Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](CC1CCC(=O)CC1)(O)=[O:2].[CH2:12]([OH:15])[CH2:13][OH:14].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:14]1[C:16]2([CH2:21][CH2:20][CH:19]([CH2:1][OH:2])[CH2:18][CH2:17]2)[O:15][CH2:12][CH2:13]1
Reactant: OCCO
Reactant: c1ccccc1
Reactant: O=C(O)CC1CCC(=O)CC1
Solvent: O
Product: OCC1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
A mixture of 4-carboxymethylcyclohexanone (21 g), ethylene glycol (19 g) and benzene (250 mL) was heated at reflux for 20 h with Dean Stark azeotropic removal of water. After cooling the solution was washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The crude ketal was then taken up in diethyl ether (250 mL) and lithium aluminium hydride (7 g) was added. The mixture was stirred overnight and then water (20 mL), 10% sodium hydroxide (30 mL) and water (30 mL) was added carefully. Sodium sulphate (30 g) was then added and the mixture stirred for 20 min, The insoluble material was removed by filtration and the organic phase concentrated in vacuo to give (1,4-dioxaspiro[4.5]dec-8-yl)-methanol (21 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:32])[C:8]([OH:31])=[C:9]([C:13]3[CH:18]=[C:17]([O:19]C)[C:16]([O:21]CC4C=CC=CC=4)=[C:15]([O:29]C)[CH:14]=3)[O:10]2)=[CH:5][C:4]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:2].B(Br)(Br)Br.CO.O>ClCCl>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:32])[C:8]([OH:31])=[C:9]([C:13]3[CH:14]=[C:15]([OH:29])[C:16]([OH:21])=[C:17]([OH:19])[CH:18]=3)[O:10]2)=[CH:5][C:4]=1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH3:2]
Reactant: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2cc1CC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(O)c(O)c(O)c3)oc2cc1CC
Temperature: 25 °C
Reaction time: 21 h
Yield: 103.2 %

Procedure:
To a stirring solution of 7-ethyl-3-hydroxy-6-octyl-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 59 (0.125 g, 0.2 mmol) in dichloromethane (10 ml) under Ar at 0° C. was added boron tribromide in dichloromethane (1.0M, 1.2 ml, 1.2 mmol, 5.2 equ). The mixture was warmed to room temperature and then stirred for 21 hours. Methanol (5 ml) was then added. The reaction was heated to reflux for 2 hours, then concentrated in vacuo to give a brown solid. Water (10 ml) was added then extracted into ethyl acetate (3×). The organic layer was washed with brine then dried (MgSO4) and concentrated in vacuo to give 12 (0.088 g, 100% over 2 steps) as a green solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]2([F:20])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.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(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]2([F:20])[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:11]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:12])[C:7](=[O:21])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3(F)CCCC3)N3CC(Oc4c(F)cccc4F)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid (0.264 g, 0.71 mmol) in dry N,N-dimethylformamide (6 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49 0.170 g, 0.86 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.470 g, 1.06 mmol). To this mixture was added N,N-diisopropylethylamine (0.282 g, 2.18 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over magnesium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (Supelco Flash Column 23 g, 50% to 60% ethyl acetate/hexanes) which afforded 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-3-(1-fluoro-cyclopentyl)-propionamide (0.330 g, 84%) as a light brown oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 3H), 1.30 (s, 3H), 1.46-2.02 (m, 8H), 2.04-2.47 (m, 2H), 3.73 (dd, J=8.4, 6.0 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.06-4.20 (m, 2H), 4.28-4.39 (m, 2H), 4.53 (d, J=18.7 Hz, 1H), 5.03 (s, 1H), 5.09 (dd, J=9.5, 4.4 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.28-7.49 (m, 3H), 7.61 (s, 1H), 10.84 (s, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:9]1[C@@H:8]([CH2:7][CH2:6][C:5]([OH:22])=[O:4])[CH2:12][O:11][C:10]1([CH3:14])[CH3:13])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1[C@@H](CCC(=O)O)COC1(C)C
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 90.8 %

Procedure:
An aqueous solution of sodium hydroxide (195 mL, 4.0 M in H2O, 0.261 mol, 3.0 eq) was added to a solution of (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (25.1 g, 0.087 mol), and the resulting cloudy reaction mixture was stirred at 23° C. for 3.5 hr. The mixture was concentrated under reduced pressure to ˜50 mL volume and then was partitioned between 0.5 M HCl (360 ml) and EtOAc (2×360 ml). The combined organic layers were dried over Na2SO4 and were filtered. The filtrate was concentrated under reduced pressure to give (S)-3-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propanoic acid (21.6 g, 91%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC=CC=1.NC1C=CC(C(OC)=[O:28])=C(Br)C=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:11]=[C:10]([OH:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: COC(=O)c1ccc(N)cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].O.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>CC(C)=O>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[C:11]([OH:13])=[O:12])=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 29 %

Procedure:
Into 60 mL acetone was dissolved 0.905 g 5 mmol) 4-aminoisophthalic acid. To the solution was added 30 mL water. The mixture was cooled in an ice bath, and 1.08 mL (5.5 mmol) 4-tert-butylbenzoyl chloride in 10 mL acetone was added dropwise. The mixture was allowed to warm slowlyly to room temperature and after 24 h was concentrated under vacuum and shaken between EtOAc (150 mL) and cold dilute HCl (150 mL). The organic layer was dried (MgSO4) and evaporated. The desired crystalline product (0.489 g, 29%) was obtained from methylene chloride-hexane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](OC)(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=[O:54])[CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:41]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.[OH-].[Na+]>C1COCC1>[CH2:47]([O:46][C:42]1[CH:41]=[C:40]([CH2:39][CH2:38][C:37]2([CH2:36][CH2:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)[O:54][C:13](=[O:18])[CH:14]=[C:15]([OH:16])[CH2:17]2)[CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)CCc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=C1C=C(O)CC(CCc2cccc(OCc3ccccc3)c2)(CCc2cccc(OCc3ccccc3)c2)O1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of 3.3 mL of diisopropylamine (23.5 mmol) in dry THF (500 mL) was cooled to 0° C. under nitrogen, treated with 14.3 mL of 1.64 M n-butyllithium (22.8 mmol), and stirred at 0° C. for 25 minutes. To this solution was added 1.2 mL (11.1 mmol) of methyl acetoacetate, and the mixture was stirred for 30 minutes. The solution was then cooled to -78° C. A solution of 5.00 g (11.1 mmol) of 1,5-bis-(3-benzyloxy-phenyl)-pentan-3-one (prepared in Example J) dissolved in dry THF (100 mL) was added dropwise, and the mixture was stirred at low temperature for 3 hours. Dilute acetic acid (2 equivalents) was added, and the mixture was extracted with EtOAc. The extracts were dried (MgSO4) and concentrated. The residue that was obtained was dissolved in THF (250 mL), treated with 0.1N NaOH (500 mL), and stirred overnight at room temperature. The mixture was cooled in an ice bath, quenched with 50% acetic acid, and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel, eluting with MeOH:CH2Cl2 (2:98), to give 6,6-bis-[2-(3-benzyloxy-phenyl)-ethyl]-5,6-dihydro-4-hydroxy-pyran-2-one. 1H NMR (DMSO-d6) δ 1.93 (m, 4 H), 2.56 (m, 4 H), 3.35 (s, partially obscured by H2O, 2 H), 4.99 (s, 1 H), 5.02 (s, 4 H), 6.72-6.78 (m, 4 H), 6.82 (br s, 2 H), 7.14 (t, 2 H), 7.26-7.39 (m, 10 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:25](#[N:28])[CH:26]=[CH2:27]>O1CCOCC1>[C:25]([CH2:26][CH2:27][C:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:28]
Reactant: CCOC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (1.55 g, 5.64 mmol) in anhydrous dioxane (10 mL) was added sodium ethoxide (0.38 g, 5.61 mmol), and the reaction was stirred at a temperature between 40-50° C. for 30 minutes. Acrylonitrile (0.35 mL, 5.61 mmol) was added dropwise with stirring, and the reaction was heated at 60-70° C. for an additional 1 hour. The dioxane was removed in vacuo, and the residue was taken up in ether, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexane gave the title compound. MS (DCI) m/z 342 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[C:26]([F:27])=[C:25]([F:28])[C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[C:6]([F:29])[C:5]=1[OH:30])([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:26]([F:27])=[C:25]([F:28])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:23][CH:24]=2)=[C:6]([F:29])[C:5]=1[OH:30]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(O)c([N+](=O)[O-])c(F)c2F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1c(O)c(F)c(Oc2ccc(C(=O)O)cc2)c(F)c1F
Reaction time: 72 h
Yield: 93 %

Procedure:
50 g of benzyl 4-(4-nitro-3-hydroxy-2,5,6-trifluorophenoxy)benzoate prepared as described in Example 1 (0.12 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]([NH2:44])[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:44][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]([CH3:33])[CH2:35][CH2:36]1)=[O:31]
Reactant: CC1CCC(N)c2ccccc21
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCC(C)c3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 4-methyl-1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:6][CH:5]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28].CO>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:8][CH:9]=1)=[S:28]
Reactant: CN(C)C(=S)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A suspension of sodium hydride in mineral oil (0.44 g of 60%) in anhydrous DMF (10 mL) was cooled to 0° C. N-[4-(4-hydroxyphenyl)butyl]phthalimide (2.95 g, 10 mmol) dissolved in dry DMF (15 ml) was added into the mixture which was then stirred for 30 min at 0° C. and allowed to warm to room temperature over 1 h. To the mixture was added portionwise N,N-dimethylthiocarbamoyl chloride (1.35 g, 11 mmol) dissolved in DMF (10 ml). The newly formed mixture was stirred at room temperature overnight, then at 50° C. for 1 h, and was cooled back to room temperature, at which point methanol (10 mL) was added into the mixture. The solvent was removed under reduced pressure. The residue was purified by flash chromatography over silica gel (dichloromethane/hexane/ethyl acetate, 10:1:0.2, v/v) to give N-{4-[4-(dimethythiocarbamoyloxy)phenyl]butyl}phthalimide 34 (2.27 g, 59%) as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.72 (m, 4H), 2.66 (m, 2H), 3.33 (s, 3H), 3.45 (s, 3H), 3.70 (m, 2H), 6.96 (d, 2H), 7.18 (d, 2H), 7.71 (m, 2H), 7.84 (m, 2H). m/z (ESI) 383 [C21H22N2O3S+H]+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].[NH:8]1[CH:12]=[CH:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:6])#[C-:2]
Reactant: C1=CNCC1
Reactant: [C-]#[N+]CC(=O)OC
Product: [C-]#[N+]CC(=O)N1CC=CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (1.00 g, 10.10 mmol) and dihydro-1H-pyrrole (1.01 mL, 15.15 mmol). The reaction mixture was stirred 5 h at 50° C. and concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. 2-Isocyano-1-(2H-pyrrol-1(5H)-yl) ethanone SLA 07178 was obtained (1.0 g, 73% yield) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH:10]([CH3:29])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH:40][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[C@H:10]([CH3:29])[CH2:9][NH:8][CH2:13][C@@H:12]4[CH3:14])[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: C[C@@H]1CNC[C@H](C)N1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 439. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.57 (s, 1H), 8.36 (t, 2H), 7.94 (d, 1H), 7.74 (m, 2H), 6.99 (d, 2H), 6.75 (t, 1H), 3.77 (m, 5H), 3.64 (m, 5H), 3.07 (t, 2H), 1.69 (d, 6H).
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[C:37](Cl)(=[O:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C1(C)C=CC=CC=1.C(O)(C)C>O1CCCC1>[CH:20]1([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:37](=[O:49])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
10 g of the compound from Example 1 are suspended in 20 ml of tetrahydrofuran, 10 g of sodium carbonate are added and 10 g of dodecanoyl chloride in 10 ml of tetrahydrofuran are then added dropwise. When the reaction is complete (checked by thin layer chromatography on silica gel 60 6:1 toluene/isopropanol), the solid is filtered off, the filtrate is evaporated in vacuo to a syrup, and the crude product is purified by column chromatography on silica gel 60 using 10:1 toluene/isopropanol as the mobile phase.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+:6].Cl[CH:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10].[Na]>C(O)C>[S:1]([CH:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])([OH:4])(=[O:3])=[O:2].[Na:5][Na:6]
Reactant: [Na+]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: O=S([O-])[O-]
Agent: [Na]
Solvent: CCO
Product: O=C(O)C(CCc1ccc(-c2ccccc2Cl)cc1)S(=O)(=O)O
Product: [Na][Na]
Reaction time: 15 h

Procedure:
To a solution of 250 ml. of anhydrous ethanol and 0.12 moles of sodium sulfite is added 0.1 moles of α-chloro-γ-(2'-chloro-4-biphenylyl) butyric acid, sodium salt. The reaction mixture is stirred for 15 hours, filtered and the residue worked with ethanol. The filtrate is evaporated to dryness to obtain α-sulfo-γ-(2'-chloro-4-biphenylyl)butyric acid, disodium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[Cl-].[Li+].[CH2:14]([Li])[CH2:15]CC.BrC(Br)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:15][CH2:14]1
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: [Li]CCCC
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C12CC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
7-Fluorooxindole (1.28 g, 8.50 mmol) and lithium chloride (0.899 g, 21.3 mmol) were suspended in 80 mL of THF and cooled to 0° C. n-Butyllithium (8.5 mL, 16.9 mmol) was added slowly, and the mixture was stirred for 20 min, and then dibromoethane (0.73 mL, 8.5 mmol) was added. The mixture was warmed to 25° C. and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with ether. The organics were washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (10% acetone/hexane) afforded 0.54 g (36%) of 7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one as a white solid: HRMS: calcd for C10H8FNO, 177.0590; found (ESI, [M+H]+), 178.0659