Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]([CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH3:20].C1(O)C=CC=CC=1.[ClH:36]>CC(C)=O.C(O)C>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:27][CH3:28])[CH2:19][CH3:20])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: CCN(CC)CCCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Solvent: Oc1ccccc1
Product: CCN(CC)CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)nc12

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido[3,2-b]quinoline, 1.5 g. of 4-diethylaminobutylamine and 6.5 g. of phenol is heated at 100° C. for 3 hours. The reaction is cooled, 20 ml. of ethanol is added and this mixture is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The yellow solic is collected, air-dried and recrystallized from ethanol, giving the desired product, mp. 246°-274° C. (dec.).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:11][CH:12]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:13][CH:14]([OH:36])[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([NH:8][C:9]([CH2:11][CH:12]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH2:13][C:14](=[O:36])[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21

Procedure:
To a stirred solution of 2.9 g (4.6 mmol) 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-hydroxy-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester and 5.2 ml (37 mmol) triethyl amine in 22 ml DMSO is added a solution of 4.4 g (28 mmol) SO3.pyridine complex in 22 ml DMSO. After 2 hours at room temperature the mixture is poured on ice and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent evaporated. The residue is chromatographed over silica gel (hexane/ethyl acetate 9/1 to 7/3) to afford 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as an oil. MS (FAB) m/z 630 ([M+Li]+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)CCNC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to 2-(methylsulfonyl)ethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 26.8 mg of 169. MS (Q1) 487.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14](OC)=[O:15])[C:11]([CH2:18][CH3:19])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:18][CH3:19])=[N:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCc1nn(-c2cc(F)cc(F)c2)cc1C(=O)OC
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nn(-c2cc(F)cc(F)c2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
A solution (35 mL) of methyl 1 (3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carboxylate (6.5 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (65 mL) of lithium aluminum hydride (0.94 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was ice-cooled again, and water (2.5 mL), 1N aqueous sodium hydroxide solution (12.5 mL) and water (2.5 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (3.3 g) of 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (100 mL), manganese dioxide (6.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title object compound (3.1 g, 51%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:61][CH2:62][CH2:63][NH2:64]>CN(C)C=O>[Cl:61][CH2:62][CH2:63][NH:64][C:9](=[O:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13]
Reactant: NCCCl
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C(=O)NCCCl)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step A (40 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol), N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 2-chloroethanamine (16 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. The crude product was purified by CombiFlash (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound as a white amorphous solid. LC/MS m/z=467.9[M+H]+.
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[C:11]([CH3:19])=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].[NH2:20]/[C:21](/[CH3:37])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])=[O:24]>C(O)(C)C>[CH3:2][C:1]1[NH:20][C:21]([CH3:37])=[C:22]([C:23]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:29])=[O:24])[CH:9]([C:10]2[C:11]([CH3:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=Cc1c(C)nn2ccccc12)C(C)=O
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1c(C)nn2ccccc12

Procedure:
A solution of 24.9 g of methyl 2-acetyl-3-(2-methylpyrazolo[1,5-a]pyridin-3-yl)acrylate and 28.8 g of 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate in 125 ml of isopropylalcohol was refluxed for 8.5 hours, then concentrated. The resulting residue was dissolved in 100 ml of ethyl acetate, washed with 1 N-hydrochloric acid, and then extracted with 2 N-hydrochloric acid three times. The resulting hydrochloric acid layer was alkalized with 5 N-aqueous sodium hydroxide at pH 9, and then extracted with ethyl acetate. The ethyl acetate layer was washed with salt water, dried over anhydrous sodium sulfate and then concentrated. Hexane was added to the resulting residue, and insoluble layer was collected, then recrystallized from diethyl ether-hexane mixtures.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11](I)[CH:12]=1)[C:7]([OH:9])=[O:8]>O>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([OH:1])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)cc(I)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(Br)c1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a solution of NaOH (12.2 g; 305.8 mmol) in 300 mL of water was added 3-bromo-5-iodo-benzoic acid (20 g, 61.2 mmol) and Cu2O (866 mg, 6.1 mmol). The reaction mixture was heated at 100° C. for 24 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through Celite™. The filtrate was then acidified with 10% aq. HCl and extracted into ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a tan solid (12.3 g, 93% yield). HR-ES (−) calcd for C7HSO3Br [M−H]− 214.9349, observed 214.9350
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:38])=[C:6]([C:35]([OH:37])=[O:36])[C:7](=[O:34])[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])[C:9]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13]2)[CH:2]=[CH2:3]>CCOC(C)=O.[Pd]>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:8]1[C:9]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13]3)=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:38])=[C:6]([C:35]([OH:37])=[O:36])[C:7]1=[O:34]
Reactant: C=CCc1c(O)c(C(=O)O)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2[nH]c(CN(C)C)cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)c(C(=O)O)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2[nH]c(CN(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-allyl-1-(2,4-dimethoxybenzyl)-6-(2-((dimethylamino)methyl)-1H-indol-5-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid (45 mg, 0.085 mmol), prepared according to the procedure described in Example 164, Steps 1-6, and Pd/C (10 mg, 10%) in EtOAc (1 mL) was stirred under H2 (1 atm) at room temperature for 2 h. The solvent was evaporated and the residue was chromatographed (0-2.5% MeOH in CH2Cl2) to give the intermediate of 1-(2,4-dimethoxybenzyl)-6-(2-((dimethylamino)methyl)-1H-indol-5-yl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridine-3-carboxylic acid. LC-MS 489.2 [M+H]+, RT 1.17 min. This intermediate was stirred in TFA (0.5 mL) and TIPS-H (0.5 mL) at room temperature for 15 h, and then the mixture was concentrated to dryness. The residue was dissolved in CH2Cl2 (0.5 mL), then HCl (2.0M in Et2O, 1.0 mL) was added. The precipitate was collected by filtration and washed by ether to afford the title compound as an off-white solid (15 mg, 44% over 2 steps).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.[OH-].[Na+]>C(O)C>[C:11]1([C:9]2[N:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(CCC(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Yield: 94.4 %

Procedure:
150 mg of 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid methyl ester were dissolved in 1 mL of ethanol and treated with 0.7 mL of a 1M aq. solution of sodium hydroxide. The mixture was partitioned between water and Et2O. The aq. layer was separated, acidified with 25%-HCl and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo to give 137 mg of 3-[4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-propionic acid the product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)cc4)cc3CC[C@@H]12
Yield: 66.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 140 mg (67%) of the title compound as a white solid. mp 121°-122°. FDMS: m/e=323. α[D]589 =+79.46 (c=0.99, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:14][CH2:13][Br:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCCBr)c1
Temperature: 25 °C

Procedure:
A flask is charged with 3-hydroxybenzoic acid methyl ester (2.54 g, 16.0 mmol) and acetone (50 mL). 1,2-Dibromo-ethane (5.69 mL, 66.0 mmol) and potassium carbonate (2.76 g, 19.0 mmol) are added and the mixture is refluxed for 24 h. The reaction mixture is then cooled to room temperature. The solids are filtered off and the filtrate concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:1) to afford 3-(2-bromo-ethoxy)-benzoic acid methyl ester as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.66 (t, J=6.2 Hz, 2H), 3.93 (s, 3H), 4.35 (t, J=6.2 Hz, 2H), 7.14 (m, 1H) 7.37 (m, 1H) 7.57 (m, 1H) 7.68 (m, 1H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2n1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 7.1 ml (63.6 mmol) of ethyl chlorooxoacetate in 100 ml of 1,2-dichloroethane is cooled to 0° C. 7.0 ml (63.6 mmol) of titanium tetrachloride are added in small portions and the mixture is stirred for 30 min at 0° C. A solution of 7.4 g (35.3 mmol) of ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate is added and the mixture is stirred for 3 h at room temperature. The mixture is poured onto water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution, dried over sodium sulphate and concentrated under reduced pressure to produce an oil which is purified by chromatography on a silica column (eluant: cyclohexane/dichloromethane: 2/8). 9.51 g (29.4 mmol) of compound are isolated in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][C:15]#[CH:16]>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.[Cu]I>[CH3:12][N:13]([CH3:17])[CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C#CCN(C)C
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a stirred solution of 4-bromo-2-nitro-phenylamine (1.08 g, 5 mmol) and dimethyl-prop-2-ynyl-amine (1.0 g, 12 mmol) in TEA (20 mL) was added Pd(PPh3)2Cl2 (0.7 g, 1 mmol) and CuI (360 g, 2 mmol). The solution was stirred at 60° C. under nitrogen for 3 hours. The solution was evaporated with silica gel and purified by flash chromatography on silica to give the title compound (1.1 g, 70% purity). The title compound was taken directly to the next step without further purification. MS (ESI) 221 [M+H]+.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:67][C:68](=[O:71])[CH2:69][NH2:70])(C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([C:27]([NH:70][CH2:69][C:68]([OH:67])=[O:71])=[O:28])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-phenylalanine (1.0 g, 2.58 mmol) in DMF (13 mL) at 0° C. was added DIEA (899 μL, 5.16 mmol) and HBTU (979 mg, 2.58 mmol). After stirring for 10 min at 0° C., glycine t-butyl ester (353 μL, 2.58 mmol) was added and stirring was pursued for 1 h at 0° C. The reaction mixture was diluted with ethyl acetate, washed with H2O, 1N HCl solution, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system using 50% ethyl acetate in hexanes. Dipeptide 72 was obtained as a white solid (1.05 g, 81%). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 3.08-3.13 (m, 2H), 3.78-3.95 (m, 2H), 4.18 (t, J=6.9 Hz, 1H), 4.31-4.37 (m, 2H), 4.40-4.47 (m, 1H), 5.27 (bs, 1H), 6.21 (bs, 1H), 7.17-7.22 (m, 2H), 7.24-7.32 (m, 5H), 7.40 (t, J=7.5 Hz, 2H), 7.53 (t, J=7.9 Hz, 2H), 7.76 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:40]1COCC1.O>>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:40])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Reactant: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 142.6 mg (0.339 mmol) of ethyl 4- [(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2- naphthalenyl)ethynyl]benzoate (Compound 1) and 35.6 mg (0.848 mmol) of LiOH--H2O in 12 ml of THF/water (4:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the hexane fraction extracted with 5% aqueous NaOH. The aqueous layers were combined and acidified with 1M HCl, and then extracted with EtOAc and Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6 -DMSO): δ 7.91 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.47 (2H, s), 7.23 (4H, q, J=8.1 Hz), 7.01 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.33 (2H, d, J=4.8 Hz), 1.30 (6H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:6][N:7](C)C)[CH3:2].C(OC(=O)C(C(=O)C1C=CC(Cl)=C(Cl)C=1)=CN(C)C)C>CCCCC>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][O:18][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)cc1
Agent: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)c(Cl)c1
Solvent: CCCCC
Product: CCOC(=O)c1cnoc1-c1ccc(F)cc1
Yield: 74.5 %

Procedure:
The procedure of Example 20 was employed utilizing ethyl-2-(4'-fluorobenzoyl)-3-dimethylaminopropenoate in lieu of ethyl-2-(3',4'-dichlorobenzoyl)-3-dimethylaminopropenoate to yield upon recrystallization with pentane, ethyl-5-(4'-fluorophenyl)-4-isoxazolecarboxylate (1.75 g.; 74.5% yield) as a white solid having a melting point of 34°-38° C. and the following analysis:
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([CH2:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)=[O:21])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:26]([C:25]4[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=4[O:23][CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1ccccc1C=O
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)COc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 38.4 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.26 g, 23.7 mmol), 2-(ethoxycarbonylmethoxy)benzaldehyde (9.10 g, 47.3 mmol), p-toluenesulfonic acid (0.2 g) and xylenes (100 ml) was refluxed for 18 hours with the azeotropic removal of water. The solvent was removed in vacuo, and the residue was treated with ethanol and evaporated to dryness. The residue was partitioned between chloroform and 10% aqueous K2CO3, the layers were separated and the aqueous layer was extracted with chloroform (100 ml). The organic layers were combined, and concentrated to dryness. The residue was preloaded on silica gel and then was purified by column chromatography on silica gel eluting with hexanes (100%) to 20% ether/hexane to afford 3.74 g (38%) of 1-cyclopentyl-3-ethyl-6-[2-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 116-117° C.