Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3cccnc3)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cccnc3)cc2)nc1

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(4-pyridin-3-ylbenzyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 407-1 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=75:25 to 30:70) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][CH:7]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)=[CH:15][CH:14]=1)[C:8]#[N:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][CH:7]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C@@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)=[CH:17][CH:18]=1)[CH2:8][NH2:9]
Reactant: COc1ccc(CNC(C#N)CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CNC(CN)CCCc2ccc(OC[C@@H]3COC(C)(C)O3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2,4-dimethoxy-benzylamino)-5-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-pentanenitrile (513 mg, 1.12 mmol) in diethyl ether (15 mL) under argon is slowly added lithium aluminium hydride (2.25 mL of a 1.0 M solution in diethyl ether, 2.25 mmol). The resulting reaction mixture is stirred at RT for 3 h, then is left standing at RT overnight. Water (0.1 mL) is added cautiously, followed by sodium hydroxide (0.2 mL of a 15% aqueous solution) and a further portion of water (0.1 mL). The reaction mixture is diluted with diethyl ether (5 mL) and then dried over MgSO4 and the solvent is concentrated in vacuo to afford the title compound as a pale yellow oil that is used without further purification. [M+H]+ 459.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH2:4][CH3:5])[CH3:3].[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:7]([O:6][C:2]([CH2:4][CH3:5])([CH3:3])[CH3:1])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
To a solution of 2-methylbutan-2-ol (10 g, 113 mmol) in DCM (100 mL) was added DMAP (0.693 g, 5.67 mmol) and TEA (17.39 mL, 125 mmol). Mixture was then cooled to 0° C. and acetic anhydride (15.56 mL, 125 mmol) was added and the mixture was stirred at room temp for 24 h. The mixture was then washed with sat.NaHCO3 (100 mL), 1N HCl (100 mL), 10% NaOH (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to afford dark oil which was dilstilled by short path distillation (product distilled at 90-95° C.) to afford tert-pentyl acetate (8 g, 61.5 mmol, 54.2% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.98 (s, 3H), 1.78 (q, J=7.5 Hz, 2H), 1.43 (s, 6H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:33][C:22]3=[CH:23][C:24]4[C:25](=[O:32])[N:26]([CH3:31])[C:27](=O)[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:20][C:21]3=[CH:29][C:28]4[CH2:27][N:26]([CH3:31])[C:25](=[O:32])[C:24]=4[CH:23]=[C:22]3[N:33]=2)[CH3:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C)C3=O
Yield: 82.8 %

Procedure:
2-(4-(1-(5-Fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-methyl imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.35 g, 0.76 mmol) and zinc powder (1.20 g, 18.28 mmol) were suspended in acetic acid (30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (100 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a pale-yellow solid product, 0.28 g, 82.8% yield. MS: 444.0 [M−H]−. 1H-NMR (DMSO-d6, 300 MHz): δ 13.06 (s, 1H), 11.16 (s, 1H), 11.09-11.06 (m, 1H), 7.95 (s, 0.5H), 7.85 (s, 0.5H), 7.78 (s, 0.5H), 7.69 (s, 0.5H), 7.30-7.10 (m, 3H), 6.91-6.83 (m, 1H), 6.14-6.10 (m, 1H), 4.48 (s, 2H), 4.17-4.13 (m, 1H), 3.10 (s, 3H), 3.03-2.96 (m, 2H), 2.35 (d, 3H, J=4.9 Hz), 1.34-1.32 (m, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][C:19](=[O:25])[NH:20]3)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:16]=4[CH:17]=[CH:18][C:19](=[O:25])[NH:20]5)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2cccc3[nH]c(=O)ccc23)C1=O
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2cccc3[nH]c(=O)ccc23)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]acetic acid (compound aa16-4) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-5-yl)morpholin-2-yl]ethyl]acetate (compound ap3-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Br.[CH:15]([C:18]1[S:19][C:20]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:21]=2[N:27]=1)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:25][CH2:26][C:20]4[S:19][C:18]([CH:15]([CH3:17])[CH3:16])=[N:27][C:21]=4[CH2:22][CH2:23]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC(C)c1nc2c(s1)CCNCC2
Agent: Br
Product: CC(C)c1nc2c(s1)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-isopropyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrobromide. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 15 mg (17% of theory). ESI-MS: m/z=420 (M+H)+; Rt(HPLC): 1.34 min. (Method J).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O:21][C:22](=[O:36])[C@H:23]([CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[NH2:24])C1C=CC=CC=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([NH:24][C@H:23]([C:22]([OH:36])=[O:21])[CH2:25][C:26]([OH:28])=[O:27])(=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material was synthesised as follows. To a solution of hippuric acid (0.90 g, 5×10−3 moles) and L-aspartic acid dibenzyl ester (2.31 g, 5×10−3 moles) in DMF (35 ml) was added 1-hydroxybenzotriazole (0.73 g, 5.5×10−3 moles), triethylamine (1.4 ml, 9.7×10−3 moles) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide, HCl salt (1.05 g, 5.5×10−3 moles). The mixture was stirred for 4 hours at room temperature then poured into water (450 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to dryness to obtain the desired starting material as a yellow oil. 1.90 g (80%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C1COCC1>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7.00 g (46.6 mmol) 1-(4-hydroxymethyl-phenyl)-ethanone in 100 mL THF is added 22.5 g (46.6 mmol) tetrabutylammonium-tribromide dissolved in MeOH/THF. The reaction mixture is stirred 1 h at RT and the solvent is evaporated. The residue is dissolved with water and tertbutylmethylether. The organic phase is washed eight times with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated with diisopropylether and the precipitate is collected and dried.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]([CH3:28])[C:6]1[N:11]=[CH:10][C:9]2[O:12][C:13]3[C:18]([C:19](=[O:20])[C:8]=2[CH:7]=1)=[CH:17][C:16]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:15][CH:14]=3>C1COCC1>[CH3:4][N:5]([CH3:28])[C:6]1[N:11]=[CH:10][C:9]2[O:12][C:13]3[C:18]([C:19]([CH3:1])([OH:20])[C:8]=2[CH:7]=1)=[CH:17][C:16]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:15][CH:14]=3
Reactant: C[Mg]Cl
Reactant: CN(C)c1cc2c(=O)c3cc(-c4cccnc4F)ccc3oc2cn1
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1C2(C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium chloride, 22 wt % in THF (1.6 mL, 4.76 mmol), was added via syringe to a suspension of 3-(dimethylamino)-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (0.53 g, 1.57 mmol) in THF (16 mL) at 0° C. The resulting solution was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride at 0° C. and diluted with water and extracted with DCM. The combined organic extracts were washed with a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:2 EtOAc in hexane, to provide 3-(dimethylamino)-7-(2-fluoropyridin-3-yl)-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([O:17][CH2:18][CH2:19][C:20]2([CH2:26][CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:9]=[C:10]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:11]=1)(=[O:3])[CH3:2].IC1C=CC=CC=1.C(O)(=O)C.C(O)(=O)C.C(OCC)C>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([O:17][CH2:18][CH2:19][C:20]2([CH2:26][CH:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:9]=[C:10]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCO)CCCCC2)c1
Solvent: CCOCC
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CC=O)CCCCC2)c1
Reaction time: 15 h
Yield: 112 %

Procedure:
To a solution of 2-[1-[2-(3,5-diacetoxymethylphenyoxy)ethyl]cyclohexyl]ethanol (synthesized in Example 31) (430 mg) dissolved in dichloromethane (5 mL) were added diacetic acid iodobenzene (388 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (18.5 mg) successively at room temperature. The solution was stirred for 15 hours. Diethyl ether was added to the solution and it was washed in turn with a 10% aqueous sodium thiosulfate solution, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (479 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][N:6]([O:18][CH3:19])[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])[O:12][C:11](C)(C)[O:10]1>CO>[CH3:11][O:12][C:13](=[O:14])[C:9]([OH:10])=[CH:8][C:7](=[O:17])[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([F:23])=[C:2]([Br:1])[CH:3]=1)[O:18][CH3:19]
Reactant: CON(Cc1ccc(F)c(Br)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(Br)c1)OC
Yield: 44 %

Procedure:
N-(3-Bromo-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (44% yield); mp 107–108° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.09 (1H, m, aromatic), 7.25 (1H, m, aromatic), 7.53 (1H, m, aromatic). Anal. calcd for C13H13BrFNO5: C, 43.11; H, 3.62; N, 3.86. Found: C, 43.10; H, 3.54; N, 3.87.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:22]C1CCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(=O)([O-])O.[Na+]>O1CCCC1.O>[CH2:30]([O:29][CH2:28][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[OH:22])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)OC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(O)COCCCCCCCC/C=C\CCCCCCCC
Reaction time: 8 h
Yield: 57 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 628 mg (0.95 mmol) of 1,3-O-dioleyl-2-O-tetrahydrofuranylglycerol followed by addition of 5 ml of diluted (10%) hydrochloric acid, and the mixture was stirred overnight. The reaction mixture was then diluted with water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ether. The extract was dried and concentrated and the residue was subjected to column chromatography (silica gel/n-hexane-ethyl acetate) to provide 321 mg (57%) of the title compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[F:18])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].O.[CH3:34][S:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])=[O:36]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH:43]=2)=[CH:13][C:12]=1[F:18])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Br)cc1F)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1F)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 0.450 g (0.943 mmol) rac-[2-(4-bromo-2-fluoro-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester in 10.5 ml toluene/ethanol 19:1 were added 69 mg (0.094 mmol) PdCl2 (dppf), 0.238 g (2.83 mmol) sodium bicarbonate, 5 ml water and 212 mg (1.04 mmol) 3-methylsulfonylphenylboronic acid and the mixture heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, filtered through a Dicalite pad and the filtrated extracted with tertiary butyl methyl ether. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash-chromatography over silica gel with a heptane/AcOEt gradient with 10-50% AcOEt: rac-[1-(3,4-dichloro-phenyl)-2-(3-fluoro-3′-methanesulfonyl-biphenyl-4-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as colorless solid: MS (ISN): 550.2 and 552.2 (M−H)−.
Reaction SMILES: [OH-].[Na+].[C-]#[N:4].[Na+].O.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12](O)[C:13]([O-])=O)=[CH:10][CH:9]=1.[Na+].[Cl-].[Na+]>CN(C)C=O.O.C(O)=O>[OH:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][C:13]#[N:4])=[CH:10][CH:9]=1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(O)cc1
Temperature: 135 °C

Procedure:
Sodium hydroxide (4.0 g.) and sodium cyanide (5.0 g.) are added to a stirred suspension of sodium p-hydroxymandelate monohydrate (19 g. of 89% w/w material, the impurity being sodium chloride) in N,N-dimethylformamide (100 ml.) and the mixture is stirred and heated at 135° C. for 4 hours and then cooled. Formic acid (7.7 ml.) and water (200 ml.) are added and the mixture is extracted twice with methyl isobutyl ketone (100 ml. and 75 ml.). The combined extracts are washed twice with water (40 ml. each time) and are then concentrated by evaporation. There is thus obtained a solution of p-hydroxybenzyl cyanide in methyl isobutyl ketone which is suitable for conversion to p-hydroxyphenylacetamide without further purification.
Reaction SMILES: O[C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.O>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:42])[CH3:43])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (10.54 g, 15.6 mmol) synthesized in Example (125e) was dissolved in tetrahydrofuran (160 mL), and anhydrous methanesulfonic acid (5.51 g, 31.6 mmol) and triethylamine (8.70 mL, 62.4 mmol) were added, followed by stirring at room temperature for 3 hours under nitrogen atmosphere, and subsequently the temperature was raised to 60° C., followed by stirring for 3 hours. To the reaction solution, water (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (9.72 g, yield 95%) as a brown oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]3[CH:40]=[CH:39][NH:38][C:35]3=[N:36][CH:37]=2)[CH:27]=1.[OH-].[K+].O>CO>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:18])=[C:11]([CH:12]([C:40]2[C:34]3[C:35](=[N:36][CH:37]=[C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH:33]=3)[NH:38][CH:39]=2)[OH:13])[C:14]([F:17])=[CH:15][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-dibenzylamino-2,6-difluoro-benzaldehyde (53, 0.76 g, 2.3 mmol) in methanol (50 mL) were added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 0.40 g, 2.1 mmol, prepared as described in Example 17) and potassium hydroxide (0.50 g, 8.9 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to provide the compound (54, 0.60 g, 50%). MS (ESI) [M+H+]+=533.2.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C.C=O.C(O)(=O)C.[NH3:19]>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:19])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: N
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(O)cc1

Procedure:
Parahydroxybenzoic acid ethyl ester is dissolved in methanol, added with formalin and acetic acid to react overnight, added to NH3(aq) to obtain para-hydroxy benzoic amide. This product was added with formalin, acetic acid and N7-bromoethyl 3-isobutyl-1-methylxanthine processed through a Mannich reaction to obtain compound 33. Through purification and then dissolution into methanol, add NaOH and ethyl bromide to gain compound 34. Various substitutions can be made to produce other desired compounds. For example, by replacing ethyl bromide with propyl bromide, compound 35 can be obtained. By replacing theophylline with IBMX, compounds 36, 37, and/or 38 can be obtained.