Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:7]([O:17][CH2:18][CH2:19][O:20][CH3:21])[N:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:16][C:13]1([F:15])[CH2:14][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:12]1
Reactant: COCCOc1nc(C(=O)OC)ccc1N1CC(F)(F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1nc(C(=O)O)ccc1N1CC(F)(F)C1
Yield: 83.3 %

Procedure:
A solution of 5-(3,3-difluoroazetidin-1-yl)-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (0.25 g, 6 mmol) in THF/H2O (30 mL) was stirred at room temperature for 3 h. After removal of the organic solvent, the aqueous phase was extracted with ethyl acetate (20 mL) and then acidified with 6 N hydrochloric acid to pH 2 to form a precipitate which was collected by filtration and dried under reduced pressure to give the target compound (0.24 g, 84%) as off-white solid which was used directly in the next step without further purification; MS (EI): m/e=289.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C(F)(F)F)OCc1ccccc1
Temperature: 120 °C

Procedure:
To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (17.0 g, 92.3 mmol) in toluene (80 mL) was added benzylalcohol (11.4 mL, 109.6 mmol). The mixture was stirred at 120° C. by using Dean-Stark for 5 h, and then the reaction mixture was cooled to 0° C. Drying the solution under high vacuum yielded compound D1-3 (21.2 g, quant.) as a colorless oil, which was used to the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:17]=[N:18][CH:19]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: O=Cc1cncc(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2cccs2)=NC1=Cc1cncc(F)c1
Temperature: 90 °C
Yield: 68.1 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 5-fluoro-3-pyridinecarboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 56 mg of the above-captioned compound.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21](Cl)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(Cl)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCC1CCNCC1

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (10 g) in ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon (5 g, 50% wet) at ordinary temperature under atmospheric pressure. After the absorption of hydrogen has ceased, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield ethyl 6-(4-piperidyl)hexanoate. This ester is dissolved in a mixture of water (100 ml), ethyl acetate (200 ml) and sodium bicarbonate (10 g). Benzyloxycarbonyl chloride (7.2 ml) is added dropwise at room temperature and the resulting mixture is stirred overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluent to give ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.7 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[CH:6]=[C:5]2[S:14]([CH3:16])=O.C(=O)(O)[O-].[Na+].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:6]1[N:7]([CH2:11][C:12]#[N:13])[C:8]2[C:4]([C:5]=1[S:14][CH3:16])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: CS(=O)c1cn(CC#N)c2ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1c(Cl)n(CC#N)c2ccc(Cl)cc12
Yield: 71.7 %

Procedure:
Following a procedure similar to that reported by Greenhouse et al., J. Org. Chem. 53 (1988) 2634, a solution of (5-chloro-3-methanesulfinyl-indol-1-yl)-acetonitrile (0.851 g, 3.38 mmole) in methylene chloride (85 ml) was cooled to 0° C. and solid sodium bicarbonate (3.66 g) was added. Thionyl chloride (0.422 g, 3.55 mmole) was dissolved in methylene chloride and added dropwise over a 45 minute period. Upon termination of addition, the reaction mixture was stirred an additional 15 m. Tlc analysis revealed the presence of a small amount of starting material. Additional thionyl chloride was added, one drop at a time until tlc analysis revealed the total consumption of starting material. When no more starting material was present, the entire reaction mixture was poured onto a short silica gel column and the product was eluted with methylene chloride and isolated by evaporation of the solvent to afford 0.657 g (72%) pure (2,5-dichloro-3-methylsulfanyl-indol-1-yl)-acetonitrile.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[C:20]([I:21])=[C:19]([CH3:22])[NH:18][N:17]=1>C(Cl)Cl>[I:21][C:20]1[C:16]([CH3:15])=[N:17][N:18]([C:5](=[O:7])[CH3:6])[C:19]=1[CH3:22]
Reactant: Cc1n[nH]c(C)c1I
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(C)c(I)c1C
Yield: 84.2 %

Procedure:
Acetic anhydride (0.51 mL, 5.4 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added to a solution of 3,5-dimethyl-4-iodopyrazole (1 g, 4.5 mmol) in CH2Cl2. After 1 h the reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with 1 N HCl, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to give the title compound as a white solid (1 g, 85%).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.O1CCCC1>[C].[Pd].C(O)C>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Catalytic hydrogenation of a mixture of ethyl(E)-3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propenoate (1.32 g), 5% palladium-carbon (1.0 g), tetrahydrofuran (40 ml) and ethanol (40 ml) was conducted at ordinary temperature and ordinary pressure. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in a mixed solution of tetrahydrofuran (10 ml) and ethanol (10 ml), then 1N aqueous sodium hydroxide solution (10 ml) was added to the solution, which was stirred at room temperature for 2 hours. The reaction mixture was poured into water, then neutralized with 1N hydrochloric acid (10 ml), which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (900 mg, yield: 72%). This was recrystallized from acetone-ethyl acetate. Melting point: 110–111° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25](O)=[O:26])=[CH:9]2.[CH2:28]([S:35][CH:36]([CH:39]([O:42][CH3:43])[O:40][CH3:41])[CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:28]([S:35][CH:36]([CH:39]([O:40][CH3:41])[O:42][CH3:43])[CH2:37][NH:38][C:25]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.5 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (4.24 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.88 g), 1H-1,2,3-benzotriazol-1-ol (1.80 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.70 g) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:3-1:4, volume ratio) to give the title compound (6.03 g, yield 91%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])[C:6]=2[N:7]=1.[CH3:31][NH:32][CH2:33][CH3:34].C(N(C(C)C)C(C)C)C.[F-].[Cs+]>CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)=[N:3][C:2]([N:32]([CH2:33][CH3:34])[CH3:31])=[N:7][C:6]=2[C:8]([C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:17])=[N:9]1)[CH3:15]
Reactant: CCNC
Reactant: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(N(C)CC)nc(Nc3cc(C)ccn3)c21
Temperature: 110 °C
Yield: 57.7 %

Procedure:
The chloro compound of Step 9 (110 mg, 0.24 mmol), N-methyl-ethylamine (79 mg, 1.2 mmol), N-ethyldiisopropylamine (210 μL, 1.20 mmol) and caesium fluoride (37 mg, 0.24 mmol) were dissolved in dimethyl sulphoxide (1 mL) and the reaction mixture heated to 110° C. for 5 hours in a ReactiVial™. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL) and the organic phase separated and washed with water (2×10 mL). The organic phase was then dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol 99:1 to 97:3. The purified material was evaporated and dried to yield a pale yellow solid (66 mg). The PXRD pattern for the solid is shown as FIG. 14.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@:13]12[C:19]([CH3:21])([CH3:20])[C@@:16]([CH3:22])([CH2:17][CH2:18]1)[C:15](=[O:23])[O:14]2)=[O:12])[CH2:2][CH2:3][CH3:4].[OH-:28].[K+].Cl>C(O)C.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([OH:28])[CH2:18][CH2:17][C@@:16]([CH3:22])([C:15]([OH:14])=[O:23])[C:19]1([CH3:20])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(O)CC[C@@](C)(C(=O)O)C1(C)C
Temperature: 60 °C
Yield: 75.2 %

Procedure:
A mixture of the product from Example 102 (50.0 mg, 0.127 mmol) and potassium hydroxide (71.5 mg, 1.27 mmol) in ethanol (1 mL) and water (0.2 mL) was heated to 60° C. for 24 hours. After cooling to ambient temperature, 1N HCl (aq) was added to adjust the pH to −1. The mixture was extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated by rotary evaporator to give a white solid. Recrystallization of the solid from ethyl acetate afforded 39.2 mg (75%) of the title compound. 1H NMR (DMSO-d6) δ 0.79 (s, 3H), 0.92 (t, J=7.2 Hz, 3H), 1.07 (br s, 3H), 1.18 (br s, 3H), 1.27-1.40 (m, 3H), 1.50-1.63 (m, 3H), 1.68 (s, 9H), 1.85 (br s, 1H), 2.51-2.59 (m, 2H), 2.91 (br s, 2H), 9.07 (br s, 1H), 12.10 (br s, 1H). MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[K].[CH3:5][C:6]1([CH3:35])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:34])([F:33])[C:28]([O:30]CC)=O)=[CH:23][CH:22]=3)=[O:19])[CH:9]=[CH:8][C:7]1=2.Cl>CO>[OH:3][NH:2][C:28]([C:27]([F:33])([F:34])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:10]2[CH:9]=[CH:8][C:7]3[C:6]([CH3:5])([CH3:35])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]=3[CH:11]=2)=[O:19])=[CH:26][CH:25]=1)=[O:30]
Reactant: NO
Reactant: CCOC(=O)C(F)(F)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [K]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(F)(F)C(=O)NO)cc3)ccc21
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Hydroxylamine hydrochloride (2.34 g, 33.7 mmol) was dissolved in methanol (12 mL) at 45° C. for 10 min in a 50 mL round bottom flask. B) Potassium hydroxyde (2.81 g, 50.0 mmol) was dissolved in methanol (7 mL) at 45° C. for 10 min in 25 mL round bottom flask. The solution B) was added in A) at 45° C. This mixture was stirred at 45° C. for 10 min and cooled to RT. The mixture was filtered and 5 mL of the filtrate were added at RT via syringe to a solution of ethyl 2-(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)phenyl)-2,2-difluoroacetate 23 (0.10 g, 0.23 mmol) in methanol (4 mL). This mixture was stirred for 16 h at RT. A solution of HCl 1M was added to about pH=5. The aqueous layer was extracted with ethyl acetate (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. N-(4-((Hydroxycarbamoyl)difluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 4996 was obtained (123 mg, 97% yield) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[C:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Product: N#Cc1cccc(-c2ccc3nc(NC(=O)c4cccnc4)nn3c2)c1
Yield: 7.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-cyanophenylboronic acid (69 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/DCM, gradient from 0:100 to 10:90) gave the title compound as a brown powder (6 mg, 7%). HPLC, Rt: 2.09 min. (purity 92.5%). LC/MS, M+(ESI): 341.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:3]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1C(=O)c1ccccc1CBr)c1ccccc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6 mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl4 (150 mL) was added 2,2′-azobisisobutrylnitrile (0.2 g, 1.5 mmol). The solution was refluxed for 4 h. The solution was then cooled to room temperature, diluted with CH2Cl2 (150 mL) and washed with H2O (3×50 mL). The organic portion was dried over Na2SO4 and evaporated to dryness in vacuo to provide N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g, 74%). A solution of the benzamide (2.3 g, 5.4 mmol) in CH2Cl2 (50 mL) was saturated with dimethylamine, stirred for 16 h and evaporated to dryness in vacuo. The resulting residue was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H2O (5 mL) was added. The solution was refluxed for 24 h. The solution was concentrated in vacuo and then diluted with EtOAc (150 mL) and H2O (50 mL). The organic portion was washed with H2O (3×50 mL), dried over Na2SO4 and purified by column chromatography (silica gel, 18:80.2 MeOH:CH2Cl2:NHOH) to provide lq (0.9 g, 53% yield) MS m/z=289 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]([CH2:18]OC)[CH2:13][Si](C)(C)C)([CH3:11])([CH3:10])[CH3:9].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:12]1[CH2:13][C@@H:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[C@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH2:18]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
Trifluoroacetic acid (38.9 mL, 0.505 mmol) was added to a solution of the product of step B (1.03 g, 5.05 mmol) and methyl (2E)-3-(4-fluorophenyl)prop-2-enoate (1.00 g, 5.05 mmol) in methylene chloride (10 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished the title compound as a colorless liquid (1.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([OH:12])=O.[CH3:16][O:17][CH:18]([O:27][CH3:28])[CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][CH:18]([O:27][CH3:28])[O:17][CH3:16])=[O:12]
Reactant: COC(CNC1CCCCC1)OC
Reactant: O=C(O)CCOCCc1cccc(Br)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 3-(3-bromophenethoxy)propanoic acid (3.3 g, prepared as in Preparation 3, Step ii), Procedure B) in acetonitrile (60 mL) was added TEA (20.21 mL) and N-(2,2-dimethoxyethyl)cyclohexanamine (2.26 g). T3P (1.56M in THF, 15.39 mL) was then added portionwise. The reaction was stirred overnight, and then worked up by the addition of saturated sodium hydrogen carbonate, which was extracted twice with ethyl acetate. The pooled organics were washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent removed to afford a brown oil, which was purified on silica (5% Ethyl acetate/isohexane to 20% Ethyl acetate/isohexane). The solvent was evaporated to afford an orange oil (4.5 g). MS [M+H-MeOH]+=410/412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.40-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.20-7.12 (m, 2H), 4.54 (t, J=5.0 Hz, 0.5H), 4.39 (t, J=5.4 Hz, 0.5H), 4.08-3.98 (m, 1H), 3.73-3.59 (m, 4H), 3.39-3.36 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H), 2.83-2.78 (m, 2H), 2.67-2.61 (m, 2H), 1.82-1.74 (m, 2H), 1.70-1.55 (m, 3H), 1.55-1.42 (m, 2H), 1.38-1.26 (m, 2H), 1.19-1.04 (m, 1H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:25]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH3:32])[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: CCOc1ccc(CCl)cc1OCC
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Temperature: 70 °C
Reaction time: 3 h
Yield: 122 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (403 mg), 3,4-diethoxybenzyl chloride (802 mg) and potassium carbonate (311 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 70° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg) as a yellow amorphous substance.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1NC(C)=O

Procedure:
A solution of acetyl chloride (1.38 g.) in methylene chloride (10 ml.) was added to a mixture of ethyl 2-(2-amino-3-phenoxyphenyl)acetate (4.3 g.), pyridine (1.9 g.) and dried methylene chloride (50 ml.) over 10 minutes at 5° C. with stirring and stirred for 30 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added 10% hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and then evaporated. The residue was crystallized with a mixture of benzene and n-hexane to give the captioned compound (3.65 g.). mp 106° to 107° C.