Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CC[CH2:4]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:3]([CH3:4])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([F:44])=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:59][CH2:60]1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)cc(F)c34)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cc(F)cc(F)c45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(4,6-difluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (115, see example 66) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([N:33]2[CH2:34][CH:35]=[C:30]([C:26]3[CH:25]=[C:24]([C:23]([F:37])([F:22])[F:36])[CH:29]=[CH:28][N:27]=3)[CH2:31][CH2:32]2)=[O:16])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(C2=CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CC=C(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.288 g, 1.06 mmol) and 4-(trifluoromethyl)-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine dihydrochloride (0.320 g, 1.06 mmol) in dry methylene chloride (11.5 mL) was added triethylamine (0.592 mL, 4.25 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phospsphonium hexafluorophosphate (0.517 g, 1.17 mmol). After being stirred at room temperature overnight, the brown reaction mixture was washed with NaHCO3 and brine, dried (MgSO4), filtered, and concentrated The residue was purified by column chromatography on silica gel (30:70 EtOAc/hexanes) to provide a light yellow solid product: 265 mg (52%). LC-MS calculated for C25H34F3N3O3: (M+H) 482; found 382.2 (M-Boc+1).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20].CN(C)[CH:23]=[O:24]>O1CCCC1.CCCCCC.C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:23]=[O:24])=[C:14]([F:20])[CH:15]=1
Reactant: Fc1cc(Br)ccc1Br
Reactant: CN(C)C=O
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=Cc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.45M hexane (4.85 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. To the suspension was added dropwise a toluene solution (25 mL) containing ice-cooled 1,4-dibromo-2-fluorobenzene (2.54 g, 10.0 mmol) over a period of 10 minutes, while keeping the temperature below 5° C. The resultant yellowish suspension was stirred at 0° C. for one hour, and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and 1M aqueous acetic acid solution (15 mL) was added. The reaction mixture was extracted twice with ethyl acetate (15 mL). The organic extracts were combined, and 20% aqueous sodium hydrogen sulfite solution (5 mL) was added at room temperature. The mixture was stirred vigorously at room temperature for one hour. The aqueous phase was separated, washed with ethyl acetate (15 mL), adjusted to pH 10 with 6N sodium hydroxide solution, and extracted twice with ethyl acetate (25 ml). The organic extracts were combined, washed successively with aqueous ammonium chloride saturated solution (10 mL) and saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give the title compound (1.666 g, 82% yield) as an almost colorless crystalline solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][C:12]=2[CH3:13])[S:5][C:4]=1[C:14]([NH2:16])=[O:15].[F:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(N(C)C)=O>[F:17][CH:18]1[C:19]2([N:2]([CH3:1])[C:3]3[CH:7]=[C:6]([C:8]4[CH:9]=[N:10][NH:11][C:12]=4[CH3:13])[S:5][C:4]=3[C:14](=[O:15])[NH:16]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CNc1cc(-c2cn[nH]c2C)sc1C(N)=O
Reactant: O=C1CCCCC1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCCCC1F)N2C
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 57.8 %

Procedure:
A mixture of 3-(methylamino)-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide (70 mg, 0.30 mmol), 2-fluorocyclohexanone (105 mg, 0.90 mmol), CSA (7.0 mg, 0.030 mmol), MgSO4 (72 mg, 0.60 mmol) and DMA (1 mL) was stirred at 70° C. for 5.5 h. Then, saturated aqueous NaHCO3 and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (58 mg, 58%) as a yellow solid:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:25])[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>CCOC(C)=O>[Cl:34][C:33]([Cl:36])([Cl:35])[CH2:32][O:31][C:29](=[O:30])[NH:25][C:7]1[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:11]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 5 h
Yield: 107.9 %

Procedure:
To a bi-phasic mixture of Intermediate 62c (807 mg, 2.12 mmol) in EtOAc (7.5 mL) and 1N NaOH solution (1.38 ml, 1.38 mmol) at 0° C. was added 2,2,2-trichloroethyl chloroformate (0.35 mL, 2.54 mmol) and the mixture stirred for 5 h. The layers were separated and the organic layer was washed with brine, dried and concentrated in vacuo to give the title compound (1.27 g, 99%). LCMS (Method 3): Rt 5.66 min, m/z 553, 555, 557 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH2:11][Br:20])[C:5]=2[S:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c2c(Br)csc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1ncc(CBr)c2scc(Br)c12
Temperature: 25 °C

Procedure:
A solution of Example 277C (1 g, 3.81 mmol) in CCL (30 mL) was treated with NBS (0.755 g, 4.24 mmol) and benzoyl peroxide (0.093 g, 0.38 mmol), heated to reflux for 24 hours, cooled to room temperature, and filtered. The filtrate was concentrated to provide 3-bromo-7-(bromomethyl)-4-chlorothieno[3,2-c]pyridine, which was used directly. MS (ESI(+)) m/e 339.5, 341.6, 343.4 (M+H)+. The crude product was dissolved in DME (7.5 mL), treated with sodium acetate (1.6 g, 19.5 mmol), heated to 100° C. overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography with 10% ethyl acetate/hexanes to provide 0.65 g (53% yield) of the desired product. MS (ESI(+)) m/e 319.7, 321.7, 323.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH:4]=[C:5]1[C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][C:12]=3[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6]1.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH:4]=[C:5]1[C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:12]=3[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C=C1CCc2c1oc1ccc(C(=O)O)cc1c2=O
Yield: 83.4 %

Procedure:
3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester (3 g) was hydrolized by treatment with 1% KOH in 95% ethanol (59 ml) at reflux temperature for 15 minutes. After cooling, acidification with HCl and dilution with ice water, the precipitate was filtered and washed with water. Crystallization from dimethylformamide-ethanol gave 2.4 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 296°-298° C., NMR (CF3COOD) δppm: 2.59 (s) (3H, --CH3), 3.40 (bs) (4H, C-1 and C-2 protons), 7.38-7.87 (m) (4H, phenyl protons), 8.10 (d) (1H, C-5 proton), 8.30 (bs) (1H, =CH--), 8.80 (dd) (1H, C-6 proton), 9.30 (d) (1H, C-8 proton).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:15][S:16]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:18])=[O:17]
Reactant: CC(C)OCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 126.4 %

Procedure:
A round bottom flask was charged with 2-isopropoxyethanol (0.5 mL, 4.34 mmol) and dichloromethane (21.68 mL) and was cooled to 0° C. Triethylamine (1.208 mL, 8.67 mmol) was added along with a tip of DMAP. Methanesulfonyl chloride (0.338 mL, 4.34 mmol) was added dropwise. The reaction mixture was slowly warmed to rt over 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 2-Isopropoxyethyl methanesulfonate (1 g) was isolated as a clear oil and was immediately used in the next reaction.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[NH3:16]>>[CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)[NH2:16])[CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CC1
Product: NC(c1ccc(C(F)(F)F)cc1)C1CC1

Procedure:
The title compound was prepared using the product from Example 141B and the procedures described in Examples 136A and 136B. 1H NMR (300 MHz, d6-DMSO) 7.92 (m, 4H), 3.24 (d, 1H), 1.92 (broad s, 2H), 0.93 (m, 1H), 0.50-0.27 (m, 4H); MS (DCI/NH3) m/e 216 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].[Cl-].[NH4+].C(=O)([O-])[O-].[Ca+2:28]>Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O-:19])=[O:18].[Ca+2:28].[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O-:19])=[O:18]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C([O-])Cc1ccc2c(c1)CCc1ccccc1S2

Procedure:
Three hundred milligrams of 10,11-dihydrodibenzo[b.f]thiepin-2-acetic acid are dissolved in an excess of 1N aqueous sodium hydroxide and the resultant solution is buffered with 0.3 g. of ammonium chloride. The buffered solution is added to a solution of 200mg. of calcium carbonate in 1N aqueous hydrochloric acid. The formed precipitate is collected by filtration, washed consecutively with water, dimethoxyethane and ether, to yield calcium 10,11-dihydrodibenzo[b.f]thiepin-2-acetate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([NH:12][NH:13][C:14]([NH:16][C:17](=[O:28])[C:18]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[O:26][CH3:27])=[S:15])=O.CS(O)(=O)=O.S1C2C=CC=CC=2N=C1C1(C2C=CC(OC)=C(C=2OC)C(N)=O)NN=CS1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[S:15][C:14]([NH:16][C:17](=[O:28])[C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[N:13][N:12]=1
Reactant: COc1cccc(OC)c1C(=O)NC(=S)NNC(=O)c1nc2ccccc2s1
Agent: COc1ccc(C2(c3nc4ccccc4s3)NN=CS2)c(OC)c1C(N)=O
Agent: CS(=O)(=O)O
Product: COc1cccc(OC)c1C(=O)Nc1nnc(-c2nc3ccccc3s2)s1

Procedure:
A 4.2 g. portion of 1-[(2-benzothiazolyl)carbonyl]-4-(2,6-dimethoxybenzoyl)thiosemicarbazide was added dropwise with stirring to 16 g. of methanesulfonic acid. The product was 2.6 g. of N-[5-(2-benzothiazolyl-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide, m.p. > 260°.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[C:14]([N+:6]([O-:9])=[O:7])=[N:15][CH:16]=1
Reactant: CCOC(=O)Nc1cncc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1cc(Br)cnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a mixture of concentrated H2SO4 (60 mL, 1126 mmol) and fuming HNO3 (40 mL, 895 mmol), ethyl (5-bromopyridin-3-yl)carbamate (21.5 g, 88 mmol) was added portionwise at 0° C. After stirring at 0° C. for 5 min, the mixture was stirred at rt overnight and poured onto ice water. A crash out formed and was filtered off and washed thoroughly with water and dried. Ethyl (5-bromo-2-nitropyridin-3-yl)carbamate (21.26 g, 84%) was thus obtained as a white solid. LCMS (m/z): 290.1 (MH+), 0.76 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.63 (br. s., 1H) 9.33 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.0 Hz, 1H) 4.32 (q, J=7.3 Hz, 3H) 1.68 (br. s., 2H) 1.38 (t, J=7.0 Hz, 4H).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+:12]>O>[CH2:1]([O:3][CH:4]=[CH:5][C:6]([O-:8])=[O:7])[CH3:2].[Na+:12]
Reactant: CCOC=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC=CC(=O)[O-]
Yield: 98.9 %

Procedure:
A mixture of ethyl β-ethoxyacrylate (26.50 g, 183 mmol) and 2 N sodium hydroxide (110 mL, 220 mmol) was refluxed for 2 h and cooled to 0° C. water was removed under vacc., and the yellow solids were triturated with toluene and evaporated to give the sodium β-ethoxyacrylate (25 g, 97%). The mixture of sodium β-thoxyacrylate (10.26 g, 74.29 mmol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated to give the β-ethoxyacryloyl chloride crude product, which was used without purification. To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6-methylaniline (6.2 mL, 50.35 mmol) and pyridine (9 ml, 111 mmol). The mixture was then warmed and stirred overnight at room temperature. Water was added at 0-10° C., extracted with EtOAc. The organic layer was washed with CuSO4 (3×50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids. The solids was diluted with toluene and kept at 0° C. The solid was collected by vacuum filtration, washed with water and dried to give 5.2 g (43% yield) of compound 1, (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz, CDCl3) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz); ESI-MS: calcd for (C12H14ClNO2) 239. found 240 MH+).
Reaction SMILES: [Br-].[Li+].[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:26][C:25]2[C@H:20]([CH2:21][CH2:22][C:23](=[O:27])[CH:24]=2)[C@@H:19]2[C@@H:10]1[C@H:11]1[C@@:15]([CH2:17][C@@H:18]2[F:28])([CH3:16])[C:14](=[O:29])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+].Cl>C(#N)C.[Cu](Br)Br.O>[Cl:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[CH2:26][C:25]2[CH:24]=[C:23]([OH:27])[CH:22]=[CH:21][C:20]=2[C@@H:19]2[C@@H:10]1[C@H:11]1[C@@:15]([CH2:17][C@@H:18]2[F:28])([CH3:16])[C:14](=[O:29])[CH2:13][CH2:12]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
25.4 g of copper(II) bromide and 4.9 g of lithium bromide in 95 ml of anhydrous acetonitrile are added to 22.1 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione in 160 ml of anhydrous acetonitrile at 80° C. After 20 minutes, the reaction mixture is cooled to 0°C., and 200 ml of saturated sodium bicarbonate solution is added in drops. Then, the solution is stirred into 750 ml of water, brought to pH=6 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 14.7 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one.
Reaction SMILES: [C:1]([O:5][C:6](OC=CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC=Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1

Procedure:
U.S. Pat. No. 4,461,628 of Ito et al., issued Jan. 1, 1985 teaches the preparation of t-butoxycarbonyloxystyrene by reaction of p-hydroxybenzaldehyde with di-t-butyldicarbonate in the presence of base to yield p-t-butoxycarbonyloxybenzaldehyde, which is then reacted with methyltriphenylphosphonium bromide and potassium t-butoxide to yield the desired product.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of t-butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography ethyl acetate eluent/ to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)C2CC2)CCCC1
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-oxopropanoate (2.0 g, 14 mmol) in DMF (70 mL) was added sodium hydride (60% in mineral oil, 1.41 g, 35 mmol). The reaction mixture was stirred for 10 min then 1,4-dibromobutane (1.85 mL, 15 mmol) was slowly added. The reaction mixture was stirred for 2.5 h then carefully quenched with water and extracted with diethyl ether (2×). The combined organics were washed with water (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 60 g SiO2 (0% to 10% EtOAc/hexanes) to afford 0.63 g (23%) of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[S:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(Nc2nc(-c3ccncc3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(Nc2nc(-c3ccncc3)cs2)c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
A solution of methyl 3-(4-pyrid-4-ylthiazol-2-ylamino)benzoate (500 mg, 1.27 mmol) in a 3/2 mixture of methanol/THF (100 mL) was treated with an aqueous solution of sodium hydroxide ((240 mg, 6 mmol, 20 mL). The reaction mixture was stirred at 40° C. for approximately 12 hours and then concentrated. The residue was diluted with water (20 mL) and the diluted solution was acidified to pH 5 with dilute hydrochloric acid. A resulting solid was collected by filtration and washed with water to provide 3-(4-pyrid-4-ylthiazol-2-ylamino)benzoic acid (328 mg, 87% yield). HNMR (dmso-d6): 10.80 (1H, s), 8.63 (2H, m), 7.90 (7H, m). LC/MS: M+1: 297.86.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCOCc1cccc(-c2ccc(C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: COCOCc1cccc(-c2ccc(C(=O)O)cc2)c1
Yield: 80.8 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3′-methoxymethoxymethylbiphenyl-4-carboxylate (445 mg), which is the product of Reference example 15(b), and aqueous sodium hydroxide (1N, 3.10 ml) and the reaction mixture was treated to afford the desired compound (342 mg) as colorless crystals.