Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26][OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C[C:37](CC(O)=O)(C(O)=O)[OH:38]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[NH:28][C:37](=[O:38])[O:27][N:26]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3noc(=O)[nH]3)ccc2c1=O
Yield: 93 %

Procedure:
Tert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl}methylcarbamate (0.25 g, 0.54 mmol) was dissolved in ethyl acetate (10 ml) and N,N′-carbonyldiimidazole (0.26 g, 1.6 mmol) was added. The mixture was refluxed under heating for 3 h. To the reaction mixture were added 0.1 M aqueous citric acid solution (25 ml) and ethyl acetate (50 ml). The organic layer was washed with 0.1 M aqueous citric acid solution (25 ml), and then saturated brine (25 ml), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-ethyl acetate=2:1 (v/v) to give tert-butyl[2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.24 g, 93%) as a colorless powder.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[CH3:14][C:15]([CH3:17])=O>>[CH3:13][O:12][C:1]([C:2]1[CH:3]=[C:4]([OH:5])[C:6]2[O:7][C:15]([CH3:17])([CH3:14])[O:9][C:8]=2[CH:10]=1)=[O:11]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: CC(C)=O
Product: COC(=O)c1cc(O)c2c(c1)OC(C)(C)O2

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester is prepared from methyl gallate and acetone according to Percec, Virgil; Bera, Tushar K.; Tetrahedron; 58; 20; 2002; 4031-4040.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([C:14](=[O:15])[N:13](OCC3C=CC=CC=3)[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:14](=[O:15])[NH:13][CH2:12]2)[CH2:24][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(OCc2ccccc2)CC12CCN(Cc1ccccc1)CC2
Agent: [Ni]
Solvent: CO
Product: O=C1NCC12CCN(Cc1ccccc1)CC2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A 2-L pressure bottle, equipped with a thermocouple and H2 inlet/outlet, was charged with Raney®-nickel (7.0 g). The Raney®-nickel was washed with methanol (3×, slurry and decant supernatant) and a solution of 7-benzyl-2-benzyloxy-2,7-diaza-spiro[3.5]nonan-1-one from Example 7C (28.3 g, 0.084 mol) in methanol (280 mL) was added. The reaction was placed on a Parr shaker and agitated overnight at 50° C. under an atmosphere of H2 (40 psi). The catalyst was removed by filtration and rinsed with methanol. The solution of product with benzyl alcohol was concentrated in vacuo. The benzyl alcohol was removed by azeotropic distillation, twice adding water (250 mL) and concentrating in vacuo. 2-Propanol was used to chase the water, twice adding 2-propanol (250 mL) and concentrating in vacuo to an oil. Heptane (500 mL) was added and the product was allowed to crystallize. After concentrating in vacuo to a final volume of 100 mL, the product was collected by filtration and washed with heptane (25 mL). Drying in a vacuum oven at 40° C. under a flow of N2 afforded the titled compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.75-1.84 (m, 2H) 1.98-2.08 (m, 2 H) 2.19-2.31 (m, 2 H) 2.71-2.83 (m, 2 H) 3.13 (s, 2 H) 3.50 (s, 2 H) 5.69 (s, 1 H) 7.21-7.38 (m, 5 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][C:10](=[O:16])[C:9]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C)C=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][C:10](=[O:16])[C:9]=2[O:17][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: O=c1cc(CO)oc(CN2CCOCC2)c1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(CN3CCOCC3)oc(CO)cc2=O)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a suspension of 5.45 g of 6-morpholinomethyl-5-hydroxy-2-hydroxymethyl-4-pyrone in 50 ml of dimethylformamide were successively added 3.32 g of potassium carbonate and 4 ml of p-methoxybenzyl chloride. The mixture was stirred at 70° C. for 4 hours and at room temperature for a further 17 hours. The reaction liquid was concentrated and 100 ml of water and 200 ml of dichloromethane were added to the concentrate. The organic phase was then washed with 100 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure. The concentrate was then separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (200 g) to give 1.8 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.[O:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:31]1[CH2:32][CH:33]=[C:34]([C:2]2[CH:3]=[C:4]3[N:10]([C:11]4[C:20]5[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=5)[N:14]=[C:13]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)[C:12]=4[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]3=[N:6][CH:7]=2)[CH2:35][CH2:36]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C3=CCOCC3)cc21
Temperature: 100 °C

Procedure:
A mixture of 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (150 mg, 0.324 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (102 mg, 0.486 mmol), potassium phosphate tribasic (206 mg, 0.971 mmol), Pd(OAc)2 (72.7 mg, 0.324 mmol) and SPhos (26.6 mg, 0.065 mmol) in toluene (2.5 mL) was heated in the microwave for 1 h at 100° C. After this time the reaction was partitioned between EtOAc (60 mL) and water (30 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 0:1 as eluent) gave 4-(6-(3,6-dihydro-2H-pyran-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline. 1H NMR (500 MHz, chloroform-d) δ ppm 8.71-8.77 (1H, m), 7.97 (1H, d, J=2.0 Hz), 7.83-7.94 (3H, m), 7.79 (1H, dd, J=9.3, 5.9 Hz), 7.41 (1H, ddd, J=7.3, 4.9, 1.5 Hz), 7.30 (1H, ddd, J=9.2, 8.1, 2.6 Hz), 6.20 (1H, d, J=1.7 Hz), 5.90-5.95 (1H, m), 4.18-4.27 (2H, m), 3.78-3.90 (4H, m), 2.29-2.44 (5H, m), 1.61 (3H, s), 1.55 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: Cl.NCC1C=C(CNC(C2NC(=O)C3C(=CC=C(C#N)C=3)N=2)=O)C=CC=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]([CH2:36][NH:37][C:38]([C:40]2[NH:41][C:42](=[O:50])[C:43]3[C:48]([CH3:49])=[CH:47][S:46][C:44]=3[N:45]=2)=[O:39])[CH:33]=[CH:34][CH:35]=1.N1C=NC(CC(O)=O)=N1.[C:60]1([C:66]([C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[N:67]2[CH:71]=[N:70][C:69]([C:72](O)=[O:73])=[N:68]2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:49][C:48]1[C:43]2[C:42](=[O:50])[NH:41][C:40]([C:38]([NH:37][CH2:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][NH:28][C:72]([C:69]4[N:70]=[CH:71][N:67]([C:66]([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)([C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=5)[C:81]5[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=5)[N:68]=4)=[O:73])[CH:31]=3)=[O:39])=[N:45][C:44]=2[S:46][CH:47]=1
Reactant: Cc1csc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c12
Reactant: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c2c1
Agent: O=C(O)Cc1nc[nH]n1
Product: Cc1csc2nc(C(=O)NCc3cccc(CNC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 34, and using, instead of N-{[3-(aminomethyl)phenyl]methyl}-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide hydrochloride, N-{[3-(aminomethyl)phenyl]methyl}-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide hydrochloride obtained in Reference Example 50 and using, instead of 1H-1,2,4-triazol-3-ylacetic acid, 1-(triphenylmethyl)-1H-1,2,4-triazole-3-carboxylic acid obtained in Reference Example 35, 5-methyl-4-oxo-N-({3-[({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)methyl]phenyl}methyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide was obtained as a white powder (597 mg, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>N1C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OC(=O)c2cccnc2)cc1
Yield: 82.4 %

Procedure:
A solution of 2'-hydroxy-4,4',6'-trimethoxychalcone (1 g) and hydrochloride of nicotinoyl chloride (0.6 g) in 20 ml of pyridine was stirred at room temperature for 4 hours. After removal of the solvent followed by addition of saturated aqueous sodium bicarbonate (50 ml) to the residue, the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over Na2SO4 and evaporated under reduced pressure to give an oily residue. Crystallization from methanol/hexane gave 1.1 g (83% yield) of 2',4,4'-trimethoxy-6'-(nicotinoyloxy)chalcone as pale yellow needles; m.p. 55°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH:7]=1.O.NN.ClCCl>CO.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:21])=[C:6]([CH2:8][NH:9][CH2:10][C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH:7]=1
Reactant: COc1cccc(OC)c1CNCc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cccc(OC)c1CNCc1cc(Cl)ccc1N
Temperature: 64 °C

Procedure:
1-(5-Chloro-2-nitrophenyl)-N-(2,6-dimethoxybenzyl)methanamine (19.2 g, 57.0 mmol) was dissolved in 400 mL methanol in the heat. Activated carbon (20.0 g) and catalytic amounts of sublimed iron trichloride (0.24 g, 1.48 mmol) were added at room temperature. Finally, hydrazine hydrate (11.10 mL, 228.0 mmol) was added slowly by drops at 64° C. In doing so, it foamed up somewhat. After heating for 2 hours at 64° C., the reaction was concluded. After cooling the reaction mixture to room temperature, the batch was filtered through Hyflo Super Cel and the solid constituents were separated out. The solvent was removed in vacuo. The colorless oil was again dissolved in dichloromethane and extracted with water (3×) and with 2N hydrochloric acid (3×). The hydrochloric two-phase mixture was adjusted to a pH of 11 with 2N sodium hydroxide solution, at which point a bulky colorless precipitate was formed. When dichloromethane was added, the solids dissolved again in the organic phase which was dried over sodium sulfate after separating the aqueous phase, then filtered and freed of the solvent in vacuo. By storing into petroleum ether, a colorless precipitate was obtained from the oily yellow crude product, then filtered with suction and dried. By fractional crystallization of the mother liquor, the yield was further increased. Yield: 11.5 g (37.5 mmol, 66%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28](=[O:41])[CH2:29][C:30]1[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][NH:33][CH:34]=1)[CH3:26].O>CN(C)C=O>[CH3:18][C:17]1[O:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:33]2[CH:34]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:41])[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32]2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (513 mg, yield: 58%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.C(O)C(C)C>[CH2:2]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:1]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccc1
Reaction time: 96 h

Procedure:
N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 MI, CHCl3 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].C(N(CC)CC)C>O1CCCC1.[Cu](I)I>[CH:15]1([C:13]#[C:14][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C#CC1CC1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with bis(triphenylphosphine)palladium bischloride (151 mg, 0.216 mmol) and copper iodide (82 mg, 0.431 mmol), and the flask was degassed with nitrogen. Tetrahydrofuran (40 mL) was added through a septum, and nitrogen was bubbled through the mixture for 30 minutes. To this was added dropwise a nitrogen-degassed solution of 4-nitrobenzoyl chloride (2g, 10 8 mmol), ethynylcyclopropane (784 mg, 11.9 mmol) and triethylamine (1.31 g, 12.9 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C>N(CCO)(CCO)CCO.C(#N)C>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:16]([OH:18])[CH3:17]
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: OCCN(CCO)CCO
Solvent: CC#N
Solvent: CC(C)O
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Yield: 105 %

Procedure:
A 250 ml 3-neck flask with overhead stirrer was charged with methyl 2-benzamidomethyl-3-ketobutyrate (25 g), isopropylalcohol (37.5 ml) and 0.1 M triethanolamine(chloride)/0.04 M MgSO4 buffer pH7.2 (30 ml). The reaction mixture is stirred and temperature brought up to 37° C. using an oil bath. The reaction is started with the addition of 0.5 ml 19 g/L NADP-Na followed by 2.5 ml 30 g/L KRED of SEQ ID No. 10; both as solutions in 0.1 M triethanolamine (chloride)/0.04 M MgSO4 buffer pH 7.2. The reaction progress was followed by taking 5 μl aliquots over the course of the reaction that were diluted with 1 ml acetonitrile, filtered through a 0.25 μm syringe filter and analyzed as described in Example 3. When the conversion exceeded 96% saturated aqueous sodium chloride (12.5 ml) was added to the reaction mixture, followed by 40 ml ethyl acetate. The reaction mixture was stirred for another 15 minutes, then filtered through a Celite pad (5 g in a fritted glass filter) under vacuum. The filter cake was washed with 20 ml ethyl acetate and the two phases of the filtrate allowed to separated. The organic layer is washed three times with 20 ml water and concentrated on a rotary evaporator to an oil of constant weight. After removal of ethyl acetate, toluene (10 ml) was added and distilled under vacuum. (2S,3R)-methyl-2-benzamidomethyl-3-hydroxybutyrate (26.47 g) was obtained as an oil containing ˜10% toluene as determined by 1H-NMR-CDCl3.
Reaction SMILES: CN(C=[O:5])C.[Br:6][C:7]1[C:8]([Cl:30])=[CH:9][C:10]([O:26][CH2:27][O:28][CH3:29])=[C:11]([CH:25]=1)[CH:12]([C:15]1[C:20]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)C#N.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:8]([Cl:30])=[CH:9][C:10]([O:26][CH2:27][O:28][CH3:29])=[C:11]([CH:25]=1)[C:12]([C:15]1[C:20]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: COCOc1cc(Cl)c(Br)cc1C(C#N)c1ncccc1OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1cc(Cl)c(Br)cc1C(=O)c1ncccc1OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF (100 ml) was added to a mixture of 2-(5-bromo-4-chloro-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (10.1 g) and potassium carbonate (9.84 g). The mixture was stirred at room temperature overnight under oxygen atmosphere. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate), and concentrated. The concentrate was purified by a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-bromo-4-chloro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine (9.08 g, m.p. 70°-72° C.). The spectrum data are shown as follows:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:35]=[CH:34][C:10]([C:11]([NH:13][NH:14][C:15]([C:17]2[O:18][CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[O:12])=[CH:9][C:8]=1[S:36](=[O:40])(=[O:39])[NH:37][CH3:38].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.ClCCl>[OH:6][C:7]1[CH:35]=[CH:34][C:10]([C:11]([NH:13][NH:14][C:15]([C:17]2[O:18][CH:19]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])=[O:12])=[CH:9][C:8]=1[S:36](=[O:40])(=[O:39])[NH:37][CH3:38]
Reactant: CNS(=O)(=O)c1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1OC
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Boron tribromide (1 M dichloromethane solution; 2.37 ml) was added to a dichloromethane (10 ml) solution of the compound of Example 73 (0.40 g) at 0° C., and stirred at 25° C. for 3 hours. The reaction solution was mixed with 2 M aqueous sodium hydroxide solution, stirred for 0.3 hours, and mixed with 2 M hydrochloric acid and chloroform. The organic layer was washed with saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0→15% methanol/chloroform gradient) and recrystallized from methanol/ethyl acetate, thereby giving 0.29 g of the desired compound. Melting point: 119-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10](C(OC(C)(C)C)=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1c(Cc2ccc(Br)cc2)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Brc1ccc(Cc2cc3ccccc3[nH]2)cc1
Temperature: 0 °C
Yield: 49.5 %

Procedure:
A mixture of t-butyl 2-(p-bromophenylmethyl)indole-1-carboxylate (7) (6.0 g) (prepared, e.g., as described in Preparation 2), 10% sodium hydroxide in water (20 ml), and ethanol (150 ml), was heated under reflux for 6 hours. The mixture was then poured onto a mixture of ice water/dilute brine and extracted twice with ethyl acetate. The extract was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to produce an oil, which then crystallized. The material was recrystallized from methyl t-butyl ether to give 2-(p-bromophenylmethyl)indole (2.2 g), a compound of Formula (8), m.p. 136° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Yield: 136.1 %

Procedure:
A mixture of Toluene-4-sulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (4.47 g; 13.9 mmol; 1.0 eq.), 4-Iodo-1H-pyrazole (2.69 g; 13.9 mmol; 1.0 eq.) and cesium carbonate (6.78 g; 20.8 mmol; 1.5 eq.) was heated in DMA (50.0 mL) at 100° C. for 3 h. It was then allowed to cool to RT, diluted with EtOAc and washed with water and brine. Aqueous phases were back-extracted with EtOAc. Combined organic phases were finally dried over sodium sulfate, filtered and concentrated to give 6.32 g of a yellow oil. Recrystallisation in iPrOH afforded the title compound as a white powder (2.81 g, 61%). HPLC (Condition A): Rt 3.46 min (purity 100%). MS (ESI+): 335.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[CH:5]([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:4][CH2:3]1.OC1CCC(C)(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]=2[CH:5]([O:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O[Si](C)(C)C)cc1
Agent: CC1(C)CCC(O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(O[Si](C)(C)C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-trimethylsiloxynaphth-2-yl)ethynyl]benzoate (Compound 111), 83 mg (0.26 mmol) of 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoic acid (Compound 42) was converted into the title compound (white solid) using 0.07 ml (0.65 mmol) of triethylamine and 0.08 ml (0.65 mmol) of chlorotrimethylsilane.