Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+]([O-])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:11]=[C:10]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:28][CH:29]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(Br)nc3ccccc23)cc1

Procedure:
Ethyl 2-[4-(2-bromoquinolin-4-yloxy)phenoxy]propionate (40) was prepared from 2-bromo-4-nitroquinoline (Chem Abstracts 51: 6639) and ethyl 2-(4-hydroxyphenoxy)-propionate following essentially the same procedure as that described in Example 1. The compound was isolated as a colourless oil which solidified slowly on standing. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.5-7.4 (4H, m, quinoline protons); 7.1 (4H, d of d, phenyl protons); 6.6 (1H, s, C3 quinoline proton); 4.8 (1H, q, CHCH3); 4.3 (2H, q, OCH2CH3); 1.65 (3H, d, CHCH3); 1.3 (3H t, OCH2CH3).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH2:36])[C@H:27]([O:37][C:38](=[O:40])[CH3:39])[C@H:26]1[O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2].[CH3:45][C:46]([CH:48]1[C:54](=[O:55])[CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51][C:49]1=[O:50])=O>CO>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:30]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[O:29][C@@H:28]([NH:36][C:46](=[C:48]2[C:54](=[O:55])[CH2:53][C:52]([CH3:57])([CH3:56])[CH2:51][C:49]2=[O:50])[CH3:45])[C@H:27]([O:37][C:38](=[O:40])[CH3:39])[C@H:26]1[O:41][C:42](=[O:44])[CH3:43])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](N)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](NC(C)=C3C(=O)CC(C)(C)CC3=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 55.2 %

Procedure:
A mixture of 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-β-D-glucopyranosyl amine (157 mg, 0.24 mmol) and 2-acetyldimedone (81 mg, 0.45 mmol) in MeOH (5 ml) was refluxed for 5 h. The reaction mixture was evaporated, and the residue was purified by chromatography using CHCl3/EtOAc 1:1 as the mobile phase, to give 4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-2,3,6-tri-O-acetyl-N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl]-β-D-glucopyranosyl amine (27) (106 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19](O)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1.[NH4+].[Cl-].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([NH2:31])=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
A mixture of 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (60 mg, 0.19 mmol), NH4Cl (20 mg, 0.38 mmol), HOBT (38 mg, 0.28 mmol), EDCI (54 mg, 0.28 mmol) and triethylamine (76 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature overnight under N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (dichloromethane:MeOH=30:1) to provide 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxamide (20 mg, yield: 33.3%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.54 (d, J=8.4 Hz, 1H), 7.28˜7.31 (m, 2H), 7.20˜7.24 (m, 2H), 6.90 (s, 1H), 6.82˜6.84 (m, 1H). MS (M+H)+: 318.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:20]=[O:21].[Cl-].[NH4+].[BH4-].[Na+]>O1CCCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]=[C:17]1[CH2:20][OH:21])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C1CO
Temperature: -20 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A solution of n-butyllithium in hexanes (2.43 M, 27.6 mL, 67.0 mmol, 1.10 equiv) was added dropwise via syringe to a stirred solution of N-(tert-butoxycarbonyl)-2,3-dihydropyrrole (Oliveira et al. J. Org. Chem. 1999, 64, 6646; incorporated herein by reference) (10.3 g, 60.9 mmol, 1 equiv) in tetrahydrofuran (300 mL) at −20° C. The reaction mixture was stirred at −20° C. for 3 h, then was cooled to −78° C. The cold solution was then transferred via cannula over 25 min to a separate flask containing a stirred solution of N,N-dimethylformamide (DMF, 7.10 mL, 91.4 mmol, 1.5 equiv) in tetrahydrofuran (30 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then was transferred rapidly via cannula to a vigorously stirred solution of saturated aqueous ammonium chloride (500 mL) at 23° C. Upon completion of the addition the layers that formed were separated. The aqueous layer was then extracted with two 750-mL portions of ethyl acetate. The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (300 mL) and saturated aqueous sodium chloride solution (300 mL). The washed solution was dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue obtained was dissolved in methanol (300 mL, 1-L round-bottom flask containing a Teflon-coated stir bar). The resulting solution was cooled to 0° C. and sodium borohydride (2.53 g, 67.0 mmol, 1.1 equiv) was added in one portion (gas evolution was observed). The mixture was stirred for 35 min at 0° C. The product solution was then slowly poured into a solution of saturated aqueous ammonium chloride (200 mL), and the biphasic mixture was diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with two 500-mL portions of ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (120 mL) and hexanes (500 mL) was added. The product solution was washed with saturated aqueous sodium chloride solution (200 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (20% ethyl acetate-hexanes initially, grading to 30% ethyl acetate-hexanes) to furnish N-(tert-butoxycarbonyl)-2-hydroxymethyl-4,5-dihydropyrrole as a pale yellow oil (6.75 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH2:31])[N:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][N:15]([CH3:32])[C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[N:24]([N:28]=[C:29]([NH:31][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:30]=3)[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc4c(-c5cccc(N(C)C)c5)cccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 1h employing 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (see example 1c) and 8-(3-dimethylamino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 66a-c). The title compound was obtained as light yellow foam. MS ISP (m/e): 435.3 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9]([O-:11])=[C:8](C(OC)=O)[C:7]=1[CH3:16])=[O:5])[CH3:2].[Na+].[Cl-].[K+].CC(O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:16][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[CH:8]=1
Reactant: CCOC(=O)C1=C(C)C(C(=O)OC)=C([O-])C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CC(=O)C=C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
In a 5 L round bottom flask, sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-methylcyclo-penta-1,3-dienolate (485 g, 1954 mmol), KCl (204 g, 2736 mmol, JT Baker), and AcOH (392 mL, 6839 mmol, JT Baker) in toluene (1200 mL) and water (1200 mL) were heated at reflux for about 6 h. The reaction mixture was allowed to cool to ambient temperature for about 16 h. The reaction mixture was then poured into a 12 L flask and diluted with water (3 L). Solid NaHCO3 (450 g, 5.3 mol) was added cautiously portionwise with stirring over about 1 h. After about an additional 30 min of stirring, the basic aqueous phase was separated and further extracted with Et2O (4×400 mL). The combined organic layers were washed with water (4×500 mL) and brine (500 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to yield a yellow oil that was purified by vacuum distillation (92-94° C., 0.4 mmHg) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (229 g, 69%) as a yellow oil: 1H NMR (CDCl3) δ 6.04-6.01 (m, 1H), 4.26-4.17 (m, 2H), 3.67 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.16 (s, 3H), 1.32-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]([C:47]2[C:55]([OH:56])=[CH:54][C:50]3[O:51][CH2:52][O:53][C:49]=3[CH:48]=2)[C:39]1=[O:57])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:47]2[C:55]([OH:56])=[CH:54][C:50]3[O:51][CH2:52][O:53][C:49]=3[CH:48]=2)([CH2:5][OH:16])[C:39]1=[O:57])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCCOCc1ccccc1
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (93%): MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:7][CH2:6][C:5]2([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15]C=O)[OH:8])[CH2:3][CH2:2]1.[OH-].[K+]>CO>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1([OH:8])[CH2:6][CH2:7][CH:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=CNc1ccccc1C1(O)CCC1C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C1(O)CCC1C1CC1
Yield: 81.4 %

Procedure:
In a sulfonation flask, a mixture consisting of 3.35 g (0.0145 mol) N-[2-(2-cyclopropyl-1-hydroxycyclobutyl)phenyl]-formamide (prepared as described in Example 3), 1.3 g (0.02 mol) potassium hydroxide and 25 ml methanol was stirred at reflux temperature for 3 hours. Then the solvent was distilled off in a water jet vacuum and the residue taken up in 100 ml of ethyl acetate. The organic phase was washed three times with water and after drying with sodium sulphate the solvent was distilled off in a water jet vacuum. The raw material was purified by flash chromatography over silica gel (eluant: hexane/ethyl acetate 2:1). Yield: 2.4 g (80% of theory) of 1-(2-aminophenyl)-2-cyclopropylcyclobutanol in the form of a slightly brownish oil (1HNMR (CDCl3): 0.2-0.36 ppm/m/2H, 0.55 ppm/m/2H), 1.08 ppm/m/1H), 1.81 ppm/m/2H, 2.3-2.48 ppm/m/3H, 4.2 ppm (broad)/3H−NH2+OH), 6.6-6.72 ppm/m/2H, 7.05-7.15/m/2H− only one isomer obtained).).
Reaction SMILES: [CH2:1]([C:5]1[N:9]=[C:8]([CH3:10])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([O:27]C)=[O:26])=[CH:15][CH:14]=1>>[CH2:1]([C:5]1[N:9]=[C:8]([CH3:10])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1n[nH]c(C)n1
Product: CCCCc1nc(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Yield: 8.7 %

Procedure:
Following General Procedure A, 1.0 g (7.2 mmol) of 3-butyl-5-methyl-1H-1,2,4-triazole was reacted with 2.89 g (9.5 mmol) of the alkylating reagent prepared in step 1 of Example 1. Hydrolysis of the slower moving isomer provided 220 mg of 4′-[(3-butyl-5-methyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ 0.88 (t, J=7 Hz, 3H), 1.25–1.38 (m, 2H), 1.54–1.67 (m, 2H), 2.39 (s, 3H), 2.54 (t, J=8 Hz, 2H), 5.32 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.36 (dd, J=8 and 2 Hz, 1H), 7.46 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).
Reaction SMILES: P(=O)(O)(O)O.OO.[N+]([O-])([O-])=O.C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC.[C:38]([O:43][CH2:44][CH:45]1O[CH2:46]1)(=[O:42])[C:39]([CH3:41])=[CH2:40]>O.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C1(C)C=CC=CC=1>[C:38]([O:43][CH2:44][CH:45]=[CH2:46])(=[O:42])[C:39]([CH3:41])=[CH2:40]
Reactant: C=C(C)C(=O)OCC1CO1
Agent: O=[W](=O)([O-])[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)C(=C)C
Temperature: 45 °C
Reaction time: 30 h

Procedure:
An aqueous solution containing 1.32 g (0.004 mole), of sodium tungstate dihydrate 1.0 g (0.01 mole) of phosphoric acid and 12.5 g (0.12 mole) of 30% hydrogen peroxide in 18 ml of water (mixture pH=2.05) was added to a 24 ml toluene solution containing 7.5 g (0.06 mole) of allyl methaccrylate and 1.0 g (0.0023 equiv.) trioctylmethylammonium nitrate. The mixture was stirred at 45° C. for 30 hrs and was stopped when gas chromotrography showed that almost all starting material had disappeared and a major new peak having identical retention time as commercial glycidyl methacrylate had appeared. The mixture was cooled and the organic layer was separated and washed three time with 10 ml portions of water. It was then dried over magnesium sulfate, filtered and concentrated in vacuo to give 9.8 g of a viscous amber liquid.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C[O-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][C:3](=[O:16])[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COC(=O)CCc1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC

Procedure:
3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester is dissolved in toluene, 1.05 equivalents 2-(3,4-dimethoxy-phenyl)-ethylamine (commercially available) and 1.1 equivalents sodium methoxide (30% in methanol) are added. At normal pressure the reaction mixture is heated to a maximum of 110° C. and methanol distilled until full conversion is reached. The reaction mixture is washed with water and sulfuric acid. During cooling of the organic phase, the compound 3 crystallises and is filtered, washed with cold toluene and dried in vacuo at 50° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](F)[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:12].FC1C=C(F)C=C2C=1CCC2=O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:12]
Reactant: CCOC(=O)CC1(O)CCc2c(F)cc(F)cc21
Agent: O=C1CCc2c(F)cc(F)cc21
Product: CCOC(=O)CC1(O)CCc2c(F)cccc21
Yield: 78 %

Procedure:
This compound was prepared in an analogous manner to that described in Example 5c for ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetate substituting 4-fluoro-1-indanone (15.53 g, 0.103 mol) for 4,6-difluoro-1-indanone. Chromatography on silica gel with ethyl acetate:hexanes (19:1) as eluent gave 19.11 g (78%) of ethyl 2-(4-fluoro-1-hydroxy-1-indanyl)acetate which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[C:22]([N:23]([CH3:27])[CH:24]([CH3:26])[CH3:25])=[N:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:28]([O:30]C)=[O:29])[CH:19]=4)[N:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH3:27][N:23]([CH:24]([CH3:26])[CH3:25])[C:22]1[C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)=[N:14][C:15]2[C:20]([N:21]=1)=[CH:19][C:18]([C:28]([OH:30])=[O:29])=[CH:17][CH:16]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc(-c4ccc(F)cc4)o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of methyl 2-[5-(4-fluorophenyl)furan-2-yl]-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (110 mg, 0.26 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (42 mg, 1.05 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (19.3 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:34]([NH:30][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:35])[CH3:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (28 mg, 0.085 mmol) in DMF (0.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (30 mg, 0.085 mmol), N,N-diisopropyl ethyl amine (72 μL, 0.423 mmol) and isopropylamine (8 μL, 0.40 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (24 mg, 74%) as a white solid after trituration from water. MS: m/e=387.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O:57][C:58](=[O:68])[CH2:59][C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62](Cl)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54].[CH3:69][N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1.[NH4+].[Cl-]>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:53]([O:57][C:58](=[O:68])[CH2:59][C:60]1[C:65]([CH3:66])=[CH:64][N:63]=[C:62]([N:73]2[CH2:74][CH2:75][N:70]([CH3:69])[CH2:71][CH2:72]2)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CN1CCNCC1
Reactant: Cc1cnc(Cl)cc1CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCN(C)CC2)cc1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium tert-butoxide (227 mg, 2.37 mmol) is dried under high vacuum at approximately 80° C. After purging with argon and cooling to RT, palladium acetate (39 mg, 0.17 mmol), rac-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (rac-BINAP, 54 mg, 0.09 mmol) and (2-chloro-5-methyl-pyridin-4-yl)-acetic acid tert-butyl ester (520 mg, 2.15 mmol) are added. The mixture is dissolved in dioxane (7 ml, degassed with three freeze-thaw cycles under HV/argon), and 1-methyl-piperazine (237 mg, 2.37 mmol) is added. The round bottom flask containing the reaction mixture is immersed into a pre-heated oil bath (T=85° C.). After 30 minutes, TLC analysis indicated almost complete conversion of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (CH2Cl2/MeOH, slow gradient from 98:2 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.43 (s, 9H), 2.14 (s, 3H), 2.34 (s, 3H), 2.51 (m, 4H), 3.44 (s, 2H), 3.49 (m, 4H), 6.51 (s, 1H), 7.96 (s, 1H). ES+−MS: 306.4 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@H:16]1[C@@H:20]([O:21]C(=O)C2C=CC=CC=2)[C@H:19]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([CH2:54][NH:55][C:56]([NH:58][CH2:59][CH2:60][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[O:57])=[N:34][C:35]=3[NH:39][CH2:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:18][C@@H:17]1[C:67]([NH:69][CH2:70][CH3:71])=[O:68])(=O)C1C=CC=CC=1.CC(C)=O>CO>[C:42]1([CH:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:40][NH:39][C:35]2[N:34]=[C:33]([CH2:54][NH:55][C:56]([NH:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]3)=[O:57])[N:32]=[C:31]3[C:36]=2[N:37]=[CH:38][N:30]3[C@@H:19]2[O:18][C@H:17]([C:67]([NH:69][CH2:70][CH3:71])=[O:68])[C@@H:16]([OH:15])[C@H:20]2[OH:21])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
Potassium carbonate (20 mg, 0.14 mmol) was added to a solution of (2S,3S,4R,5R)-4-(benzoyloxy)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-2-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (100 mg, 0.13 mmol) (Preparation 14) in methanol (100 ml). The reaction mixture was stirred at room temperature for 2 hours. More potassium carbonate (20 mg, 0.14 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. The solvent was removed under reduced pressure to give a residue that was slurried with acetone and filtered. The filtrate was evaporated under reduced pressure and the residue was partially purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume). The residue after solvent evaporation under reduced pressure was repurified by more column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume). The solvent was removed by evaporation under reduced pressure to give the title compound as a foam (17 mg).