Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]([C:9]([OH:11])=[O:10])=[CH:2]1>C(OC(=O)C)(=O)C>[S:1]1[CH:2]=[C:3]2[C:9]([O:11][C:6](=[O:8])[C:4]2=[CH:5]1)=[O:10]
Reactant: O=C(O)c1cscc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cscc21
Yield: 97.8 %

Procedure:
Thiophene-3,4-dicarboxylic acid (12 g, 0.07 mol) is dissolved in acetic anhydride (60 ml) and heated at the boil for 2.5 hours. The mixture is then evaporated to dryness. 10.55 g (98%) of thiophene-3,4-dicarboxylic anhydride (mp. 147° to 149° C.) are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([OH:26])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].I[CH2:30]CC.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:28])[N:14]([CH3:27])[N:15]=[C:16]([O:26][CH3:30])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(O)nn(C)c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OC)nn(C)c1=O
Yield: 69.7 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-hydroxy-5-benzyloxy-2-methyl-3(2H)-pyridazinone (500 mg, 2.35 mmol) in acetone (10 ml) was added iodopropane (443 mg, 2.59 mmol) and cesium carbonate (920 mg, 2.59 mmol), and stirred under reflux for 2.5 hours. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 643 mg of Compound (I-8-1) (yield: 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:11][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:8])[CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-Bromo-nicotinoyl chloride (0.5 g, 2.268 mmol) is suspended in THF (24 ml) at room temperature under an atmosphere of Argon. Fe(acac)3 (0.04 g, 0.113 mmol) is added and the reaction mixture is stirred for 10 minutes until a solution forms. The reaction mixture is cooled to −78° C. and a solution of MeMgBr (3M in diethyl ether, 0.907 ml, 2.722 mmol) is added dropwise with stirring for 2 hours at −78° C. On warming to room temperature silica is added to the reaction mixture and the solvents are reduced in vacuo. Purification by flash chromatography eluting with 50:50 EtOAc/iso-hexanes affords the title compound as a yellow solid [MH+199.90 and 201.90].
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:19]P(=O)(OCC)OCC.[H-].[Na+].O>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (126 mmol, 25.04 g) and diethyl 3-fluoro-4-nitrobenzylphosphonate (126 mmol, 36.6 g) in tetrahydrofuran (220 mL) were stirred and sodium hydride (163 mmol, 6.54 g, 60% in oil) was added. The reaction was stirred for 4 hours and then water was added. The reaction was extracted with dichloromethane and the organics were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane to give a bright yellow solid. This solid was filtered, washed with heptane and vacuum dried to afford the title compound (27.47 g). 1H NMR (CDCl3, 400 MHz): δ 8.1 (t, 1H), 7.1 (s, 1H), 7.05 (s, 1H), 6.35 (s, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2.52 (m, 2H), 2.4 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C(=O)(O)[O-].[Na+]>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: COc1cccc(C=O)c1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(OC)OC)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
m-Anisaldehyde (204.3 g, 1.5 mol) was placed in a 1 liter flask under an argon atmosphere. Trimethyl orthoformate (191 g, 1.8 mol) was added quickly, followed by 150 ml anhydrous methanol. Amberlyst XN-1010 resin (2.1 g, Aldrich Chemical Co.), which had been previously boiled with methanol was added. The mixture was stirred at room temperature for 22 hours with the exclusion of moisture. Sodium bicarbonate (1.5 g) was added with stirring. After 20 minutes the mixture was filtered under vacuum into a 2 liter flask which was placed on the rotory evaporator with the water bath temperature at 40° C. Over 30 minutes the bath was heated to 80° to produce a clear, colorless oil. With magnetic stirring, the oil was pumped at 65° under vacuum (2 mm Hg) for 30 minutes. The resulting product weighted 272.5 g (99.8%). I.R. (near, cm-1): 2935, 2824, 1598, 1584, 1350, 1258, 1100, 1050, 984, 772. 1HNMR (400 MHz, CDCl3): δ3.33 (6H, s, OCH3); 3.81 (3H, s, ArOCH3); 5.35 (1H, s, ArCH(OCH3)2 ; 6.87 (1H, br d, 8.1 Hz); 7.00-7.03 (2H, m); 7.27 (1H, t, 8.1 Hz). These data indicated that the product was pure enough for use in the next step and were consistent with the following structure: ##STR28##
Reaction SMILES: C([O:8][C@H:9](C)[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46]C[C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.[NH2:60][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH:43]=[C:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[N:60]=[CH:46]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cnc(NC(=O)Nc5cccnc5)c4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU) for (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4).
Reaction SMILES: C(O[CH:4](SCC)[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:42])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[NH2:41])C.C([O-])([O-])=O.[Ca+2].CCOC(C)=O>CC#N.O.Cl[Hg]Cl>[CH3:18][O:17][C:15]1[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]2[N:41]=[CH:4][C@@H:5]3[CH2:9][CH2:8][CH2:7][N:6]3[C:10](=[O:42])[C:11]=2[CH:16]=1
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1CCC[C@H]1CN3)N=C[C@@H]1CCCN1C2=O

Procedure:
A solution of the (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV (658 mg, 1 mmol), HgCl2 (794 mg, 2.93 mmol) and CaCO3 (300 mg, 3 mmol) in CH3CN/H2O (4:1, 15 mL) was stirred at room temperature for 12 h until TLC (EtOAc), indicates complete loss of starting material. Then organic layer is evaporated in vacuum and the residue is diluted with EtOAc. To this saturated NaHCO3 was added slowly at room temperature and the mixture is filtered through celite and washed with ethylacetate. The filterate is evaporated in vacuum to get crude 7-Methoxy-8-{3-[7-methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy]propoxy}-(11aS)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one of formula V, which was further purified by column chromatography on silica gel eluting with methanol:EtOAc (2:8).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:14]([OH:16])=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.S(Cl)([Cl:19])=[O:18].[CH3:21][OH:22]>>[ClH:19].[CH3:21][O:22][C:14](=[O:16])[C@H:3]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:18])[CH:12]=2)[NH:7][CH:6]=1)[NH:2][CH3:1]
Reactant: CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: CN[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)OC
Product: Cl
Temperature: 60 °C

Procedure:
The protected tryptophan derivative from above (0.573 g, 1.00 mmol) was dissolved in DMF (3 mL) and the solution cooled in ice. Sodium hydride (60% oil dispersion, 0.048 g, 1.2 mmol) was added and the mixture stirred for 30 min. Iodomethane (0.093 mL, 1.5 mmol) was added and stirring continued for an additional hour. The reaction was then quenched with 10% citric acid (2 mL) and water (25 mL), and extracted with Et2O (100 mL). The extract was dried (MgSO4) and concentrated, and the residue purified by flash chromatography (20-30% EtOAc/hexane as eluent) to give the desired N-methyltryptophan derivative (0.284 g). The N-methyltryptophan derivative from above (0.711 g, 1.21 mmol) was dissolved in MeOH (10 mL) and thionyl chloride (0.6 mL) was added dropwise. The mixture was heated to 60° C. for 3 h. Volatiles were removed under reduced pressure and the residue triturated with TBME (25 mL). The precipitated white solid was collected, washed with TBME and dried to give N-methyl-5-hydroxytryptophan methyl ester hydrochloride (0.339 g). MS (ES+) m/z 249 (MH+). The methyl ester hydrochloride from above (0.170 g, 0.6 mmol) was suspended in concentrated aqueous ammonia (15 mL) and the mixture was stirred overnight at room temperature. Volatiles were then removed under vacuum and the residue triturated with MeOH (34 mL) and Et2O (15 mL). The amide derivative was obtained as a brown solid (0.136 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:15]2[O:14][C:13]3[CH2:16][CH2:17][CH2:18][CH:19](O)[C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:3]=1[C:4]([NH:6][C:7]1[C:15]2[O:14][C:13]3[CH2:16][CH2:17][CH:18]=[CH:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1cccc2c3c(oc12)CCCC3O)c1c(Cl)cccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2c3c(oc12)CCC=C3)c1c(Cl)cccc1Cl
Yield: 36.3 %

Procedure:
A mixture of 6-(2,6-dichlorobenzoylamino)-1-hydroxy-1,2,3,4-tetrahydrodibenzofuran (500 mg), methanesulfonyl chloride (880 mg) and triethylamine (1.19 g) in dichloromethane was refluxed for 4 hours. The mixture was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of 2-propanol and water to give 6-(2,6-dichlorobenzoylamino)-3,4-dihydrodibenzofuran (173 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:35](O)=[O:36])=[N:25][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][CH:28]=1>C1COCC1>[Cl:22][C:23]1[C:24]([C:35]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[O:15])=[CH:10][CH:9]=3)[C:5]([CH3:21])=[CH:4][CH:3]=2)=[O:36])=[N:25][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:27][CH:28]=1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1nc(N2CCCCC2)ncc1Cl
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2nc(N3CCCCC3)ncc2Cl)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 5-chloro-2-(piperidin-1-yl)pyrimidine-4-carboxylic acid (91.3 mg, 0.38 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 48 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give 5-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(piperidin-1-yl)pyrimidine-4- carboxamide (35 mg). NMR; δH CDCl3 9.50,(1 H, s), 8.40,(1 H, s), 7.83,(2H, d), 7.64,(1H, dd), 7.56,(1H, d), 7.41,(2H, d), 7.27,(1H, d), 6.24,(1H, t), 3.79,(4H, m), 3.35,(2H, m), 2.22,(3H, s), 1.65,(4H, m), 1.08,(1H, m), 0.82,(2H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.96 min, MH+504.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].Cl[C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:35](=[O:36])[O:37][CH3:38])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.030 g (0.0607 mmol) of the product from Example 26 in CH2Cl2 (0.6 mL) at 0° C. was treated with methyl chloroformate (5 μL; 0.0607 mmol) followed by diisopropylethylamine (10 μL; 0.0607 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 30% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 551.9 (M+1), 553.9 (M+3); Rt=4.24 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[CH2:24](C1(C(OCC)=O)CCC(O)CC1)[CH:25]=C>>[CH2:21]([O:20][C:18]([C:15]1([CH2:23][CH:24]=[CH2:25])[CH2:16][CH2:17][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: C=CCC1(C(=O)OCC)CCC(O)CC1
Reactant: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Product: C=CCC1(C(=O)OCC)CCC(N2C(=O)c3ccccc3C2=O)CC1

Procedure:
The title compound was prepared by a method analogous to the method used to prepare Intermediate 72 using ethyl 1-allyl-4-hydroxycyclohexanecarboxylate (Intermediate 99) as the starting material.
Reaction SMILES: [CH2:1]([O:3][C:4](=C)[CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=[O:53])C>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:53])[CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][CH2:36][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[O:22][C:18]=2[CH3:17])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Oc4ccccc4)cc3)oc2C)cc1
Reactant: CN(C)C=O
Reactant: C=C(CCc1ccc(O)cc1C#N)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCCc2nc(-c3ccc(Oc4ccccc4)cc3)oc2C)cc1C#N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-ethoxy-but-3-enyl)-5-hydroxy-benzonitrile (220 mg, 1.00 mmol), toluene-4-sulfonic acid 2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethyl ester (450 mg, 1.00 mmol; Preparation 6), and CsCO3 (978 mg, 3.00 mmol) in DMF (10 mL) was stirred overnight at 60° C. under an N2. The mixture was cooled, diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried (Na2SO4) and concentrated. The product mixture was purified by radial chromatography (10-70% EtOAc/hexanes) to give 3-(2-cyano-4-{2-[5-methyl-2-(4-phenoxyphenyl)oxazol-4-yl]ethoxy}phenyl)propionic acid ethyl ester (201 mg). A solution of this ester in EtOH (10 mL) and 5N NaOH (10 mL) was heated at 70° C. overnight, concentrated, acidified with 1N HCl, and extracted with EtOAc. The organic layer dried (Na2SO4) and concentrated to give the title compound (192 mg); MS [ES] m/z 469 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Cl:22][C:23]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:52]C([N-]C(C)C)C>>[Cl:22][C:23]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:52])=[CH:14][CH:13]=2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1ccc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc(Cl)c(/C=C/c2cc3cc(OC)ccc3[nH]2)c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-chloro-5-methoxybenzyl)(triphenyl)phosphonium bromide (578) prepared as described in example 166 using the procedure described in example 37, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA:aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (579) as a pale yellow solid (the pure E isomer) (85%), mp 119–121° C. 1H NMR (CDCl3) δ 8.22 (br s, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.26 (br d, J=8.7 Hz, 1H), 7.22 (d, J=16.5 Hz, 1H), 7.18 (d, J=3.0 Hz, 1H), 7.06 (d, J=16.7 Hz, 1H), 7.04 (br s, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.77 (dd, J=8.8, 3.0 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H). Found: C, 68.70; H, 5.11; N, 4.37. C18H16ClNO2 requires C, 68.90; H, 5.14; N, 4.46.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57](B(O)O)[CH:56]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:3](=[O:28])[C:2]=1[C:57]1[CH:56]=[N:55][C:64]2[C:59]([CH:58]=1)=[CH:60][CH:61]=[CH:62][CH:63]=2
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cnc3ccccc3c2)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Yield: 85 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (85%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:31])=[CH:11][CH:10]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1ccc(N(CC(=O)OC(C)(C)C)C(=O)CN)cc1
Product: COc1ccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)cc1
Yield: 17.7 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(4-methoxyphenyl)acetamido]acetate (6.6 g) and 3-methylphenyl isocyanate (3 g), and after recrystallisation in acetonitrile, tert-butyl 2-{N-(4-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-acetate (1.7 g), m.p. 158° C., is obtained.