Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: COc1ccsc1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccsc1
Temperature: 130 °C
Yield: 96 %

Procedure:
A mixture of 3-methoxythiophene (7.28 g, 63.76 mmol), 1-octanol (20.09 mL, 127.53 mmol), p-toluenesulfonic acid monohydrate (1.21 g, 6.38 mmol) and 60 mL toluene was heated in a 130° C. bath for 15 hours under argon. After dichloromethane/water extraction, the organic layer was dried over anhydrous Na2SO4. After solvent evaporation, the residue was purified by column chromatography (silica gel 3:1 hexane:dichloromethane) to give 2′ as a colorless solid (13.00 g, 96%). 1H NMR (CDCl3, 300 MHz, ppm): δ 7.18-7.21 (m, 1H), 6.78-6.80 (m, 1H), 6.25-6.26 (m, 1H), 3.97 (t, 2H, 6.6 Hz), 1.76-1.85 (m, 2H), 1.33-1.48 (m, 10H), 0.91-0.95 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.6 %

Procedure:
The suspension of 0.15 g (0.36 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 146 mg (1.1 mmol) 4-methylphenylboronic acid, 0.13 g (0.72 mmol) copper(II) acetate and 0.12 mL (0.11 g, 1.43 mmol) pyridine in 5 mL dichloromethane was stirred for 3 days at room temperature. The volatile components were evaporated at a rotary evaporator and the residue was purified using flash chromatography on silica gel with dichloromethane:methanol (19:1 v/v) as eluant to give 89 mg (49%) of the desired compound as a colorless foam.
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.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:34](I)[CH:35]=[CH2:36].[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.C(OCC)C.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH:15]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:36][CH:35]=[CH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCI
Reactant: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Reaction time: 0.67 h

Procedure:
Alternately, combine (S)-4-benzyl-3-(4-fluorophenyl)acetyl-2-oxazolidinone (43.08 g, 426 mmol) and tetrahydrofuran (450 ml). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium bis(trimethylsilyl)amide (153.0 ml, 1 M in tetrahydrofuran, 137.5 mmol). After 40 minutes, add a solution of allyl iodide (39.0 ml, 426 mmol) and replace the bath with a dry-ice/carbon tetrachloride bath. After 1.5 hours, quench the reaction by the addition of a saturated aqueous solution of ammonium chloride, add diethyl ether (200 ml), and stir. After about 30 minutes, separate the layers and extract the aqueous layer twice with diethyl ether. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a residue. Dry the residue in a vacuum, dissolve in ethyl acetate (about 400 ml), and extract with a saturated aqueous sodium thiosulfate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 13% ethyl acetate/hexane to give (S)-4-benzyl-3-(2-(4-fluorophenyl)pent-4-enoyl)-2-oxazolidinone.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[S:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([S:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 60 °C
Yield: 18 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate prepared as described in Example 330A (200 mg, 0.59 mmol), N,N-diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (85 mg, 0.27 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 18%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.26-7.55 (m, 5H), 6.06 (s, 1H), 4.00 (s, 6H), 3.94 (m, 1H), 1.62-1.81 (m, 7H), 1.24-1.36 (m, 12H); LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=O.[CH3:14][C:15]([CH3:17])=[O:16]>>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=[CH:14][C:15](=[O:16])[CH3:17]
Reactant: Cc1ccc(Cl)c(C=O)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(C)ccc1Cl
Reaction time: 1 h

Procedure:
To a mixture of acetone (160 ml), sodium hydroxide (2.6 g) and water (160 ml) was added dropwise at 0° C. a solution of crude 2-chloro-5-methylbenzaldehyde (18.3 g) in acetone (30 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(2-chloro-5-methylphenyl)-3-buten-2-one (18.9 g) as oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:12]2[N:13]=[CH:14][S:15][C:11]=2[C@H:10]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].OO.C(=O)([O-])[O-].[Na+].[Na+].[F:36][C:37](I)([F:39])[F:38].CS(C)=O>C1([Fe]C2C=CC=C2)C=CC=C1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:18][CH2:17][C@@H:16]([OH:19])[C:12]2[N:13]=[C:14]([C:37]([F:39])([F:38])[F:36])[S:15][C:11]=2[C@H:10]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reactant: FC(F)(F)I
Agent: C1=CC([Fe]C2C=CC=C2)C=C1
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2sc(C(F)(F)F)nc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Trifluoromethyliodide gas was bubbled through 4 mL of dimethylsulfoxide for 3 min at rt. In this way, approximately 0.9 g of trifluoromethyliodide was dissolved in this solution. Dicyclopentadienyliron(II) (21.9 mg, 0.114 mmol) and tert-butyl (4R,7S,8S)-7-(2,3-difluorophenyl)-4-hydroxy-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-8-ylcarbamate (45.3 mg, 0.114 mmol) was dissolved in 2 mL of the trifluoromethyliodide-dimethylsulfoxide solution described above. Hydrogen peroxide (0.012 mL, 0.114 mmol) was added to the reaction mixture. The reaction was stirred at rt for 1 h. Aqueous sodium carbonate was added and the reaction was extracted with ethyl acetate. The ethyl acetate layer was washed with water (2×) and dried (sodium sulfate). The product was purified by flash chromatography, eluting with ethyl acetate in hexane from 0 to 30% to 45% to give the desired product (12.5 mg, 24%): LCMS (M+H=465.08); 1H NMR (400 MHz, CHLOROFORM-d) δ 7.21-6.97 (m, 3H), 5.30-5.16 (m, 1H), 498-4.84 (m, 2H), 3.43-3.28 (m, 1H), 3.12-2.79 (m, 2H), 2.43-2.13 (m, 3H), 1.37-1.18 (m, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:12]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1.CCCCCC>[C:1]1([C:7]2[C:12]3[S:13][C:14]4[C:19]([B:25]([OH:28])[OH:26])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccc3c2sc2ccccc23)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1sc1c(-c3ccccc3)cccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3.5 g (13.4 mmol) 4-phenyldibenzothiophene was dissolved in ˜30 mL anhydrous THF in a three necked 250 mL flask and cooled down to −78° C. To the mixture, 17 mL (27 mmol) 1.6 M BuLi in hexane was added and stirred for 30 minutes. The cooling batch was removed and let reaction kept stirring for overnight. The reaction mixture was cooled down again to −78° C. and 4.5 mL (40 mmol) trimethyl borate was added and stirred at room temperature for 4 hours. ˜100 1 M HCl was added and kept stirring for 1 hour. The mixture was extracted by ethyl acetate and the organic extracts were combined. The solvent was evaporated to dryness. The solid was added with ˜100 mL 20% ethyl acetate in hexane was stinrred for few hours and then filtered. The filtered solid washed by hexane few times. ˜2.5
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]([C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[CH2:9][C:10](OCC)=[O:11].O.C1COCC1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[C:20]([N:18]1[CH:19]=[C:15]([CH:8]([OH:7])[CH2:9][CH2:10][OH:11])[N:16]=[CH:17]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Lithium aluminum hydride (8.78 g) was suspended in dry THF (500 ml) under an argon atmosphere, and ethyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate (76 g)/dry THF (350 ml) solution was added at the same temperature with stirring under ice-cooling (ice-salt). The mixture was allowed to assume room temperature and stood with stirring for 2 h. The mixture was ice-cooled again and water/THF (1/6; 58.4 ml) was added to stop the reaction. An aqueous Rochelle salt solution (240 g/1.5 L) was added and the mixture was stood with stirring for 18 h. The organic layer was separated, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from ethyl acetate-ether to give the title compound (58.8 g) as a colorless crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2].[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)=[CH:14][C:9]=2[O:8][C:7]=1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:5])[CH3:2]
Reactant: Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C)c3)ccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester from step 4 (162 mg, 0.32 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 mL) were sequential added 3-methyl benzene boronic acid (64.6 mg, 0.63 mmol, 1.5 eq), potassium carbonate (87.6 mg, 0.63 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (73.2 mg, 0.06 mmol, 0.2 eq) under argon. The reaction mixture was degassed for 5 min. The reaction was then stirred at 80° C. for 4 h followed by stirred at rt for 12 h. The mixture was cooled to room temperature then poured into ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). Combined the organic layer was washed by water (2×10 mL), dried over Na2SO4, filtrated, and evaporated In vacuo. The residue was purified by pre-HPLC to afford an yellow solid (91.3 mg, 63%) as product. 1H-NMR (CDCl3): δ 8.04 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.64 (dd, J=1.5, 8.3 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.41 (m, 2H), 7.36 (dd, J=1.9, 8.3 Hz, 1H), 7.34 (t, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.245 (q, 2H), 2.43 (s, 3H), 1.28 (t, 3H); LC-MS (MH+=453/455).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[F-].[K+].[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>CS(C)=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxy benzaldehyde (8.6 g, 0.046 mol) in dimethylsulphoxide (15 mL) was added potassium fluoride (5.36 g, 0.092 mol) at room temperature. Then it was refluxed to 100-120° C. To this 2-bromo-1-fluoro-4-nitrobenzene (20.3 g, 0.093 mol) in dimethylsulphoxide (10 mL) was added dropwise at 100-120° C. The heating was continued for 5 hours. The reaction mixture was poured into the crushed ice and stirred for 1 hour. Then the aqueous layer was decanted. The solid obtained was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (3×200 mL). The organics were dried over sodium sulphate and filtered. The solvents were removed in vacuum to give the crude product. The product was purified by column chromatography by using gradient (0-2) % of ethyl acetate in hexane. The solid obtained was washed with hexane and dried. Yield—66%. 1H-NMR (DMSO-d6) δ: 7.06 (d, 1H), 7.23-7.41-7.59 (t, 1H), 7.67 (d, 1H), 7.82 (d, 1H), 7.96-7.98 (m, 1H), 8.20-8.23 (m, 1H), 8.61 (d, 1H), 9.97 (s, 1H); HPLC (purity): 99.5%; Mass calculated for C14H8BrF2NO5-388.1, observed—388.1; Rf—0.47 (Ethyl acetate:Hexane (3:7).
Reaction SMILES: C1(CN(C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)CCC2C=CC(O)=CC=2)CC1.Cl.ClCCN1CCCC1.[CH:44]1([CH2:47][N:48]([C:65]2[CH:70]=[C:69]([O:71]C)[CH:68]=[CH:67][C:66]=2[CH:73]2[CH2:82][CH2:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([O:83]C)[CH:79]=3)[CH2:74]2)[CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:53][CH:52]=2)[CH2:46][CH2:45]1>>[CH:44]1([CH2:47][N:48]([CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:53][CH:52]=2)[C:65]2[CH:70]=[C:69]([OH:71])[CH:68]=[CH:67][C:66]=2[CH:73]2[CH2:82][CH2:81][C:80]3[CH:79]=[C:78]([OH:83])[CH:77]=[CH:76][C:75]=3[CH2:74]2)[CH2:45][CH2:46]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(OCCN3CCCC3)cc1)CC1CC1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O)cc1)CC1CC1)C2
Agent: Cl
Agent: ClCCN1CCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N(CCc1ccc(OCCN3CCCC3)cc1)CC1CC1)C2
Yield: 89.4 %

Procedure:
Synthesized from 4-{2-{cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)pyrrolidine hydrochloride according to an analogous synthetic method to Preparation Example 40, cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]{2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]ethyl}amine (284 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (241 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN.NN>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][NH2:26])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 98.7 %

Procedure:
A solution of 2.32 g (4.59 mmol) of (±)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-phthalimidoethyloxycarbonyl)-1,4-dihydropyridine and 344 mg of hydrazine monohydrate in 100 ml of ethanol is heated at reflux for 2 hr. TLC indicates the reaction is incomplete so another 1.5 equivalents of hydrazine monhydrate is added and the mixture refluxed for an additional hr. After cooling, the precipitate is collected by filtration, washed with ethanol, and the filtrate evaporated under vacuum to leave a yellow solid. This solid is taken up in 125 ml of CH2Cl2, washed twice with 0.5N KOH, once with water, dried (MgSO4), filtered, and the solvent removed under vacuum to give 1.70 g of (±)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5 (2-aminoethoxycarbonyl)-1,4-dihydropyridine as a yellow solid. 1H-NMR (CDCl3); δ 1.85 (s, 2H); 2.40 (d, 6H); 3.40 (t, 2H); 3.68 (s, 3 H); 4.35 (s, 2H); 5.15 (s, 1H); 5.90 (s, 1H); 7.40 (t, 1H) 7.68 (d, 1H); 8.03 (d, 1H); 8.13 (s, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]([F:13])([F:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.C(Cl)(Cl)(Cl)F>CS(C)=O>[N:1]([C:6]([F:13])([F:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: FC(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Powdered sodium azide (19.5 g, 0.3 mol) was added in portions, over 5 minutes, to a stirred solution of ethyl 2-bromo-2,2-difluoroacetate (50.74 g, 0.25 mol) in dry dimethyl sulfoxide (250 mL). After stirring at room temperature for 18 hours, the mixture was poured into water (750 mL) and extracted with methylene chloride (4×100 mL). The combined extracts were washed with water (4×100 mL), dried over anhydrous magnesium sulfate, then filtered, and the filtrate was distilled at atmospheric pressure through an indented (10 cm.) distillation column, at a bath temperature of 77° C., until no more methylene chloride distilled. 1H NMR spectroscopy (CDCl3 ; (CH3)4Si internal standard) of the colorless residue showed a mixture of methylene chloride (31 mol %) and the azido ester (69 mol%); 4.53 (q, 2H, CH2), 1.44 (t, 3H, CH3). This corresponds to a yield of 34.44 g (83.4%) of the azido ester. The pure product was obtained as a colorless liquid by distillation under vacuum; bp 68° C./100 mm. 19F NMR (CDCl3, CFCl3 internal standard) φ 84.8 (s). Anal. Calcd. for C4H5F2N3O2 : C, 29.10; H, 3.05; N, 25.45; F, 23.02. Found: C, 28.80; H, 3.15; N, 25.36; F, 23.15.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)=[C:11]([CH3:39])[CH:10]=1)(=[O:5])=[O:4])[CH3:2].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)=[C:11]([CH3:39])[CH:10]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC(C)(C)C)cc3)c2)c(C)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)CCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Yield: 72.1 %

Procedure:
To a solution of tert-butyl 3-[4-({4′-[2-(ethylsulfonyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)phenyl]propanoate (0.37 g, 0.67 mmol) in toluene (3.7 mL) was added trifluoroacetic acid (3.7 mL) at room temperature with stirring and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, the obtained crystals were collected by filtration, washed and dried to give the title compound (0.24 g, yield 72%) as colorless crystals.
Reaction SMILES: C([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[OH:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][S:24]([C:27]([F:30])([F:28])[F:29])(=[O:25])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
A solution of ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (6.0 grams, ˜13 mmol, semipure) in DCM (60 mL) was treated with TFA (6.0 mL) at 23° C. The reaction was diluted with H2O (60 mL) and the organic phase collected. The aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue (5.5 grams) was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 8.08-8.06 (m, 1H), 7.81-7.78 (m, 1H), 7.69 (s, 1H), 7.62-7.55 (m, 2H), 5.81 (app. s, 1H), 4.35-4.21 (m, 2H), 3.26 (app. s, broad, 1H), 2.50 (s, 3H), 1.21 (t, J=7.0 Hz, 3H).