Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH:4]=[N:5][C:6]([O:8][Si](C)(C)C)=[CH2:7])=[CH2:3].C(OC([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)/[C:22](=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)/[C:21]1=[O:38])=O)(C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]([CH:4]1[C:22]2([C:23]3[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:20][C:21]2=[O:38])[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[CH2:8][C:6](=[O:7])[NH:5]1)=[CH2:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(Br)C=NC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C=C(Br)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 7 %

Procedure:
To a toluene solution of 1-(1-bromo-vinyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene in toluene (1 M, 37 mL, 37 mmol) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (2.8 g, 7.2 mmol). The reaction mixture was refluxed overnight under argon protection and purified by Prep-HPLC to give product as a white solid (120 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([C:12]([O:14]C)=O)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[CH3:16][NH:17]C>CO>[CH3:16][NH:17][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[N:6]([C:2]([NH2:1])=[N:3][N:4]=2)[N:7]=1)=[O:14]
Reactant: COC(=O)c1cc(C)c2nnc(N)n2n1
Reactant: CNC
Solvent: CO
Product: CNC(=O)c1cc(C)c2nnc(N)n2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-amino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate (W1.146; 210 mg) was dissolved in methanol (4 ml), cooled to 0° C., slowly admixed dropwise with dimethylamine (2.02 ml; 2 M in THF) and stirred at 0° C. After 3 h, a further 5 equivalents of dimethylamine solution were added and the mixture was stirred at 40° C. for 4 h. After standing overnight, another 5 equivalents of dimethylamine solution were added and the mixture was stirred at 40° C. for a further 8 h. After standing overnight again, a further 5 equivalents of dimethylamine solution were added and then the mixture was stirred at 100° C. in a microwave for 30 min. Subsequently, the mixture was concentrated and purified using silica gel (24 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 92 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1>>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:23])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CON=C(C#N)C1=CCCNC1
Product: CON=C(C#N)C1=CCCN(C(=O)Oc2ccc(OC)cc2)C1
Yield: 85.6 %

Procedure:
α-(Methoxyimino)-α-(1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D8) (0.5 g, 0.003 moles) was treated with 4-methoxyphenylchloroformate (0.5 ml, 0.0033 moles) as in the method of Example 1. The crude produce was triturated with pentane to give the title compound (E4) as a white crystalline solid (0.81 g, 85%) m.p. 75°-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH3:2]
Reactant: CCOC(=O)CCCCCCC1=C(OCC)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC1=C(CCCCCCC(=O)O)C(=O)CC1
Reaction time: 48 h

Procedure:
A mixture containing 22.16 parts of ethyl 2-ethoxy-5-oxocyclopent 1-eneheptanoate, 785 parts of 0.1N aqueous sodium hydroxide and 320 parts of ethanol is stored at room temperature for about 48 hours, then is concentrated to approximately 2/3 volume by distillation under reduced pressure. The residual solution is washed with ether, acidified with dilute hydrochloric acid, then extracted with ethyl acetate. The ethyl acetate extracts are washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness by distillation under reduced pressure. The residual solid residue is purified by recrystallization from ether-benzene to afford 2-ethoxy-5-oxocyclopent-1-eneheptanoic acid, melting at about 65°-66°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([Cl:20])[CH:22]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: NCc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
Following general procedure A: to a solution of [(R)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.25 g, 0.94 mmol) in CH2Cl2 (20 ml) was added 3-chloro-benzylamine (0.14 ml, 1.13 mmol) and the mixture was stirred for 5 min. NaBH(OAc)3 (0.30 g, 1.41 mmol) and acetic acid (10 drops) were added and the mixture was stirred at rt under N2 overnight. The crude product was purified by flash chromatography (CH2Cl2, 5% MeOH, 1% NH4OH) to afford {(R)-3-[4-(3-chloro-benzylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester as a yellow oil (305 mg, 82%). 1H NMR (CDCl3) δ 0.92-0.94 (d, 3H, J=6 Hz), 1.27-1.39 (m, 2H), 1.44 (s, 9H), 1.60-1.72 (m, 2H), 1.82-1.97 (m, 2H), 2.02-2.14 (m, 1H), 2.32-2.51 (m, 2H), 2.68-2.87 (m, 3H), 3.05-3.11 (m, 1H), 3.23-3.37 (m, 1H), 3.79 (s, 2H), 4.40 (s, 1H), 6.01 (br s, 1H), 7.16-7.25 (m, 3H), 7.33 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][CH:8]([NH2:14])[C:7]1=[O:15])[CH3:2].C(Cl)Cl.[C:20]1([C:30](O)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][CH:8]([NH:14][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:31])[C:7]1=[O:15])[CH3:2]
Reactant: CCOC(=O)CN1CC(C)=CCC(N)C1=O
Reactant: O=C(O)c1nccc2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(C)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
The crude (3-amino-6-methyl-2-oxo-2,3,4,7-tetrahydroazepin-1-yl}-acetic acid ethyl ester, 10, obtained in the previous step is dissolved in 6 mL of 1:1 DMF:CH2Cl2 and treated with 1-isoquinolinecarboxylic acid (0.24 g, 1.2 mmol), 1-hydroxybenzotriazole (0.23 g, 1.5 mmol), and 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (0.32 g, 1.5 mmol). The solution is stirred for 1 hour at room temperature, diluted with EtOAc, washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the crude isolate is purified by HPLC to afford 70 mg (30% yield) of the desired product. 1H NMR (CDCl3) δ 9.51–9.48 (d, J=8.1 Hz, 1H), 9.22–9.20 (d, J=6.9 Hz, 1H), 8.51–8.49 (d, J=5.4 Hz, 1H), 7.84–7.77 (m, 2H), 7.72–7.63 (m, 2H), 5.57 (bs, 1H), 5.48–5.40 (m, 1H), 4.775–4.715 (d, J=18 Hz, 1H), 4.24–4.19 (q, d, J=15.3, 7.5 Hz, 3H), 3.27–3.21 (d, J=18 Hz, 1H), 2.86–2.81 (d, J=16.5 Hz, 1H), 2.45–2.36 (d, d, J=15, 12.6 Hz, 1H), 1.79 (s, 3H), 1.30–1.25 (t, J=7.5 Hz, 3H); 13C (CDCl3) 172.8, 169.2, 165.6, 148.2, 140.8, 137.5, 131.8, 130.5, 128.7, 127.7, 127.0, 124.5, 123.4, 61.6, 52.3, 50.8, 49.6, 32.6, 25.0, 14.3; MS 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].[H][H]>CN(C=O)C.CCOCC.CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1O
Reactant: [H][H]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ncc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
Intermediate (23t) (1.78 g, 13.0 mmol), 2-chloro-4-methyl-5-nitropyridine (2.31 g, 13.0 mmol) and potassium carbonate (1.80 g, 13.0 mmol) were dissolved in DMF (120 mL). When the mixture was warmed to 60° C., the colorless solution turned blue in 10 minutes. After 16 hours of stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and then diluted with 100 mL of Et2O. The inorganic precipitate was removed by filtration and washed with Et2O. The combined organic solution (600 mL total) was transferred to a separatory funnel and washed with 60 mL of water three times and with brine one time. The solution was dried over MgSO4 and then concentrated under reduced pressure to obtain crude brown solid. The crude solid was dissolved in MeOH (240 mL). To the solution was added 10% palladium on activated carbon under nitrogen atmosphere. Replacing nitrogen gas with hydrogen gas, the reaction mixture was stirred at room temperature (if the reaction did not proceed in 30 minutes, filtrated the Pd/C was filtered off and the reaction was set up again. After 1.5 hours of stirring, palladium on carbon was filtered off and washed with MeOH. The solution was concentrated under reduced pressure to obtain a pale yellow solid. The crude compound was purified on silica gel with EtOAc/hexane (1/1-3/2) to afford (1u) as a white solid (2.21 g, 70% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.33 (ddd, J=7.8, 3.1, 1.6 Hz, 1H), 7.29-7.22 (m, 1H), 7.23 (s, OH), 7.15 (ddd, J=9.3, 4.7, 1.6 Hz, 1H), 6.82 (s, 1H), 2.22 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:33])[CH2:9][NH:10][C:11]([CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]([NH:18][CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)N)(C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:33])[CH2:9][NH:10][C:11]([CH2:13][NH:14][CH2:15][C:16]([NH:18][CH:19]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)CN(CC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(N)=O
Product: CC(C)C(NC(=O)CNCC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)O

Procedure:
2-[2-({[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-amino)-acetylamino]-3-methyl-butyric acid was prepared using method 804 substituting 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-tert-butoxycarbonyl-amino)-acetylamino]-3-methyl-butyric acid for 1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester. C17H22BrN3O5 calculated 427.1 observed [M+1]+ 428.0; rt=2.39 min.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:6])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1]1(=[O:2])=[O:3]
Reactant: ClCCCCCl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCCl
Yield: 12.9 %

Procedure:
Sodium saccharin (5.6 g, 0.027 mole) and 1,4-dichlorobutane (14.9 ml, 0.135 mole) were taken into 100 ml of dimethylformamide and heated on a steam bath for 4 hours. The reaction mixture was evaporated in vacuo to an oil and the oil extracted with 100 ml of hexane. Residual hexane was removed from the remaining oil by vacuum evaporation to yield the title product (956 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O.O>[Si:13]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
8-Hydroxyquinaldine (10 g), t-butyldimethylsilyl chloride (10 g) and imidazole (8.6 g) were dissolved in N,N-dimethylformamide (150 ml) and stirred at ambient temperature overnight. Further t-butyldimethylsilyl chloride (4.7 g) was added and the reaction stirred for another 30 minutes. The reaction was diluted with water (600 ml) and extracted with dichloromethane (3×300 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo to afford the title compound as an orange oil (17 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]#[N:19].[OH-:20].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:6]=2[C:18]([NH2:19])=[O:20]
Reactant: N#Cc1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c2ccc(Br)cc2nn1-c1ccc(F)cc1
Temperature: 70 °C
Yield: 93.5 %

Procedure:
To a stirred suspension of compound (xiv) (50 mg, 0.16 mmol) in ethanol:water (1:1, 6 mL) was added sodium hydroxide (63 mg, 0.16 mmol) and the reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to RT and the volatiles were removed under reduced pressure. The residue was acidified to pH 2 upon addition of 2N hydrochloric acid. The resulting precipitate was filtered, washed with water (2×20 mL) and dried (Na2SO4) to give 6-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxamide (xv) (50 mg, 94%) as white solid. ESI-MS m/z calculated for [M+H]+: 334.00; found: 334.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1cccc(F)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 13 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3-fluorophenyl isocyanate. The compound of example 13 was used directly without isolation for the preparation of compound of example 14.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]OC(=O)C(N)CCC.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2)c1
Reactant: CCCC(N)C(=O)OC
Agent: CN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Oc2ccccc2)c1
Yield: 131.8 %

Procedure:
A mixture of (3-Phenoxy-phenyl)-acetic acid (10.00 g, 0.0438 mol), 2-amino-pentanoic acid methyl ester (7.34 g, 0.0438 mol.), HBOT (6.20 g, 0.046 mol), EDC. HCl (12.59 g, 0.067 mol) and a trimethylamine (30.45 ml, 0.22 mol) in methylene chloride (150 ml) was stirred at room temperature overnight. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with 1N HCl, then brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide 13.99 g of (3-phenoxy-phenyl)-acetic acid methyl ester as a thick oil, LC-MS M+1=342.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[CH:20][CH:19]=1)[C:12]3=[CH:32][CH:33]=2)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:12]3=[CH:32][CH:33]=2
Reactant: c1ccc(COc2ccc(-c3cc4ccc(OCc5ccccc5)c5ccc3n45)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-c2cc3ccc(O)c4ccc2n34)cc1
Yield: 98.5 %

Procedure:
A solution of 5-benzyloxy-2-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine (48 mg, 0.11 mmol) in 2 ml of tetrahydrofuran and 3 ml of ethanol was hydrogenated in the presence of 10% palladium on carbon (30 mg). When the theoretical amount of hydrogen had been consumed the catalyst was filtered off and the filtrate was evaporated to afford 27 mg (99%) of the title compound. M.p. 165° C. (dec.). 1H-NMR (DMSO-d6, 200 MHz) δ: 6.92 (d, 2H), 7.15 (d, 1H), 7.36 (d, 1H), 7.43 (s, 1H), 7.73 (d, 1H), 7.88 (d, 2H). (Compound 53).
Reaction SMILES: [OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C=CC([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=CC=2C(=O)CC1>>[OH:1][C:2]1([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[CH:6][C:5]([C:44]#[C:45][C:46]3[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate (Compound 113), 1.00 g (2.88 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (light yellow solid) using 1.00 g (15.30 mmol) of zinc, 0,639 ml (5.76 mmol) of ethyl bromoacetate and 70 ml of dry benzene.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH2:14]1>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=3)=[CH:25][CH:24]=2)[CH2:14]1
Reactant: O=c1oc2ccccc2c(O)c1C1CC(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)Cc2ccccc21
Solvent: CCO
Product: O=c1oc2ccccc2c(O)c1[C@@H]1C[C@@H](c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)Cc2ccccc21
Reaction time: 72 h

Procedure:
An approximately 1:1 mixture of the cis and trans isomers of 1-(4-hydroxycoumarin-3-yl)-3-[4-(4-trifluoromethylbenzyloxy)phenyl]-1,2,3,4-tetrahydronaphthalene in the form of a viscous oil (13.Og) was dissolved in ethanol (250 cm3) at the ambient temperature and the solution kept in an open flask at the ambient temperature for 3 days during which time some of the ethanol evaporated and some precipitation of a solid material occurred. This was collected by filtration and dried to give trans-(4-hydroxycoumarin-3-yl)-3-[4-(4-trifluoromethylbenzyloxy)phenyl]-1,2,3,4-tetrahydronaphthalene (containing 7% by weight of the cis-isomer, 1.5g), melting point 153° -155° C. The filtrate was concentrated by removal of the ethanol by evaporation under reduced pressure. The residual oil was then dissolved in boiling ethanol (100cm3) and the solution allowed to cool to 35° to 40° C. and maintained at this temperature whilst a precipitate formed rapidly. This was collected by filtration and dried to give cis-1 -(4-hydroxycoumarin-3-yl) -3-[4-(4-trifluoromethylbenzyloxy)phenyl]1,2,3,4 -tetra-hydronaphthalene (containing 5% by weight of the trans-isomer, 5.5g) melting point 183° -184° C.
Reaction SMILES: CO.[N+]([O-])([O-])=O.[Ag+:7].[C:8]1([C:19]#[C:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1>O>[C:8]1([C:19]#[C:20][C:21]([O-:23])=[O:22])[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([O-:18])=[O:17])=[CH:12][CH:13]=1.[Ag+2:7]
Reactant: [Ag+]
Reactant: O=C(O)C#Cc1ccc(C#CC(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C([O-])C#Cc1ccc(C#CC(=O)[O-])cc1
Product: [Ag+2]

Procedure:
5.5 g of phenyl-1,4-dipropiolic acid was dissolved in 100 ml of a solvent composed of 50% by volume of methanol and 50% by volume of water. On the other hand, a solution was prepared by dissolving 8.0 g of silver nitrate in 100 ml of water, and it was mixed with the solution of 1,4-phenylene bispropiolic acid with stirring. After the pH was adjusted to 6.0, the formed yellowish white precipitates were filtered off to obtain silver 1,4-phenylene-bispropiolate (40).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9]4=[C:10]([NH:17][C:18](=[O:19])[N:8]24)[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C>[Br:20][C:13]1[CH:12]=[CH:11][C:10]2[NH:17][C:18](=[O:19])[N:8]3[C:9]=2[C:14]=1[CH2:15][CH2:16][CH:7]3[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A suspension of 4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.200 g, 0.799 mmol) in acetonitrile (10.0 mL) and acetic acid (2.42 mL) was heated to dissolve residual solids and the resultant solution was cooled to 0° C. The resulting solution was treated with a solution of N-bromosuccinimide (0.144 g, 0.807 mmol) in acetonitrile (3.0 mL), added dropwise, at 0° C. and subsequently stirred at 0° C. for 1 h. The reaction mixture was concentrated to a residue which was dissolved in chloroform (50 mL) and washed with saturated aqueous sodium bicarbonate (40 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol) gave the desired product (0.177 g, 67%) as a racemic mixture along with an additional other brominated isomer, 8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (which was not be separated) in a 4.4:1 ratio. LCMS calculated for C16H14BrN2O (M+H)+: m/z=329.0, 331.0. found: 329.0, 331.0.