Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: [H][H]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 10% Platinium on carbon (10 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][O:13][C:14]([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)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:39][CH2:40][CH2:41][CH2:42][CH2:43]Br>CN(C=O)C.CCOC(C)=O>[Br:39][CH2:40][CH2:41][CH2:42][CH2:43][N:12]([O:13][C:14]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10](=[O:11])[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(CSc1ccc(F)cc1)NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CSc1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-fluoro-phenylsulfanyl)-N-trityloxy-acetamide (132.1 mg, 0.228 mmol) from step C and Cs2CO3 (125.6 mg, 0.385 mmol) in anhydrous DMF (3 mL) was added 1,4-dibromo-butane (0.2 ml, 364.8 mg) in one portion and the resulting solution was warmed to 60° C. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was then used in next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.[CH3:18]OS(OC)(=O)=O>O.C(O)C>[OH:16][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH3:18])=[CH:15][C:14]=1[O:13]2
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Reactant: COS(=O)(=O)OC
Solvent: CCO
Solvent: O
Product: COc1ccc2c(=O)c3ccc(O)cc3oc2c1
Yield: 50 %

Procedure:
7.0 g (30.7 mmol) of 3,6-dihydroxyxanthone is dissolved in aq. NAOH (2.5 g(62.5 mmol) in 200 mls H2O). 3.2 mls (33.6 mmol) of dimethylsulfate is added dropwise with stirring, and solid forms immediately upon completion. Stirred further 1 hour and heated to reflux for 15 minutes. Additional base is added to insure complete solubility of phenols. The solution is acidified with HCl, and filtration yields a mixture of staring material and the target compound. Solid is heated to reflux in about 200 mls ethanol for 15 minutes to dissolve starting material, and solid is filtered out, washing with ethanol and water. This may have to be repeated several times to obtain pure compound in about 50% yield; mp=303-306-C.NMR (200 MHZ in d-DMSO) s 3.89 (3H,s), 6.82 (1H,d,J=2.24 Hz), 6.87 (1H,m), 6.99 (1H,dd,J=8.78 Hz, 2.20 Hz),, 7.09 (1H,d,J=2.26 Hz), 7.99 (1H,d,J=8.52 Hz), 8.03 (1H,d,J=8.78 Hz).
Reaction SMILES: [C:1]([C@H:5]1[CH2:9]OS(=O)(=O)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C.CO.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:2][C:1]([CH3:4])([CH3:3])[C@H:5]([OH:6])[CH2:9][N:16]1[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)O1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](O)Cn1ccc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To 999.9 mg (5.55 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide in 18 mL of N,N-dimethylformamide was added 755.0 mg (5.55 mmol) of 3-(trifluoromethyl)-1H-pyrazole. Then, 805.2 mg (5.83 mmol) of potassium carbonate was added, and the mixture was heated at 100° C. for 22 h. The resulting solution was cooled and 20 mL of acetyl chloride:methanol (1:9) were added. The reaction mixture was stirred for 2 h, and then saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 736.5 mg (56%) of (2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol and a small amount of the other regioisomer. Rf=0.23 (1:4 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 7.90 (s, 1H), 6.65 (d, J=2 Hz, 1H), 4.93 (br s, 1H), 4.30 (dd, J=14 Hz, J=2 Hz, 1H), 3.96 (dd, J=14 Hz, 10 Hz, 1H), 3.45 (d, J=10 Hz, 1H), 0.90 (s, 9H); ES-LCMS m/z 237 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:20]([F:23])([F:22])[F:21])([O-:3])=[O:2].F[P-](F)(F)(F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.CN(C)C=O>[CH3:35][NH:31][C:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:20]([F:23])([F:21])[F:22])[CH:6]=2)[CH2:12][CH2:13]1)=[O:18]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (500 mg, 1.50 mmol, prepared in accordance with Example 42), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (570 mg, 1.5 mmol), and diisopropylethylamine (600 μL, 3.30 mmol) were dissolved in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 10 min, and then cooled to 0° C. A solution of methylamine in tetrahydrofuran (750 μL, 2M, 1.50 mmol) and dimethylformamide (1 mL) was added, and the resulting mixture was stirred at room temperature for 3 hr. The mixture was then concentrated under vacuum. The resulting residue was taken up in dichloromethane (25 mL), and the organic phase was washed with water (10 mL), and then with aqueous saturated hydrogencarbonate (3×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was diluted in dioxane (5 mL), and a concentrated solution of HCl in dioxane was added (10 mL, 4N). A precipitate formed, which was then washed with diethylether (10 mL) and dried under vacuum. The desired product was isolated as a yellow solid (498 mg, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][C@H:12]3[CH3:26])=[N:10][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:18]([Cl:25])=[CH:19][C:20]([CH2:23][OH:24])=[CH:21][N:22]=5)[CH2:13][C@H:12]4[CH3:26])=[N:10][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(N)c2[nH]1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3ccc(Cl)cc3)c2[nH]1

Procedure:
{6-[(3R)-4-(7-Amino-5-trifluoromethyl-1H-benzoimidazol-2-yl)-3-methyl-piperazin-1-yl]-5-chloro-pyridin-3-yl}-methanol (221 mg, 0.5 mmol, Example 175b) and 4-chloro-benzoic acid (86 mg, 0.55 mmol, Aldrich) reacted under the conditions of Example 65 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 579 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:19]([S:21]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:23])=[O:22])[CH3:20]
Reactant: CC(C)(C)c1ccccc1O
Reactant: CCS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
8.00 g (53.3 mol) of 2-tert-butylphenol and 5.93 g (58.6 mol) of triethylamine were dissolved in 80 mL of toluene followed by dropping in 7.53 g (58.6 mol) of ethanesulfonyl chloride over the course of 10 minutes at 10° C. followed by stirring for 10 minutes at 25° C. and confirming the 2-tert-butylphenol to no longer be present by gas chromatography. The reaction liquid was placed in water and following separation of the organic layer, was washed three times with water, once with saturated aqueous NaHCO3 solution and once with saturated brine followed by drying with MgSO4, concentrating and purifying the resulting residue by vacuum distillation to obtain 11.93 g (yield: 92%) of 2-tert-butylphenyl ethanesulfonate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])C.C(O)C.Cl>O1CCCC1>[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:21]2[C:16](=[C:17]([O:26][CH3:27])[C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)CCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(NCCCC(=O)O)ncnc2c(OC)c1OC
Temperature: 25 °C
Yield: 74.7 %

Procedure:
5 ml of a 1N aqueous solution of sodium hydroxide is added to a solution of 0.52 g (1.5 mmol) of the 4-(3-ethoxycarbonylpropyl)amino-6,7,8-trimethoxyquinazoline obtained in Example 1 in tetrahydrofuran (5 ml)/ethanol (5 ml), followed by stirring at room temperature one whole day and night. The reaction liquid is neutralized with 5 ml of 1N hydrochloric acid, and then concentrated under reduced pressure. The crystals thus precipitated are recovered by filtration, washed with water, and dried with air. Thus, 0.36 g (yield 744%) of a pale-yellow crystal is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([NH:29][CH2:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=3[C:30]([F:31])([F:32])[F:33])=[O:19])[CH2:12]2)[N:3]=1
Reactant: COc1ccc(CN)c(C(F)(F)F)c1
Reactant: CNc1nc(C)nc(NC2CCCC(C(=O)O)C2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(C)nc(N[C@@H]2CCC[C@H](C(=O)NCc3ccc(OC)cc3C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.9 %

Procedure:
To a solution of 3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.377 mmol) in N,N-Dimethylformamide (DMF) (5 ml) was added ({[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl} amine (0.132 g, 0.415 mmol), followed by diisopropylethylamine (0.197 ml, 1.131 mmol) and 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.183 g, 0.415 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-3-{[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino}-N-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (31 mg, 0.06 mmol, 16%). MS (ES+): m/e 453 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:21](O)=[O:22])=[N:4][C:5]([N:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[S:13]2(=[O:20])=[O:19])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[CH3:25][NH:26][C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][NH3+:37])=[O:28].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:35][C:33]1[CH:32]=[CH:31][C:30]([CH2:36][NH:37][C:21]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[C:5]([N:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[S:13]3(=[O:19])=[O:20])[N:4]=2)=[O:22])=[C:29]([C:27]([NH:26][CH3:25])=[O:28])[CH:34]=1
Reactant: CN1CCCN(c2nc(C(=O)O)c(O)c3ncccc23)S1(=O)=O
Reactant: CNC(=O)c1cc(F)ccc1C[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc(N2CCCN(C)S2(=O)=O)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-Hydroxy-5-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxylic acid was coupled with {2-[(methylamino)carbonyl]4 fluorophenyl}methanaminium chloride (prepared as described in Example 3). A solution of 8-hydroxy-5-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)-1,6-naphthyridine-7-carboxylic acid (200 mg, 0.59 mmol) in dry DMF (2 mL) was stirred at zero degrees. To this was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (147 mg, 0.77 mmol), 1-hydroxy-7-azabenzotriazole (181 mg, 1.18 mmol). The mixture was stirred for 35 minutes at which time the {4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride (194 mg, 0.89 mmol) and diisopropylethylamine (124 μL, 0.7 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was filtered through a glass fiber filter. The filtrate was injected directly into the preparative HPLC (Gilson semi preparative HPLC system using a Waters Nova pak column (10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.025% TFA)/acetonitrile (0.025% TFA) at 35 mL/min). The desired fractions were freeze dried to give the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27].O>C(O)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:26][OH:27])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ncn2c1COC(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 96 h
Yield: 68.3 %

Procedure:
A mixture of 7-chloro-5,6-dihydro-6-oxo-4H-imidazo [1,5-a][4,1]benzoxazepine-3-carbonitrile (16.86 g, 0.06 mole), potassium carbonate (13.5 g, 0.9 mole) and hydroxylamine hydrochloride (4.6 g, 0.06 mole) in isopropanol (843 ml) containing water (13.5 ml) was stirred at room temperature for 4 days. The reaction mixture was then concentrated to a volume of 256 ml by distillation, cooled to room temperature and water (256 ml) added. The resulting mixture was cooled at 0° C. for 1 hour and the solid collected, washed with water and dried in vacuo at 50° C. to give the product (12 g, 63%), m.p. 252°-254° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[OH:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([C:42]5[CH:41]=[CH:40][CH:39]=[C:38]([OH:37])[CH:43]=5)[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(I)c4)C(=O)O3)ccc2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCOC
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(-c5cccc(O)c5)c4)C(=O)O3)ccc2O1
Yield: 45.9 %

Procedure:
A stirred mixture of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{[(3-iodophenyl)methyl]oxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (300 mg), 3-hydroxyphenylboronic acid (102 mg), tripotassium phosphate (417 mg) and dichlorobis(triphenylphosphine)palladium(II) (100 mg) in dimethoxymethane (10 ml) under nitrogen was heated under reflux for 4 h. The mixture was cooled to 20° and diluted with water (50 ml). The mixture was extracted with EtOAc (2×25 ml) and the combined extracts washed with water (50 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by Biotage. Elution with diethyl ether gave the title compound (130 mg). LCMS RT=3.74 min, ES+ve 593 (MNH4)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:16]=[C:11]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:12]=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(C2=Cc3ccccc3C2)cc(C(F)(F)F)c1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 6.8 g (20 mmole) of 1-iodo-3,5-bis(trifluoromethyl)-benzene and 0.134 g (0.6 mmole) and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under relux for 12 h. After it all triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of water and 50 ml of diethyl ether.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([C:37]2[CH:45]=[CH:44][C:43]([C:46]([O:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:51][CH:50]=3)=[O:47])=[CH:42][C:38]=2[C:39]([OH:41])=[O:40])=[O:36])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[N+:67]([C:70]1[CH:75]=[CH:74][C:73]([N:76]=[N:77][C:78]2[CH:94]=[CH:93][C:81]([C:82]([O:84][C:85]3[CH:90]=[CH:89][C:88]([CH2:91]O)=[CH:87][CH:86]=3)=[O:83])=[CH:80][CH:79]=2)=[CH:72][CH:71]=1)([O-:69])=[O:68].O>CN(C)C1C=CN=CC=1.ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([C:37]2[CH:45]=[CH:44][C:43]([C:46]([O:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63](=[O:66])[CH:64]=[CH2:65])=[CH:53][CH:54]=3)=[O:47])=[CH:42][C:38]=2[C:39]([O:41][CH2:91][C:88]2[CH:89]=[CH:90][C:85]([O:84][C:82](=[O:83])[C:81]3[CH:80]=[CH:79][C:78]([N:77]=[N:76][C:73]4[CH:74]=[CH:75][C:70]([N+:67]([O-:69])=[O:68])=[CH:71][CH:72]=4)=[CH:94][CH:93]=3)=[CH:86][CH:87]=2)=[O:40])=[O:36])=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Reactant: O=C(Oc1ccc(CO)cc1)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCc3ccc(OC(=O)c4ccc(N=Nc5ccc([N+](=O)[O-])cc5)cc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
0.2 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 0.6 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenyl)methanol and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction as mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases are combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from acetone of the fractions which are pure according to thin-layer chromatography gives 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenyl)methyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate.
Reaction SMILES: CN(C)C(N(C)C)=N.[N+:9]([CH3:12])([O-:11])=[O:10].[C:13]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C@H:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:22]([CH:32]=[O:33])[CH2:21]2)[CH:14]=1>O1CCCC1>[N+:9]([CH2:12][CH:32]([C@@H:22]1[CH2:21][C@@H:20]([O:19][C:15]2[CH:14]=[C:13]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:24][N:23]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:33])([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C=O
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cccc(-c3ccccc3)c2)C[C@H]1C(O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1,3,3-Tetramethylguanidine (52 μL) and nitromethane (222 μl) were added to a solution of crude (2S,4R)-4-(3-biphenyloxy)-N-tert-butoxycarbonyl-2-pyrrolidinecarboxaldehyde (B, 754 mg) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature for 3 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give crude the titled compound (877 mg), which was used in the subsequent step.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([C:7]3=[O:14])[CH2:5]1)[CH2:11]2.[CH3:15]I.[Cl-].[Na+]>CN(C)C=O>[CH3:15][O:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([C:7]3=[O:14])[CH2:5]1)[CH2:11]2
Reactant: CI
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
55% sodium hydride (40 mg, 0.917 mmol) in N,N-dimethylformamide (1 mL) was mixed with 5-hydroxy-2-adamantanone (100 mg, 0.602 mmol) and methyl iodide (750 μL, 12 mmol) at 0° C. and stirred at 50° C. for 8 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step.