Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]([CH2:31][N:32]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:33])=[O:30]>>[NH2:28][C:29]([CH2:31][N:32]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:41]=1)[CH3:33])=[O:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(CC(N)=O)Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CC(N)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C27H26N4O4
Reaction SMILES: OS(O)(=O)=O.[O:6]=S(=O)=O.[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13](F)([F:15])I>>[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13]([F:15])=[O:6]
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)I
Reactant: O=S(=O)=O
Agent: O=S(=O)(O)O
Product: O=C(F)C(F)(F)C(F)(Cl)C(F)(F)Cl
Temperature: 110 °C

Procedure:
A 1 L three-necked flask, fitted with a stir bar and condenser, was charged with 3.0 g of HgO (yellow), 25 mL of 20% oleum, 25 mL of 65% oleum and 75.6 g of 3,4-dichloro-1-iodoperfluorobutane. After the reaction mixture was heated at 110° C. for 2 hours, the condenser was replaced by a distillation head with a 250 mL flask for receiver cooled with ice water. Volatiles were collected, washed with 98% sulfuric acid to remove sulfur trioxide and redistilled to give 40.3 g of 3,4-dichloroperfluorobutyryl fluoride, bp 72°-75° C., 99.8% GC purity.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=3)[CH:8]=2)[CH2:3]1.[CH3:24][S:25](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:27])=[O:26].N1CCCN2CCCCCC=12>C1COCC1>[OH:23][CH2:22][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=1)[CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][C@H:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]2
Reactant: CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-(3-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (50, mg, 0.16 mmol) in THF (1 mL) was added perfluorophenyl methanesulfonate (39 mg, 0.15 mmol) followed by 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.1 mg 0.22 mmol). The reaction was allowed to stir at RT overnight before removing the solvent in vacuo. The sample was redissolved in DMSO (500 μL) before purifying by reverse phase preparative HPLC-MS to give the title compound as a clear film (11 mg, 17.2%). MS (ESI): m/z [M+H]+ 400.1
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH:10]=[C:9]([CH3:12])[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:12][C:9]1[CH2:8][O:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH:10]=1
Reactant: CCOC(=O)C1CC=C(C)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=CCC(C(=O)O)OC1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (140 mg, 0.823 mmol) in MeOH (3.5 mL) and 10% aq. NaOH (1.0 mL, 2.5 mmol) was heated at 65° C. for 3 h, reaction mixture was cooled to room temperature, solvent was evaporated, diluted with water. The aqueous solution was washed with ether, and acidified with aq. 1 N HCl, extracted with ether. The ethereal solution was washed with brine and dried. Evaporation of the solvent furnished 5-methyl-3,6-dihydro-2H-pyran-2-carboxylic acid (82 mg, 70% yield. NMR 1H (CDCl3, 400 MHz): 5.54-5.5 (m, 1H), 4.24-4.1 (m, 3H), 2.4-2.3 (m, 2H), 1.6 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([F:8])=[CH:6][CH:7]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)C>[C:16]([NH:1][C:2]1[C:3]([F:15])=[C:4]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccc(F)c(-c2ccncc2)c1F
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc(F)c(-c2ccncc2)c1F
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 4-(3-amino-2,6-difluorophenyl)-pyridine (6.5 g), acetic anhydride (4.9 g) and ethanol (200 ml) was heated at reflux. After 1 hour, a further 3.3 ml acetic anhydride was added and a third portion (1.5 ml) after another 3.5 hours. Reflux was continued for a total of 6 hours after which time the solution was cooled and evaporated and the residue was partitioned between aqueous sodium bicarbonate and chloroform. The organic layer was washed with water, dried and evaporated to give the solid product of m.p. 148°-150° C. (6.8 g, 86% yield). NMR (CDCl3, 60 MHz): 8.8 (m, 2H), 8.05 (m, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 2.2 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ncccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Yield: 38.6 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-amine (6-3, 0.23 g, 0.77 mmol) in THF (3.9 mL) was added triethylamine (0.23 g, 2.30 mmol) followed by isonicotinoyl chloride hydrochloride (0.27 g, 1.52 mmol). The reaction mixture was heated at 60° C. overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in MeOH to give N-{4-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)thiazol-2-yl}isonicotinamide (6, 0.12 g) as yellow solids in 38% yield: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=6.0 Hz, 2 H), 8.58 (d, J=4.5 Hz, 2 H), 7.65 (d, J=6.0 Hz, 2 H), 7.04 (t, J=4.8 Hz, 1 H), 6.83 (s, 1 H), 6.70 (s, 2 H), 3.47 (s, 3 H), 1.97 (s, 6 H). ESI-MS: m/z 403.8 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[C:20]([C:11]1([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccncc2)CCNCC1

Procedure:
Prepare by the method of example 30.3 using 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-4-yl)-piperidine (3 mmol) and HCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dry under high vacuum to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][C:18](OC)=[O:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH3:22][C:15]1([CH3:23])[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COC(=O)CCC(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Methyl 4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpentanoate (0.31 g, 0.94 mmol), prepared in the previous step, was dissolved in tetrahydrofuran (18 mL) and sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 0.94 mL, 0.94 mmol) was added. The mixture was stirred at 25° C. for 2 h. The reaction was quenched with saturated NH4Cl, diluted with ethyl acetate, washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone/hexane) afforded the title compound (0.27 g, 97%) as a white solid. HRMS: calcd for C16H15N3OS+H+, 298.10086; found (ESI, [M+H]+), 298.1; Analytical HPLC: purity 94.8% at 210-370 nm, 9.9 min; 98.2% at 244 nm, 9.9 min; the Xterra® RP18 column, 3.5%, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)(=O)C>[Br:1][C:11]1[CH:12]=[C:7]([S:4]([CH3:3])(=[O:5])=[O:6])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of bromine (0.9 ml, 17.45 mmol) in glacial acetic acid (10 ml) was added dropwise to a stirred solution of 4-(methanesulfonyl)phenol (Description 26; 3 g, 17.45 mmol). The resulting solution was stirred at ambient temperature for 16 h. Bromine (0.45 ml) in glacial acetic acid (5 ml) was added dropwise and the solution was stirred for 2 h. The excess acetic acid and bromine were removed in vacuo and the residue was azeotroped with toluene to give the desired compound as an off-white solid (3.54 g, 81%). 1H NMR (250 MHz, CDCl3) δ8.06-8.05 (1H, d, J 2.3 Hz), 7.73-7.69 (1H, dd, J 8.6, 2.3 Hz), 7.06-7.02 (1H, d, J 8.6 Hz), and 3.06 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[CH:7]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.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>[Cl:8][C:6]1[CH:7]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]=1[O:9][CH3:10]
Reactant: CCc1cc(Br)cc(Cl)c1OC
Reactant: C=CC(O)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)cc(Cl)c1OC
Temperature: 140 °C
Yield: 80.6 %

Procedure:
A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol), 1-Cyclopentyl-2-propen-1-ol (1.31 g, 10.4 mmol), dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.16 mmol), and sodium bicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (1.9 g, 82%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3H), 1.53-1.81 (m, 8H), 2.65 (q, J=7.6 Hz, 2H), 2.74 (m, 2H), 2.79-2.87 (m, 3H), 3.81 (s, 3H), 6.90 (s, 1H), 7.03 (m, 1H).
Reaction SMILES: O[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13]C)[CH2:3][CH2:4][CH2:5][C:6](=[O:9])C=C.CC1C(=[O:21])CCC1=O.C1(C)C(C)=CC=CC=1>C(O)(=O)C>[O:9]1[C:13]2[CH2:12][C:11](=[O:21])[CH:10]=[CH:2][C:3]=2[CH:4]=[CH:5][CH2:6]1
Reactant: C=CC(=O)CCCC(O)CCCCC
Reactant: CC1C(=O)CCC1=O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: O=C1C=CC2=C(C1)OCC=C2

Procedure:
A mixture of the optically active 7-hydroxy-1-dodecen-3-one, obtained as described in Example 4, 2.25 grams of 2-methylcyclopentane-1,3-dione, 50 milliliters of xylene, and 25 milliliters of acetic acid was refluxed for 11/2 hours under a nitrogen atmosphere. After evaporation under vacuum, the residue was extracted with cold benzene leaving 400 milliliters of unreacted methylcyclopentanedione as an insoluble residue. The benzene solution was then evaporated to yield 5.56 grams of optically active 3-pentyl-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta]f][1]benzopyran-7(8H)-one. After chromatographing the crude product on alumina, followed by crystallization from methanol-water, the product melted at 60°-61°C., [α]D25 -166°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of 7.25 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride, prepared using substantially the procedure of Step A of Example 1 from the corresponding acid, in 20 ml of acetonitrile was added to solution of 1.43 g (7.25 mmol) of 4-aminobenzotrifluoride, hydrochloride and 1.83 g (18.1 mmol) of triethylamine in 10 ml of acetonitrile. The reaction mixture was warmed at reflux for a period of 4 hours and then poured over crushed ice. The resulting precipitate was collected by filtration and then recrystallized from acetonitrile to give 2.40 g (68 percent of theoretical) of the above-named product as a tan solid which melted at 176°-178° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 5)
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1O
Solvent: CO
Product: CC1(C)SC(c2ccccc2O)N[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
A solution containing 4.5 g (30 mmoles) of D-penicillamine and 3.16 ml (30 mmoles) of salicylaldehyde in 90 ml of 30% methanol is stirred for 3 hours. The precipitated product is filtered out, washed with 50% methanol and dried to give the title acid in a yield of 7.05 g (92.7%) which is recrystallized from methanol, m.p. 179°-181° C., [α]D =129.8° (c=0.48, dimethylformamide).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[NH:11][C:10]=2[CH:9]=1.[OH-].[K+]>C(C(C)=O)C>[CH3:6][O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:27])(=[O:26])[N:23]([CH3:24])[CH3:25])[N:11]([CH2:2][CH2:3][CH2:4][Cl:5])[C:10]=2[CH:9]=1
Reactant: ClCCCBr
Reactant: COc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)N(CCCCl)c1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 60.4 %

Procedure:
2-Methoxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine (m.p. 124°-126°C.; 62.6 g.) is prepared by reacting 1-bromo-3-chloropropane (147 g.) with 2-methoxy-6-dimethylsulphamoylphenothiazine (84.4 g.) in the presence of powdered potassium hydroxide (25.8 g.) in methyl ethyl ketone (300 cc.).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]2[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][C:32]=2[CH3:33])[CH:21]=1)[CH3:18])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:17]([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])=[O:36])=[CH:21][C:22]=1[C:27]1[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCC(=O)OC(C)(C)C)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCC(=O)O)ccc1Cl

Procedure:
4-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid tert-butyl ester (60 mg, 0.12 mmol) was stirred in a mixture of DCM (400 μL) and TFA (400 μL) for 1 hr. The mixture was concentrated, dissolved in MeOH and purified by prep LCMS to yield 4-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-butyric acid 5-1. MS [M+H]+: 463.7; tR=3.46 min, (method 2)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:20]=[CH:21][C:22]4[C:26]([C:27]([OH:29])=O)=[C:25]([CH3:30])[S:24][C:23]=4[CH:31]=3)[CH:10]=2)=[O:8])[CH2:3]1.[NH2:32][CH2:33][CH:34]1[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:34]1([CH2:33][NH:32][C:27]([C:26]2[C:22]3[CH:21]=[CH:20][C:19]([O:18][C:15]4[CH:14]=[CH:13][N:12]=[C:11]5[CH:10]=[C:9]([C:7]([N:4]6[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]6)=[O:8])[S:17][C:16]=45)=[CH:31][C:23]=3[S:24][C:25]=2[CH3:30])=[O:29])[CH2:36][CH2:35]1
Reactant: NCC1CC1
Reactant: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 66.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 126a (65 mg, 0.14 mmole) with (aminomethyl)cyclopropane (37 μL, 0.43 mmole), diisopropylethylamine (50 μL, 0.29 mmole), and HBTU (81 mg, 0.22 mmole) in a similar manner previously described for example 117 to give a pale yellow solid (47 mg, 46%). 1H NMR (DMSO-d6, 300 MHz) δ8.60 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.68 Hz), 8.07, 8.01 (1H, s), 7.97 (1H, d, J=2.27 Hz), 7.84 (1H, d, J=8.59 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.78 (1H, d, J=5.31 Hz), 4.38, 4.33 (0.5H, br s), 4.01-3.93 (3H, m), 3.67-3.47 (2H, m), 3.20 (2H, t, J=6.19 Hz), 2.62 (3H, s), 2.07-1.81 (2H, m), 1.08 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Li+].[H-].[Na+].Cl[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.O>CN(C)C=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][N:12]=[C:11]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])[CH:16]=1
Reactant: CC(O)C(=O)[O-]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1cc(C(F)(F)F)ccn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of lithium lactate (7.8 g, 81 mmol) in 100 mL of anhydrous dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80 mmol). After stirring at room temperature for 30 min, 2-chloro-4-trifluromethylpyridine (10 g, 55 mmol) was added, and the mixture was heated at 100° C. overnight. The reaction was cooled to room temperature, poured into 500 mL of water, and was washed with hexane (200 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH>2), and was extracted with ether (2×500 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@H:15]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48.7 %

Procedure:
To a room-temperature solution of (S)-4-benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3 mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2 mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to −78° C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was added dropwise by syringe. After stirring for 15 minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with sat'd. aq. NH4Cl, and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (7-20% EtOAc/Hexanes) provided the title compound (2.6 g, 49%). m/z=328.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>CN(C)C(=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Cc1ccccc1S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred, cooled (-15° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13 g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -10° C. for 1 hour. 4-(2-Methylphenylsulfonyl)benzenamine (1.48 g, 6.0 mmol) was then added in one portion, washed in with 2 mL of N,N-dimethylacetamide and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the cloudy solution decanted from the resulting gum and filtered through a thin pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The combined methylene chloride solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting gum was dissolved in a few mL of methanol and added dropwise to 100 mL of rapidly stirred 3N HCl The aqueous phase was decanted from the gum, the gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was dissolved in 125 mL of methylene chloride and heated on a steam bath as 100 mL of hexane was slowly added to replace the methylene chloride. When a volume of 125 mL was reached more hexane (ca. 50 mL) was added to the cloud point. After cooling overnight the resulting solid was filtered to yield impure product. This material was further stirred with 300 mL of 0.5N HCl for 45 min., the aqueous phase decanted off and the residual gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The material was dissolved in 100 mL of methylene chloride, 50 mL of hexane added and the solution heated on a steam bath to a final volume of 100 mL. After cooling the resulting solid was filtered and dried at 100°-120° C./0.1 torr. for 2.5 hours to yield the title propanamide (1.78 g, 77%) as a light tan solid; mp 126°-128° C. 1H-NMR (300 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 2.39 (s, 3H, aryl CH3), 7.37-8.10 (m, 8H, aromatic), 7.6 (broad s, 1H, OH), 10.4 (broad s, 1H, NH). MS (CI, CH4): 388(M+1).