Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:11](Br)[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1CCCCC1)C1CCCCC1.[CH:47]([O:49]CCCC)=[CH2:48].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:47]([C:11]1[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]2=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:49])[CH3:48]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Reactant: C=COCCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 8-(benzyloxy)-6-bromo-2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.32 g, 0.64 mmol) and N-methyldicyclohexylamine (0.20 mL, 0.96 mmol) in dioxane (1 mL) was purged with nitrogen for 5 minutes, n-butyl vinyl ether (0.83 mL, 6.4 mmol), tris(dibenzylidene-acetone)dipalladium (0.12 g, 0.13 mmol), and tri-tert-butylphosphine (0.065 g, 0.32 mmol) were added. After stirring at room temperature for 2 days, the reaction mixture was treated with 1 N HCl and stirred at room temperature overnight. The reaction mixture was partitioned between chloroform and brine. The organic extract was dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluted with a hexanes and ethyl acetate gradient to provide titled product.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([OH:21])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[O:7][CH2:6][C:5]2[C:8]([CH:13]([O:21][C:23](=[O:25])[CH3:24])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: Cc1ncc(C(O)c2ccc(Cl)cc2)c2c1OC(C)(C)OC2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c2c1COC(C)(C)O2
Reaction time: 18 h
Yield: 100 %

Procedure:
210 mg (0.66 mmoles) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 2 ml vial and dissolved in 500 μl of pyridine and 110 μl of acetic anhydride (1.16 mmole). The reaction mixture is stirred for 18 hours, then poured into 30 ml of saturated NaHCO3. The mixture is allowed to stir at room temperature for 1 hour, then extracted with 3×30 ml of CH2Cl2. The combined CH2Cl2 layers are washed with 3×20 ml of 2N HCl. The organic phase is dried over Na2SO4, filtered and the filtrate is evaporated to dryness. 24 g are obtained as a white solid with a yield of 100%.
Reaction SMILES: [C:1]1([NH:17][NH2:18])[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O>[CH:10]1[CH:11]=[C:12]2[C:13]3[C:14]4[C:1](=[CH:2][CH:3]=[CH:4][C:5]=4[C:6](=[O:16])[C:7]2=[CH:8][CH:9]=1)[NH:17][N:18]=3
Reactant: NNc1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 55 parts of a moist filter cake containing 24 parts of 1-anthraquinonyl hydrazine (dry weight) obtained by the the procedure described in any one of Examples 1 to 11 are added 150 parts by volume of concentrated sulfuric acid, such that the temperature does not rise above 100° C. (about 1/2 hour). The reaction mixture is then stirred for 2 hours at 100° to 110° C., subsequently cooled to 40° C. and diluted dropwise with 150 parts by volume of water. The suspension is then poured into a mixture of ice and water and filtered. The filter cake is washed neutral with water and dried, affording 22.2 parts of pyrazolanthrone of the formula. ##STR6##
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5](CC)[C@@H:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7])C.[OH-].[Na+]>O1CCOCC1>[CH2:9]([O:8][C@@H:6]([CH3:7])[CH2:5][C:4]([OH:18])=[O:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CC)[C@H](C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H](CC(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of the above ethyl (3S)-3-(benzyloxy)butanoic acid ethyl ester (339 g) in 1,4-dioxane (1.5 L), 2N aqueous sodium hydroxide solution (0.75 L, 1.5 mol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and after the aqueous phase was washed with diethyl ether, concentrated hydrochloric acid (0.14 L) was added to acidify it. After it was extracted with ethyl acetate, it was successively washed with water and saturated brine, and then it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give (3S)-3-(benzyloxy)butanoic acid (254 g) as a mixture. The present compound was used for the subsequent reaction without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])([CH3:8])([CH3:7])[CH3:6].C([O-])(=O)C([O-])=O.C([O-])(=O)C.[Na+].[CH2:33]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][CH2:50][CH2:51][CH2:52][C:53](=O)[C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C.C(O)(=O)C>[C:5]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH:46]1[CH2:47][CH2:48][N:43]([C:41]([O:40][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:42])[CH2:44][CH2:45]1)([CH3:6])([CH3:8])[CH3:7]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(=O)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 0.57 g of sodium cyanoborohydride in 40 ml of ethanol is added dropwise to a stirred mixture of 2 g of N-(L-alanyl)-L-proline tert-butyl ester.oxalate, 1 g of sodium acetate, 0.72 g of acetic acid, 10 g of molecular sieves 3 A, 3.4 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate and 50 ml of ethanol at room temperature over a period of 2 hours. The reaction mixture is allowed to stand overnight and filtered, and the filtrate is concentrated under reduced pressure. The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to hexane:acetone=1:1) to give 0.66 g of N-[N-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-L-proline tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([C:19]#[C:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1.[H][H]>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([CH2:19][CH2:20][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:9][N:8]=1
Reactant: [H][H]
Reactant: COc1ccc(CNc2nnc(C#CC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(CCC3(O)CCCC3)c3ccc(C#N)cc23)cc1Cl
Yield: 57.4 %

Procedure:
690 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)-1-ethynyl]-6-phthalazine carbonitrile was dissolved in 200 ml tetrahydrofuran, 50 mg of 10% Pd—C was added thereto, and the mixture was stirred for 0.5 hr in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was evaporated. The resulitng residue was purified by silica gel column chromatography to give 400 mg of 4-[(3-chloro-4-methoxybenzyl)amino]-1-[2-(1-hydroxycyclopentyl)ethyl]-6-phthalazine carbonitrile. This product was converted in a usual manner into the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1.[OH-].[Na+]>CN(C=O)C>[O:26]1[CH2:27][CH2:28][O:29][CH:25]1[CH2:24][NH:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: BrCC1OCCO1
Reactant: Nc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc(-c2oc3ncnc(NCC4OCCO4)c3c2-c2ccccc2)cc1
Temperature: 150 °C
Yield: 57.5 %

Procedure:
A stirred mixture of 4-amino-5,6-diphenylfuro[2,3-d]pyrimidine (100 mg, 0.34 mmol), 2-bromomethyl-1,3-dioxolane (116 mg, 0.69 mmol) and sodium hydroxide granules (42 mg, 1.05 mmol) in DMF (1.5 mL) was heated at 150° C. for 1 hour. The resulting mixture was filtered and purified by preparative HPLC to give a beige solid (73 mg). 1H NMR (CDCl3): 8.50 (1H, s), 7.62-7.49 (7H, m), 7.32-7.25 (3H, m), 5.70 (1H, br s), 5.00 (1H, br s), 3.85-3.63 (6H, m). LC/MS: 374 (MH+).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde in 100 ml of acetone was treated dropwise with 10 ml of Jones' reagent. The mixture was stirred at room temperature for 1 hour and then poured into 100 ml of water. The precipitate which thereby resulted was filtered off, washed portionwise with water and dried in a vacuum. The crude product was recrystallized from ethanol and gave 2.2 g of pure 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzoic acid with m.p. (C-N) 204° C. and cl.p. (N-I) 215° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].[N:42]1([C:47]2[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[N:43]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[N:42]1([C:47]2[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:32]([C:31]3[CH:35]=[CH:36][N:37]=[C:29]([C:18]4[CH:19]=[C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:21]=[CH:22][C:17]=4[NH:16][C:14]([C:13]4[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=4)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:41])=[O:15])[CH:30]=3)=[O:33])=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[N:43]1
Reactant: NCc1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(-n4cccn4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, was placed 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid (125 mg, 0.22 mmol, 1.00 equiv), (4-(1H-pyrazol-1-yl)phenyl)methanamine (41 mg, 0.24 mmol, 1.10 equiv), EDC HCl (62 mg, 0.32 mmol, 1.50 equiv), 4-dimethylaminopyridine (40 mg, 0.33 mmol, 1.51 equiv), and dichloromethane (15 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was extracted with 40 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×15 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was obtained as 0.132 g (83%) of a yellow crude solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O>[Cl:26][C:24]1[CH:25]=[C:20]([C:14]2([C:16]([F:18])([F:19])[F:17])[CH:13]=[N:12][CH:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:21]=[C:22]([Cl:27])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)ccc1C(=O)O
Yield: 77 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid ethyl ester (Example 10.5) (2.8 g) in ethanol (40 ml) was added a solution of sodium hydroxide (0.51 g) in water (15 ml). The reaction mixture was stirred at reflux for 1 hour. After cooling to ambient temperature aqueous hydrochloric acid (1M) (20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallised from diisopropyl ether to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 13.07 (s, 1H), 7.91-7.58 (m, 6H), 4.85 (d, 1H), 4.44 (d, 1H), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]=[C:16]1[C:29](=[CH2:30])[CH:28]2[O:31][CH:17]1[C:18]1[CH2:19][C:20]3[C:25]([CH2:26][C:27]=12)=[C:24]([O:32][CH3:33])[CH:23]=[CH:22][CH:21]=3>C1C=CC=CC=1>[CH2:15]=[C:16]1[C:29](=[CH2:30])[CH:28]2[O:31][CH:17]1[C:18]1[C:27]2=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[O:32][CH3:33])[CH:19]=1
Reactant: C=C1C(=C)C2OC1C1=C2Cc2c(cccc2OC)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: C=C1C(=C)C2OC1c1cc3cccc(OC)c3cc12
Reaction time: 1 h
Yield: 70.4 %

Procedure:
1.24 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added at room temperature under a nitrogen atmosphere to a solution of 1.56 g of crude 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene in 50 ml of benzene. After 1 hour, the suspension was filtered and the filtrate was washed with benzene. The organic solution was washed with two 75 ml portions of sodium hydrogen sulphite solution and two 75 ml portions of water. The aqueous phase was extracted with 50 ml of benzene and the combined organic solutions were dried over magnesium sulphate. After concentration, the residue was dissolved in 150 ml of diethyl ether, the solution was stirred with active carbon, the mixture was filtered and subsequently the filtrate was concentrated. Crystallisation of the residue from methanol yielded 1.09 g (70%) of 1,2,3,4-tetrahydro-2,3-dimethylene-1,4-epoxy-5-methoxyanthracene of melting point 154°-155° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[F-].[K+].[F:49][C:50]([F:60])([F:59])[C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH2:54]Cl>CN(C=O)C.O>[F:49][C:50]([F:59])([F:60])[C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH2:54][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3cccc(C(F)(F)F)c3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 13; 40 mg, 0.126 mmol) was dissolved in DMF (1.5 mL). K2CO3 (19 mg, 0.14 mmol), 18-crown-6 (6 mg, 0.02 mmol), KF (8 mg, 0.14 mmol), and 3-(trifluoromethyl)benzyl chloride (20 μL, 0.129 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and then at 40° C. for 12 h. H2O (2.5 mL) was added and the mixture was extracted with EtOAc. The organic layer was evaporated to give 3-[4-(3-trifluoromethyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (32.7 mg, 72%) as an off-white powder. HRMS Calcd. for C18H13F3N2O3 (M+), 362.0878. Found: 362.0872.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH:7]=[CH:6]2>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(Oc3ccc(N)cc3)ccc2c1

Procedure:
The nitro intermediate (10 mmol) obtained above was dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10% Pd/C (360 mg) until completion according to General Procedure H, as indicated by TLC or HPLC. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: CO.[C:3](Cl)(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[C:11]([OH:13])=[O:12].C(=O)([O-])O.[Na+]>O>[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[OH:17])[C:11]([O:13][CH3:3])=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(=O)O)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
100 ml of methanol are introduced into a 500 ml three-necked flask and then, at 0° C., 9.75 ml of acetyl chloride are added dropwise. 5 g of 3-amino-4-hydroxybenzoic acid are subsequently added at 0° C. and then the reaction medium is stirred at ambient temperature for eighteen hours. A saturated solution of sodium hydrogencarbonate in water is subsequently added at 0° C. and the mixture is extracted three times with ethyl acetate. The organic phases are combined and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 5.16 g of methyl 3-amino-4-hydroxybenzoate.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>OS(O)(=O)=O>[N+:1]([C:14]1[C:9]2[N:8]=[CH:7][S:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2scnc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2scnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
KNO3 (1.95 g, 19.3 mmol) was added portionwise to an ice-cold solution of 1,3-benzothiazole (2.0 g, 14.8 mmol) in H2SO4 (5 ml) while maintaining the temperature below 10° C. and the mixture was stirred at 0° C. for 2 h. The mixture was poured onto ice and the aqueous phase was extracted with DCM. The organic phase was washed with sat NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was diluted with MeOH (15 ml) and heated under stirring at 65° C. for 1 h, on cooling the resulting precipitate was collected by filtered and washed with MeOH to give the title compound (500 mg, 38%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1I.Cl>[Cu]I.C(NCC)C>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6]
Reactant: Brc1ccccc1I
Reactant: C#CCCC(=O)O
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccccc1Br
Reaction time: 2 h

Procedure:
To 10 ml of diethylamine was added with stirring 0.5g (5.1 mmol) of 4-pentynoic acid, 1.4g (5 mmol) of 1-bromo-2-iodobenzene, and 60 mg (0 05 mmol) of trakis(triphenylphosphine)palladium(0) The slurry was degassed with argon and 0.19 g (1.0 mmol) of CuI was added. The reaction mixture was stirred for 2 hr. at room temperature and then poured into approximately 100 ml of a 10% HCl solution. The resulting precipitate was filtered, washed with water and dried. The solid was taken up in hot CHCl3 and filtered to remove insoluble salts. After evaporation of the solvent, the resulting orange solid was recrystallized from a chloroform-hexane mixture to produce a tan solid, m.p. 87-91° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.Cl[CH2:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[H-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C@H:31]([CH2:33][O:34][CH2:36][C:37]3=[O:38])[CH2:32]2)=[CH:4][N:3]=1
Reactant: O=C(O)CCl
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncc([C@H]2C[C@H]3COCC(=O)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
A solution of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (45 mg, 0.063 mmol) (see Example 7) and chloroacetic acid (7.2 mg, 0.076 mmol) in THF (2.5 mL) was treated with HATU (36 mg, 0.095 mmol) and DIEA (55 μL, 0.316 mmol). The reaction was maintained at room temperature for 1 h. The reaction mixture was then treated directly with NaH (15.2 mg, 0.631 mmol). After 15 min, the reaction was quenched with water (2 mL) and the reaction mixture was extracted with ethyl acetate (10 mL). The organics were washed with brine, then dried over Na2SO4, concentrated, then purified by reverse phase prep HPLC yielding 4-(2-amino-5-((7R,8aS)-4-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (13.0 mg, 39% yield). LCMS (m/z): 525.2, 527.2 (MH+), 0.59 min; 1H NMR (400 MHz, CD3OD) ppm 8.61 (dd, J=4.30, 7.04 Hz, 1H), 7.91 (d, J=1.96 Hz, 1H), 7.84-7.76 (m, 2H), 7.40-7.31 (m, 3H), 7.30-7.24 (m, 2H), 7.24-7.16 (m, 1H), 5.16-5.05 (m, 1H), 4.18-4.08 (m, 2H), 3.99-3.85 (m, 2H), 3.85-3.70 (m, 3H), 3.53-3.42 (m, 2H), 3.39-3.29 (m, 1H), 2.34-2.19 (m, 1H), 1.67 (q, J=11.48 Hz, 1H).