Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:35])=[O:26])=[CH:20][CH:19]=3)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(N(C)C(=O)OC(C)(C)C)cc3)nc2c1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A solution of 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylic acid (213.5 mg, 0.46 mmol, 1.00 equiv, 99%) and K2CO3 (324.2 mg, 2.35 mmol, 5.00 equiv) in DMF (8 mL) was stirred 45 min at room temperature under an inert atmosphere. CH3I (333.7 mg, 2.35 mmol, 5.00 equiv) was added dropwise, with stirring, at 0° C. The resulting solution was stirred for 1 h at room temperature, then quenched by water. The solution was extracted with 5×10 mL of CH2Cl2, and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out, and the resulting mixture was concentrated under vacuum affording 218 mg (98%) of methyl 3-(4-(t-butoxycarbonyl(methyl)amino)phenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:37]=[CH:36][C:23]([CH2:24][CH2:25][NH:26][C:27](=[O:35])[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:44]CCl>CS(C)=O>[Cl:44][C:22]1[CH:21]=[C:20]([Cl:19])[CH:37]=[CH:36][C:23]=1[CH2:24][CH2:25][NH:26][C:27]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])=[CH:30][CH:29]=1)=[O:35]
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C(=O)OC(C)(C)C)c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3Cl)cc2)c(C#N)c1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A flask was charged with tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (0.07 g), N-(4-chlorophenethyl)-4-hydroxybenzamide (0.105 g), and potassium carbonate (0.047 g) in 1 ml of DMSO and stirred at 95° C. for one day. The reaction was taken up in dichloromethane and washed with water. The organic layer was collected, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography, eluting with a solvent system of 5%-80% ethyl acetate/hexanes gave tert-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)propanoate (0.102 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-:27].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[O:27].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: CC(C)C1CCCCCCCCC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: NCc1ccccc1
Product: CC(C)C(N)CCCCCCCCC(C)(C)C=O
Yield: 56.4 %

Procedure:
The procedure described in Example 2(b) is repeated, except that 68.5 g (0.5 mol) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene, 50 g of 37% hydrochloric acid, 54 g (0.5 mol) of benzylamine and 200 ml of water are used. After neutralisation with 22 g (0.55 mol) of solid sodium hydroxide,97 g (0.282 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undecanal-benzylamine are obtained; yield 56.4% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19].C(N(CC)CC)C>C1COCC1.O>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:24])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.71 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (prepared as described in example 10 step A, 4 g, 15.26 mmol) in THF (25 ml) at 0° C. was added chlorocarbonyl-acetic acid ethyl ester followed by triethyl amine (3.2 ml, 22.89 mmol) drop wise under nitrogen, then the reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with water (50 ml), and extracted with EtOAc (3×75 ml). The organic phases were combined and washed with brine (40 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc/hexane) to afford N-[4-chloro-2-(2-chloro-phenylethynyl)-phenyl]-malonamic acid ethyl ester (3.6 g, 62.71%) as an off white solid. LC-MS (ESI): 376 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClC1C=C(C=CC=1)C(OO)=O>[Br:12][C:3]1[C:2]([CH3:1])=[CH:11][C:6]2=[N:7][C:8](=[O:10])[N:9]=[C:5]2[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc2c(cc1Br)=NC(=O)N=2
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 6-methyl-1,3-dihydro-benzoimidazol-2-one (1.00 g, 6.76 mmol) as prepared in Example 1, N-bromosuccinimide (1.30 g, 7.30 mmol) and 3-chloroperoxybenzoic acid (0.05 g, 0.29 mmol) in carbon tetrachloride (15 ml) was heated under reflux for 4 h. When cooled to room temperature, the mixture was filtered and the solid was recrystallised from methanol to give (17) as a beige solid (0.80 g). Furthermore, the solid insoluble in methanol was collected to give more (17) (0.50 g) and the solids were combined (1.30 g, 85%).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].Cl.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][CH:9]=1>CCO>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][C:3]([CH3:4])=[C:2]2[CH3:1]
Reactant: CCC(C)=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccc(Br)cc2c1C
Yield: 67 %

Procedure:
Following a published procedure (Gundersen, E. G. U.S. Patent App. Publ. US 2005/070592) 2-Butanone (0.11 mL, 1.278 mmol) was added to a solution of 4-bromophenylhydrazine hydrochloride (0.300 g, 1.342 mmol in EtOH (3.8 mL). The mixture was heated to reflux for 22 h, concentrated in vacuo, and partitioned between EtOAc and 1N HCl. The organic layer was washed with H2O and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by chromatography (SiO2, 0-20% EtOAc/Hexane) to afford the desired indole as a pink powder (200 mg, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](=O)[CH:13]=O>CCO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[N:10]=[CH:13][CH:12]=[N:11]2)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=CC=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nccnc2c1
Yield: 97.1 %

Procedure:
A suspension of 4-nitrobenzene-1,2-diamine (15.3 g, 0.1 mol) and oxalaldehyde (40% in water, 17.4 g, 0.12 mol) in EtOH (150 mL) was stirred at reflux for 16 h. The mixture was then filtered, and the solid was collected to give 6-nitroquinoxaline as a yellow solid (17.0 g, yield 97%). ESI MS: m/z 176.0 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.[CH3:14][N:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C@@H:25]4[CH2:30][NH:29][CH2:28][CH2:27][C@@H:26]4[N:18]([C:19]=23)[CH2:17][CH2:16]1.N>>[ClH:1].[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C@@H:26]3[N:18]4[C:19]5[C:20]([C@@H:25]3[CH2:30]2)=[CH:21][CH:22]=[CH:23][C:24]=5[N:15]([CH3:14])[CH2:16][CH2:17]4)=[N:6]1
Reactant: ClCCCc1noc2ccccc12
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12
Agent: N
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCc3noc4ccccc34)CC[C@@H]12
Product: Cl

Procedure:
The title compound was prepared from addition 3-(3-chloropropyl)-1,2-benzisoxazole from Step D Example 22 and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline following the General procedure A of Example 197. 1H NMR (300 MHz, CDCl3) δ 7.59-7.62 (m, 1H), 7.46-7.50 (m, 2H), 7.20-7.25 (m, 1H), 6.57 (dd, J=7.7 Hz, 7.3 Hz, 1H), 6.43 (d, J=6.9 Hz, 1H), 6.33 (d, J=7.3 Hz), 3.48-3.52 (m, 1H), 3.06-3.25 (m, 4H), 2.94-2.99 (m, 2H), 2.70-2.89 (m, 4H), 2.79 (s, 3H), 2.20-2.65 (m, 3H), 1.92-2.07 (m, 4H) ppm. MS (CI, NH3) m/e 389 (base, M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[C:4]([CH:21](O)[CH2:22][CH3:23])[CH:3]=1.[OH:25]S(O)(=O)=O.[C:30](#[N:32])[CH3:31]>>[C:30]([NH:32][CH:21]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[CH:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[CH2:22][CH3:23])(=[O:25])[CH3:31]
Reactant: CC#N
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(O)CC)C2
Product: CCOC(=O)N1C2CCC1CC(c1ccc(Cl)cc1C(CC)NC(C)=O)C2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[4-chloro-2-(1-hydroxypropyl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (2-8) (2.25 g, 6.39 mmol) in acetonitrile (100 mL) was add concentrated H2SO4 (5.11 mL, 95.9 mmol) in 50 mL of acetonitrile. The mixture was stirred at 60° C. for 1 h, quenched with 1 N NaOH (200 mL), and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (a mixture of 9:1:0.1 methylenechloride:MeOH:30% NH4OH as eluent) afforded (2-9) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30]O>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCc1ccc2ccccc2c1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc3ccccc3c2)cc1
Yield: 89.9 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol) prepared in Example 1 (1a) and 2-(2-naphthyl)ethanol (207 mg, 1.20 mmol) to give 314 mg of the title compound (white powder, yield: 90%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([O-])([O-])=O.[K+].[K+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O>O1CCOCC1>[N+:22]([C:25]1[CH:30]=[C:29]([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1NCCc2c(-c3cccc([N+](=O)[O-])c3)[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Tricyclic bromide 11 (27 mg, 0.10 mmol) in 1,4-dioxane (1.0 mL) was treated with solid K2CO3 (41 mg, 0.30 mmol), m-nitrophenylboronic acid (34 mg, 0.20 mmol), and water (0.25 mL). The solution was degassed and tetrakis(triphenylphosphine)palladium(0) (12 mg, 10 mol %) was added. The solution was heated at 100° C. for 1 h, then cooled to ambient temperature and diluted with water (2 mL). The aqueous layer was adjusted to pH=7-8 with saturated aqueous K2CO3 and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography (3-5% MeOH in CHCl3) to yield 14 as a yellow solid, 26.3 mg (87%). mp 268-270° C. (dec.); 1H NMR (DMSO-d6) δ3.16 (m, 2H), 3.45 (m, 2H), 7.33 (m, 1H), 7.65 (m, 1H), 7.76 (m, 1H), 7.78 (m, 1H), 8.30 (m, 1H), 8.53 (bs, 1H), 8.16 (m, 2H), 11.93 (bs, 1H); HRMS (M+Na) Calcd for C17H13N3O3+Na: 330.0855, Found: 330.0847; Anal. (C17H13N3O3.H2O) C, H, N.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].O>C(O)(=O)C>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](=[O:14])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)Oc2ccc(OS(C)(=O)=O)cc21
Yield: 70 %

Procedure:
A solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (20 parts) in warm acetic acid (200 parts) was treated with 200 parts of a 20% aqueous solution of chromic oxide. After about 15 seconds the mixture was poured into water and the solution extracted with ether. The extracts were thoroughly washed with aqueous sodium bicarbonate, then dried and the solvent evaporated to give 2-oxo-2,3-dihydro-3,3-dimethyl-benzofuran-5-yl methanesulphonate (14 parts, 70% yield), melting point 120°-121° C. after recrystallisation from benzene-petroleum.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:30]1[CH:31]=[CH:32][C:27]([C@@H:8]2[C@H:9]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:25][CH:26]=3)[C:10]3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4][C:5]=3[CH2:6][CH2:7]2)=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 400 mg (0.94 mmol) of cis-1-{2-[4-(6-methoxy-2-phenyl 1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine in 25 mL of methylene chloride at 0° C. was added, dropwise with stirring, 4.7 ml (4.7 mmol) of a 1.0 M solution of boron tribromide in methylene chloride. After 3 hours at room temperature, the reaction was poured into 100 mL of rapidly stirring saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to afford 287 mg (74% yield) of lasofoxifene as the free base.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(Cc2ccc(Cl)cc2)C1=O

Procedure:
Prepared from 4-chlorobenzylbromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16 to give 50.4 mg (21% overall yield) of the title compound: LC/MS (an10p8): Rt 2.6 min, m/z 482 [M−H]−. 1H NMR (DMSO-d6): δ 3.05 (dd, J=13.8, 9.7 Hz, 1H), 3.57 (dd, J=13.8, 4.9 Hz, 1H), 5.11 (dd, J=9.7, 4.9 Hz, 1H), 4.67 (s, 2H), 4.75 (s, 2H), 6.91 (d, J=8.7, 1H), 7.25-7.28 (m, 2H), 7.37-7.42 (m, 4H), 13.15 (br. s, 1H).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18](O)=[O:19])=[C:13]([F:22])[CH:12]=1.CN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([NH:4][CH3:1])=[O:19])=[C:13]([F:22])[CH:12]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (0.2 mL, 0.001 mol) was added to a mixture of (4-bromo-2-fluorophenyl)(hydroxy)acetic acid (0.1 g, 0.4 mmol), methylamine (2M in THF, 0.24 mL, 0.48 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.21 g, 0.00048 mol) in methylene chloride (2 mL). The mixture was stirred at RT for 2 h. The reaction mixture was concentrated. The residue was purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product. LCMS: (M+H)=261.9/263.9.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:23][C:22](=[O:24])[O:21][N:20]=4)[C:8]=3[CH:25]=2)[CH2:3][CH2:2]1.Br[CH2:37][CH2:38][Cl:39].N12CCCN=C1CCCCC2>CN(C)C(=O)C>[Cl:39][CH2:38][CH2:37][N:23]1[C:22](=[O:24])[O:21][N:20]=[C:19]1[C:9]1[C:8]2[CH:25]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:26]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:6][C:7]=2[O:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: ClCCBr
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)[nH]3)c2cc1C1CC1)S(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(-c3noc(=O)n3CCCl)c2cc1C1CC1)S(C)(=O)=O
Yield: 30.3 %

Procedure:
A mixture of Example 10G (188 mg, 0.376 mmol), 1-bromo-2-chloroethane (0.033 mL, 0.395 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL, 0.414 mmol) in N,N-dimethylacetamide (6 mL) was heated in a sealed tube at 100° C. for 16 hours, cooled and concentrated. The residue was chromatographed on silica gel eluting with hexane to 3:1 hexane/ethyl acetate to give the title compound as a solid (64 mg, 30%). MS (ESI+) m/z 579 (M+NH4)+.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)=O.[OH-].[K+]>C(O)C.O>[CH2:20]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=2[CH:7]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN(C(=O)C(F)(F)F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 2,2,2-trifluoro-N-pentyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (31) (13.6 g, 37.5 mmole) in 140 mL ethanol was treated with a solution of potassium hydroxide (10.52 g) in 25 mL water. The mixture was stirred at room temperature for two hours, diluted with 100 mL water and then extracted with two 250 mL portions of ethyl acetate. The combined organic extracts were washed with six 200 mL portions of cold water or until the pH was neutral. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes) to yield 9.86 g of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine (33) as a golden oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3(CCN(C(N)=O)C3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2C[C:34]3([CH2:39][CH2:38][NH:37][CH2:36]3)ON=2)C=CC=1.[CH2:40]([N:42]([CH2:46][CH3:47])[C:43](Cl)=[O:44])[CH3:41].CN=C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:47][CH2:46][N:42]([C:43]([N:37]([CH2:38][CH3:39])[CH2:36][CH3:34])=[O:44])[CH2:40][CH2:41]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Agent: CN=C=O
Product: CCN(CC)C(=O)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96 but replacing Compound 22c for Compound 27d and N,N-diethyl chloroformamide for methylisocyanate. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 8:2 to 6:4) giving the title compound. Yield: 47.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:11])[C:7]=1[C:8]([OH:10])=[O:9].Cl.[CH3:13][N:14]([CH3:16])O.C(N(CC)CC)C.O>O1CCCC1>[F:1][C:2]1[C:7]([C:8]([O:10][N:14]([CH3:16])[CH3:13])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(O)cccc1F
Reactant: CN(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)OC(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.56 Grams of 6-fluorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.94 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 0.6 g of 3-fluoro-2-(N,N-dimethylaminooxycarbonyl)phenol.
Reaction SMILES: [CH2:1]([C:5]1([CH2:20][C:21](=[O:23])[CH3:22])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10]([O:16][CH3:17])[C:11]=2[Cl:15])[C:6]1=O)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CCO.ClCCl>[CH2:1]([C:5]12[CH2:20][C:21](=[O:23])[CH:22]=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([Cl:15])[C:10]([O:16][CH3:17])=[C:9]([F:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC(C)=O)CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCCCC12CCc3c(cc(F)c(OC)c3Cl)C1=CC(=O)C2
Temperature: 90 °C

Procedure:
To a solution of 2-butyl-5-chloro-7-fluoro-6-methoxy-2-(2-oxo-propyl)-3,4-dihydro-2H-naphthalen-1-one (28 mg, 0.08 mmol) in EtOH (0.4 mL) was added potassium hydroxide (2M solution in EtOH, 0.05 mL, 0.1 mmol). The reaction mixture was heated at 90° C. in a sealed flask for two hours. The reaction was cooled to room temperature, diluted with dichloromethane (5 mL) and filtered through a pad of MgSO4 atop a pad of SiO2. The filter pad was washed with 5% MeOH in CH2Cl2 and the combined filtrates concentrated under vacuum to give 3a-butyl-6-chloro-8-fluoro-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil which solidified on standing.