Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([Cl:26])(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C(Cl)Cl.C(O)(C)C>[ClH:26].[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])[CH2:6][CH2:5]2)=[O:25])=[CH:18][CH:19]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)cc1
Product: Cl
Reaction time: 4 h

Procedure:
10.25 g of piperazin-1-yl-acetic acid morpholide are cooled to 0° C. in 20 ml of methylene chloride. 8.75 g of anisoyl chloride are added dropwise in the course of 15 minutes. After the mixture has been subsequently stirred for 4 hours, it is diluted with isopropanol, whereupon the colourless product precipitates. It is filtered off with suction and dried.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:21]=3)[C:15]([O:17]C)=[O:16])=[C:9]([F:29])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:5]([C:7]2[CH:28]=[CH:27][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:21]=3)[C:15]([OH:17])=[O:16])=[C:9]([F:29])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(O[C@@H](C)CO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1

Procedure:
Methyl 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (100 mg, 0.25 mmol) was dissolved in THF (2.0 mL and water (0.2 mL) and solid lithium hydroxide (21 mg, 0.5 mmol) added. The resultant mixture was stirred at ambient temperature for 16 hours. Water (10 mL) was added and the mixture partially reduced in vacuo and then extracted with ethyl acetate. The aqueous liquors were acidified with 1M hydrochloric acid and re-extracted with ethyl acetate (2×10 mL). The extracts were combined, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was used without further purification (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][NH:13][CH3:14].O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:13]([CH3:14])[CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CNC
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Product: CN(C)c1cc(C(=O)O)cc(Cl)n1
Temperature: 80 °C
Yield: 44 %

Procedure:
2,6-Dichloroisonicotinic acid (2.00 g, 10.42 mmol) was placed in a pressure tube and a solution of dimethylamine in tetrahydrofuran (26 mL, 2 M, 52 mmol) added. The vessel was sealed and heated for 22 h at 80° C. The mixture was cooled to room temperature, transferred to a round-bottom flask and concentrated to dryness. The resulting white semi-solid was taken up in 30 mL of 0.1 N sodium hydroxide solution. 1 N HCl was added dropwise with stirring to adjust the pH of the solution to ca. 3.5, at which point a pale yellow solid formed. This was collected by filtration and dried under vacuum at 45° C. overnight to provide 2-chloro-6-(dimethylamino)isonicotinic acid inner salt (916 mg, 44%). Further acidification of the aqueous solution to pH 1 resulted in the formation of a bright yellow solid, which was also collected and dried under vacuum to give 2-chloro-6-(dimethylamino)isonicotinic acid hydrochloride (1.15 g, 46%). m/z: 201+ [M+H]; 199− [M−H]. For the HCl salt: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.64 (br. s., 1H), 6.96 (d, J=1.0 Hz, 1H), 6.89 (d, J=0.8 Hz, 1H), 3.06 (s, 6H), 2.53 (t, J=5.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:22])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C3CCCCO3)[CH:10]=2)[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][OH:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[C:6]([N:8]([CH3:22])[C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][OH:33])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CN(c1cccc(OC2CCCCO2)c1)c1nc(Cl)ncc1Cl
Reactant: Nc1cccc(CCO)c1
Product: CN(c1cccc(O)c1)c1nc(Nc2cccc(CCO)c2)ncc1Cl
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-methyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3-aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 59% yield. LCMS for C19H20ClN4O2 (M+H)+: m/z=371.1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S(O[Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])(OC(F)(F)F)(=O)=O.O>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][C:8]([O:11][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)[Si](OS(=O)(=O)OC(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[Si](OC1=CCC2(CC1)OCCO2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (11.6 g) in dichloromethane (200 mL) were added dropwise triethylamine (20.7 mL) and trifluoromethyl tri(propan-2-yl)silyl sulfate (25.0 g). The reaction mixture was stirred at room temperature so for 1 hr, and ice-cooled water was added. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (22.0 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cccc(-n2cccn2)c1
Reaction time: 24 h

Procedure:
A mixture of 3-formylphenylboronic acid (2.00 g, 13.34 mmol), pyrazole (0.46 g, 6.67 mmol), copper(II) acetate (1.82 g, 10.01 mmol), pyridine (1.10 mL, 13.34 mmol), and powdered 4A molecular sieves (2.5 g) in dichloromethane (20 mL) was stirred under an air atmosphere for 24 h. The mixture was then filtered through Celite, the filtered solids were washed with methanol, and the combined filtrate was concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded the title compound. MS 173 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>CS(C)=O>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:22]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(Cl)ccc2[N+](=O)[O-])sc2ccccc12
Yield: 47 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (4.0 g), 2,4-dichloronitrobenzene (3.8 g) and dimethyl sulfoxide (55 ml), ethyl 2-(5-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (3.2 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:40]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:18][CH2:19][CH3:20])[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[O:41])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(CNCc1cccc2ccccc12)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 90.4 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, 2,2-diethoxy-N-(naphthalen-1-ylmethyl)ethanamine (Compound IX-2) (2.73 g, 10 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (6.89 g, 15 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=8:2 to 6:4) to obtain the title compound (6.46 g, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31])=[O:23])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(OC2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:62]([O:66][C:67]([NH:69][C@H:70]([C:74](O)=[O:75])[C@@H:71]([CH3:73])[OH:72])=[O:68])([CH3:65])([CH3:64])[CH3:63]>O.O1CCOCC1>[C:62]([O:66][C:67]([NH:69][C@H:70]([C:74]([NH:17][C@H:16]([C:18]([N:20]1[CH2:38][CH2:37][CH2:36][C@H:21]1[C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:31])[NH2:32])=[O:23])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:75])[C@@H:71]([CH3:73])[OH:72])=[O:68])([CH3:64])([CH3:65])[CH3:63]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Fc1c(F)c(F)c(Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
2.18 g (4.1 mmol) of Nε -benzyloxycarbonyl-lysyl-prolyl-arginine IV in 30 ml of water are added, under stirring, to a solution of 2.10 g (5.3 mmol) of pentafluorophenyl ether of tert.butyloxycarbonyl-threonine in 70 ml of dioxane. Then the reaction mixture is treated following the procedure described for the synthesis of compound III. The yield of the desired product--tert.butyloxycarbonyl-threonyl-Nε -benzyloxycarbonyl-lysyl-prolyl-arginine is 2.65 g (188%).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:18]C(C)([O-])C.[K+].[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>C1COCC1>[CH2:29]([O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1)[CH3:18]
Reactant: COC(=O)CS
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 31.3 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.21 g, 0.84 mmol) in 5 mL of THF was added potassium tert-butoxide (0.19 g, 1.68 mmol) in one portion and stirred for 1 minute. To the suspension was added methyl thioglycolate (0.15 mL, 1.68 mmol) dropwise over 1 minute. The mixture was stirred for 12 h then poured into ice water and the solids collected. Purification by trituration using ethyl acetate/hexanes gave 88 mg (33%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H), 8.90 (m, 1H), 8.11 (m, 1H), 7.74 (m, 2H), 7.48 (m, 1H), 7.17 (m, 2H), 4.10 (s, 2H), 3.63 (s, 3H); MS (EI) m/z 319.13 (M−H)−.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:15]=2[O:14][CH:13]=1.C(OC(C)C)(C)C>C(Cl)Cl>[CH:1]([NH:11][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][C:15]=2[O:14][CH:13]=1)=[O:2]
Reactant: O=CO
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)Nc1cc2occ(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 1.5 h
Yield: 73 %

Procedure:
27.6 g of formic acid was added to 30.6 g of acetic anhydride. The mixture was stirred for 1.5 hours at 40°-45° C. The reaction mixture was dropwise added to a solution of 34.6 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one dissolved in 400 ml of methylene chloride. The mixture was stirred for 1 hour at 20°-25° C. 400 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and recrystallized from acetonitrile to obtain 27.3 g (yield: 73%) of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 236°-238° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([OH:19])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]2=[O:20])=[C:9]1[C:30]([O:32][CH3:33])=[O:31])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl.CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:35])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:14]2=[O:20])=[C:9]1[C:30]([O:32][CH3:33])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)c1c2c(c(O)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1c2c(c(OC)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A mixture of methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.70 g, 1.41 mmol) and a solution of trimethylsilyldiazomethane in hexane (1.0 mL, 2.0 mmol; 2M) in dichloromethane-methanol (4 & 2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was subject to column chromatography on silica gel euting with 2% methanol in dichloromethane. Collection and concentration of appropriate fractions provided the title compound. ES MS M+1=509
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 72 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (509 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4B to give the title compound as a brown solid (72% yield). M.p.=178° C., LCMS: m/z=388.23 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.32 (3H, t, J=7.1 Hz), 4.20 (2H, d, J=1.5 Hz), 4.31 (2H, q, J=7.1 Hz), 5.26 (2H, s), 7.23 (2H, m), 7.32 (2H, s), 7.34 (2H, m), 7.39 (1H, d, J=1.8 Hz), 7.63 (2H, d, J=8.6 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06 (1H, d, J=2.0 Hz).
Reaction SMILES: C1C2C(OC([N:17]([CH3:50])[C@@H:18]([CH3:49])[C:19]([NH:21][C:22]3[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]4[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])C5C=NC=CC=5)[N:28]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:24][CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.[CH2:57]1COCC1>ClCCl>[OH:39][C@H:32]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@H:29]1[CH2:30][CH2:31][C@@H:27]([CH2:26][C:25]2[CH:47]=[CH:48][C:22]([NH:21][C:19](=[O:20])[C@@H:18]([NH:17][CH3:50])[CH3:49])=[CH:23][CH:24]=2)[N:28]1[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41]
Reactant: C[C@@H](C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1)N(C)C(=O)OC1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.410 g (0.593 mmol) of tert-butyl (2S,5R)-2-[4-({(2S)-2-[[(9H-fluoren-9-yloxy)carbonyl](methyl)amino]propanoyl}amino)benzyl]-5-[(R)-hydroxy(pyridin-3-yl)methyl]pyrrolidine-1-carboxylate from step A above in 3 mL of anhydrous THF was added 0.152 g (1.78 mmol) of piperidine. The resulting mixture was stirred at ambient temperature for 24 h and then was diluted with 25 mL of dichloromethane. The mixture was washed with water then dried over magnesium sulfate. The mixture was filtered and evaporated to dryness in vacuo to afford the crude title compound which was used without further purification. LC-MS: m/z (ES) 468 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)[C:20](O)=[O:21])([CH3:15])[CH3:14]>>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]=[C:17]([O:16][CH:13]([CH3:14])[CH3:15])[CH:18]=2)[S:3][CH:4]=1)[CH3:12]
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)n1

Procedure:
The title compound was prepared from ethyl 2-aminothiazol-4-ylacetate and 3-isopropyloxy-5-phenoxybenzoic acid following synthetic description A.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:34])=[O:36])=[CH:31][CH:32]=2)([OH:26])[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-ethanol (500 mg, 1 mmol) in methanol (50 mL) and water (10 mL) was added sodium metaperiodate (440 mg, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfinyl-phenyl)-ethanol (512 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C26H25FN2O4S2 [M+H]+ 513.63, observed 512.8.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:23]=[C:24]([OH:26])[CH:25]=3)[C:13]([N:15]3[CH2:21][CH2:20][C:19](=[O:22])[NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C([O:35][C:36](=[O:61])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]Br)[C:42]=1[CH2:54][CH2:55][C:56]([O:58]CC)=[O:57])C.Cl>CC(C)=O.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:25]=[C:24]([CH:23]=[C:12]([C:13]([N:15]4[CH2:21][CH2:20][C:19](=[O:22])[NH:18][CH2:17][CH2:16]4)=[O:14])[CH:11]=3)[O:26][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][C:43]3[C:42]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[C:41]([CH:46]=[CH:45][CH:44]=3)[O:40][CH2:39][CH2:38][CH2:37][C:36]([OH:61])=[O:35])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: O=C1CCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNC(=O)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 1-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepan-5-one (0.58 mmol) in a mixture of acetone and DMF (2:1, 2 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and used for the next step without further purification. The total amount of material from the previous step was dissolved in 1,2-dichloroethane (4 mL), followed by addition of trimethyltin hydroxide (433 mg). The resulting reaction mixture was stirred at 70° C. for 7 days. Then it was neutralized with 5% HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was purified by reverse-phase HPLC to yield the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[N+](=[CH2:20])=[N-]>>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C=[N+]=[N-]
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Yield: 58 %

Procedure:
Robins et al., 1974 J. Org. Chem. 39, 1891, describe the treatment of a methanolic solution of uridine with diazomethane (in glyme) in the presence of stannous chloride dihydrate (in methanol) to synthesize 2'-O-methyluridine (58% yield). This reaction also yielded a significant fraction (28%) of 3'-O-methyluridine which is purified away from the 2'-O-methyl form by chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2)CC1
Yield: 87.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (4.00 g, 21.5 mmol) in dry dichloroethane (70 mL) are added 3-chlorobenzaldehyde (2.49 mL, 3.08 g, 21.9 mmol), HOAc (2.58 mL, 2.71 g, 45.1 mmol) and NaBH(OAc)3 (5.46 g, 25.8 mmol) at ambient temperature. After stirring at ambient temperature for 3d, 2N NaOH (40 mL) is added, the layers are separated, and the aqueous layer is extracted with CH2Cl2 (4×50 mL). The combined organic extracts are washed with water (3×50 mL) and brine (80 mL) and dried over MgSO4. The crude material is purified by chromatography on silica gel, eluting with hexane:EtOAc mixtures, yielding 5.83 g (18.8 mmol, 87%) of the title compound as yellow oil. MS (ES): m/z 311.0/313.0 (50/18) [MH+]. tR (method A)=5.0 min.