C=O>[CH3:3][C:4]1([C:7]2[O:11][C:10](=[O:12])[N:9]([C:19]3[C:18]([Cl:21])=[CH:17][C:16]([C:22]([F:23])([F:25])[F:24])=[CH:15][C:14]=3[Cl:13])[N:8]=2)[CH2:6][CH2:5]1
Reactant: CC1(C2N=NC(=O)O2)CC1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(=O)o2)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
After 44 mg (1.1 mmol) of 60% sodium hydride was added to a solution of 0.14 g (1 mmol) of 5-(1-methylcyclopropyl)-1,3,4-oxadiazolin-2-one in 5 ml of N,N-dimethylformamide at room temperature, the mixture was stirred at the same temperature for 15 minutes. To the mixture was added 0.25 g (1 mmol) of 3,4,5-trichlorobenzotrifluoride followed by heating a 80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated under reduced pressure to give the crude product. The crude product was subjected to silica gel column chromatography to give 35 mg of 5-(1-methylcyclopropyl)-3-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazoline-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([NH:14][CH2:15][CH2:16][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: O
Product: CCCCNCCc1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.13 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[NH:21]([C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:24]=[C:22]([NH:21][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=4)[N:23]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)c2ccnc(Cl)c21

Procedure:
Prepared by treatment of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one and 3-guanidinobenzenesulfonamide hydrochloride. 1H-NMR (DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.48 (t, 2H, J=7.2 Hz, CH2), 7.30 (m, 3H, Pyrimidin-H and NH2), 7.43 (m, 1H, Ar—H or Ph-H), 7.50 (t, 1H, J=7.6 Hz, Ph-H), 7.82 (d, 1H, J=5.6 Hz, Ar—H), 7.89 (m, 1H, Ar—H or Ph-H), 8.07 (m, 1H, Ar—H or Ph-H), 8.45 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.48 (s, 1H, Ar—H), 8.61 (s, 1H, NH). MS (ESI+) m/z 426.1490 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([I:11])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cc1c(I)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 4, using 8.3 grams (0.063 mole) of 2-amino-3-cyano-4-methylpyridine (prepared as in Step B of Example 4) and 14.2 grams (0.063 mole) of N-iodosuccinimide in 250 mL of N,N-dimethylformamide, yielding 2-amino-3-cyano-5-iodo-4-methylpyridine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:25])[C:22]([O:27][CH3:28])=[O:26])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: COC(=O)C(C)O
Reactant: Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Yield: 189.6 %

Procedure:
A mixture of the 4-(4-bromo-2-fluorophenoxy)phenol (2.83 g, 0.01 mole), the methanesulfonate of S methyl lactate (18.2 g, 0.01 mole), and potassium carbonate (1.67 g, 0.012 mole) in DMSO (70 ml) was stirred at room temperature for 40 hours, then poured into water (700 ml). The mixture was extracted with ether (2×200 ml). Pentane (100 ml) was added to the combined ether extracts and the resulting solution washed with water (300 ml). The organic phase was dried (MgSO4) and the solvent evaporated to give a light yellow oil (~7 g). This oil was purified via prep HPLC (8:2 hexane-acetone) with the first peak desired product enriched in the "R" enantiomer; Optical rotation=+20.34°@25° C. R.I.=1.5614@25° C.; NMR (CDCl3) was identical with that obtained in Example 4. No attempt was made to determine the optical purity of this material.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1.[OH-].[K+]>C(O)CCC.O>[CH3:1][C:2]1([CH3:24])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:23])[CH2:3]1
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(C)(C)CN3C
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Temperature: 120 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 1,1,3-trimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (8 mg, 0.02 mmol) in n-butanol (5 mL) at rt was added KOH (50 mg, 0.89 mmol) and stirred at 120° C. for 20 hours. The solution was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate and concentrated to afford the title compound (5 mg, 81%). MS [M+H]+ 258.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[O:19]=[C:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[O:10][C:1](=[O:11])[C@@H:2]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(ON1C(=O)CCC1=O)[C@@H](O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of (S)-(+)-mandelic acid (0.50 g, 3.3 mmol) and N-hydroxy succinimide (0.38 g, 3.3 mmol) in EtOAc (10 mL) was added 1,3-dicyclohexylcarbodiimide (0.67 g, 3.3 mmol) in EtOAC (5 mL) drop wise. The resulting solution was let stir for 4 h and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].C1CCCCC1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[C:22](O)(=[O:24])[CH3:23]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH2:20][C:22](=[O:24])[CH3:23])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(C)=O)cc1OC

Procedure:
3.9 g of sodium hydride were initially introduced into 150 ml of cyclohexane, and a solution of 15 g of 1-(3,4-dimethoxyphenyl)ethanone in 16.3 ml of ethyl acetate was added. The reaction solution was boiled at 80° C. for 1 h, after which acetic acid was added and the whole was extracted with MTB-ether. The MTB-ether phase was dried over magnesium sulfate and subjected to rotary evaporation. The residue was chromatographed through silica gel (ethyl acetate/heptane 1/6). The following was obtained: 41 C12H14O4 (222.24); MS (ESI) 223 (M+H)
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccncc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 1,1-dimethylethyl (4RS,5SR)-2-oxo-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate (500 mg, 1.18 mmol) in methanol (2.8 ml) was added 0.5N sodium hydroxide (2.8 ml, 1.40 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (20 ml), and the mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (391 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[CH:8]([N:14]([CH:16]3[CH2:18][CH2:17]3)[CH3:15])[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:16]1([N:14]([CH3:15])[CH:8]2[CH2:7][CH2:6][C:5]([CH3:20])([CH3:19])[C:4]3[C:3]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:2][CH:11]=[C:10]([O:12][CH3:13])[C:9]2=3)[CH2:18][CH2:17]1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)c2c1C(N(C)C1CC1)CCC2(C)C
Yield: 76.5 %

Procedure:
Following General Procedure D and using 2-bromo-5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 79, 1.08 g, 3.2 mmol), triethyl amine (5 mL), copper(I)iodide (0.061 g, 0.32 mmol), trimethylsilyl acetylene (3 mL, 21.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.225 g, 0.32 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-10% ethyl acetate in hexane as the eluent, the title compound (0.87 g, 80%) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([I:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(I)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(I)cc1
Yield: 36 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-iodoaniline (2.54 g, 11.6 mmol) in 20 mL of pyridine. The crude product was recrystallized from water-DMF to yield 1.48 g of the title compound, mp 268°-271° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:19])([F:18])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:14]([F:19])([F:18])[F:13]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 155 °C
Reaction time: 20 h
Yield: 72.1 %

Procedure:
To a solution of 1-bromo-2-methoxy-4-nitrobenzene (10.0 g, 43.0 mmol) in N,N-dimethylformamide (200 mL) were added potassium trifluoroacetate (13.0 g, 86.0 mmol), copper iodide(I) and toluene (40 mL), and the mixture was stirred at 155° C. for 20 hr while removing the produced water drops by a Dean-Stark trap. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), the insoluble material was filtered off, and the filtrate was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=98/2→88/12). The obtained solution was concentrated under reduced pressure to give the title compound (6.86 g, 72%) as a pale-yellow oil.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([CH:25]=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([C:25]([OH:11])=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OO
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C=O)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
An aqueous solution (1 ml) of sodium dihydrogenphosphate (24 mg, 0.20 mmol), an aqueous solution (3.5 ml) of sodium chlorite (123 mg, 80%, 1.09 mmol) and aqueous hydrogen peroxide (0.08 ml, 30%) were added to an acetonitrile solution (2.5 ml) of 6-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (112 mg, 0.26 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (106 mg, 0.23 mmol, 91%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)NCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(C)N(CC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A suspension of ethyl 3-(benzylamino)butanoate (5.9 g, 26.7 mmol), methyl bromoacetate (3.0 ml, 31.7 mmol) and potassium carbonate (7.4 g, 53.5 mmol) in acetonitrile (100 ml), was stirred at room temperature for 18 hs. The reaction was filtered through celite and concentrated to give ethyl 3-[benzyl(2-methoxy-2-oxoethyl)amino]butanoate (6.45 g, 82%) as a clear oil, MS (M+H)+=294.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[C:27](Cl)(=[O:41])/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C1COCC1>[CH2:19]([O:18][C:16]([N:15]([CH2:14][C:13]([O:12][CH3:11])=[O:26])[C:27](=[O:41])/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCCCCCCCC/C=C/C(=O)Cl
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC/C=C/C(=O)N(CC(=O)OC)C(=O)OCc1ccccc1
Temperature: -70 °C
Yield: 66.2 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (44.8 ml, 1M solution) in anhydrous THF (50 ml) was cooled to −70° C. under argon in a dry flask with stirring. To the solution was added Cbz glycine methyl ester (10.0 g) in THF (20 mL) dropwise while maintaining the reaction temperature at −70° C. After 30 min stirring at −70° C., a solution of the (E)-tetradec-2-enoyl chloride (12.1 g) in THF (10 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 1 hr and then allowed to warm up to 0° C. The reaction was quenched with aqueous citric acid solution (5%, 300 ml) and warmed up to room temperature. The crude product was extracted with ethyl acetate (500 ml). The ethyl acetate phase was washed with DI water twice and dried with sodium sulfate. The solvent was removed under vacuum to yield oily residue, which was purified by silica gel column chromatography. Pure product was obtained after column purification as a clear oil (12.8 g, 66.2% yield). Proton NMR(CDCl3) δ 0.88 (t, 3H), 1.26 (m, 16H), 1.43 (m, 2H), 2.22 (m, 2H), 3.67 (s, 3H), 4.53 (s, 2H), 5.24 (s, 2H), 6.94 (d, 1H), 7.05 (td, 1H). 7.36 (m, 5H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[C:22]([C@@H:28]([NH2:30])[CH3:29])=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1>>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:30][C@H:28]([C:22]4[C:21]([F:20])=[CH:26][C:25]([F:27])=[CH:24][N:23]=4)[CH3:29])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Reactant: C[C@H](N)c1ncc(F)cc1F
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ncc(F)cc1F

Procedure:
Following a similar procedure to the synthesis of Example 1, the title compound was synthesized from 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32) and (S)-1-(3,5-difluoropyridin-2-yl)ethanamine (Method 50). 1H NMR (400 MHz) δ 0.68 (m, 2H), 0.95 (m, 2H), 1.45 (d, J=6 Hz, 3H), 1.87 (m, 1H), 5.48 (m, 1H), 6.19 (s, 1H), 6.69 (m, 1H), 7.63 (d, 1H), 7.98 (m, 1H), 8.51 (s, 1H), 9.58 (s, 1H), 12.15 (s, 1H). MS: Calcd.: 399. Found: [M+H]+ 400.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1.C(=O)([O-])N.[K+]>CN(C=O)C>[C:22]([O:21][C:20](=[O:26])[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:14][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
A mixture of 2,3-dichloro-5-(trifluoromethyl)pyridine (2.0 g, 9.26 mmol), tert-butyl piperidine-4-ylcarbamate (2.2 g, 11.11 mmol) and anhydrous potassium carbamate (3.8 g, 27.78 mmol) in DMF (15 ml) was heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated, water and EtOAc were added to the residue and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (hexane/EtOAc 90:10) to yield the title compound (2.5 g, 70%). 1H NMR (500 MHz, CDCl3): δ 1.47 s, 9H), 1.53-1.60 (m, 2H), 2.07-2.09 (m, 2H), 3.01-3.06 (m, 2H), 3.72 (br.s., 1H), 3.97-4.00 (m, 2H, 4.54 (br.s., 1H), 7.75 (s, 1H), 8.38 (s, 1H); Mass Spectrum: M+H+ 380.
Reaction SMILES: Cl[CH:2]1[CH2:14][O:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]1.ClN1C(=O)CCC1=O.[Br:31]N1C(=O)CCC1=O>>[Br:31][CH:2]1[CH2:14][O:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3]1
Reactant: CCCCCCCC[C@H]1OCC(Cl)C[C@@H]1CCCCCCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CCC(=O)N1Cl
Product: CCCCCCCC[C@H]1OCC(Br)C[C@@H]1CCCCCCC

Procedure:
10-Chloro Thromboxane B2Methyl Ester has been prepared using the same procedure except that N-chlorosuccinimide was substituted for N-bromosuccinimide. This 10-chloro compound can then be utilized in the same manner as the 10-bromo compound in the following examples.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1.[CH3:17]O>>[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:17])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1
Reactant: CO
Reactant: COc1cc(O)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Thionyl chloride (953 μL, 13.1 mmol) was added dropwise to a solution of 4-hydroxy-2-methoxy-benzoic acid (733 mg, 4.36 mmol) in methanol (30 mL) at 0° C. The mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was dissolved in water (40 mL). The solution was neutralized with saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to dryness to give methyl 4-hydroxy-2-methoxy-benzoate (99%). ESI-MS m/z calc 182.1, found 183.1 (M+1)+. Retention time: 0.73 minutes (3 min run).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:35]=[CH:34][C:9]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:19]([Cl:32])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:8]=2[CH:7]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:9]4[CH:34]=[CH:35][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:7][C:8]=4[S:33][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-acetic acid ethyl ester (400 mg, 0.766 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (161 mg, 3.83 mmol) in water (3 mL), and the resulting mixture was stirred at rt overnight. The solvent was evaporated, and aq. NaOH (0.2 N, 5 mL) was added to the residue, and the mixture was washed with diethyl ether (2×8 mL). The pH of the aqueous layer was adjusted to 5 by addition of 0.5 N HCl, and it was then extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give the product as a slightly brown solid. (350 mg, 93%). LCMS RT=3.66 min, [M+H]+=494.1.