Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[Se:16][C:15]=1[C:23]([NH2:25])=[O:24].CN(C=O)C.[OH-].[Na+]>>[CH3:12][S:11][C:9]1[S:10][C:3]2[C:2]([NH:13][C:14]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[Se:16][C:15]=3[C:23]([NH2:25])=[O:24])=[N:7][CH:6]=[N:5][C:4]=2[N:8]=1
Reactant: CSc1nc2ncnc(Cl)c2s1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2s1

Procedure:
The reaction of 7-chloro-2-(methylthio)thiazolo[4,5-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale color solid, mp 280-282° C. 1H NMR (400 MHz, DMSO-d6): δ 12.16 (1H, br s, exchangeable with D2O), 8.77 (1H, s), 8.15 (1H, s), 7.61 (2H, br s, exchangeable with D2O), 2.69 (3H, s), 1.39 (9H, s); LC-MS (positive ion mode): m/z 426, 428 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29].C(O)(=O)C>C(Cl)Cl>[CH3:29][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:20])[NH:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1OC
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Combined ethyl 5-hydroxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (2.2 g, 6.32 mmol), MeOH (5 mL), and DCM (50 mL) and added 2.0 M TMS-diazomethane in hexanes (4.42 mL, 8.84 mmol) (over about 10 minutes) and stirred at 20° C. for 20 min. The reaction was then quenched with acetic acid (0.145 mL, 2.53 mmol) and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.0 g, 87% yield) as a white solid. MS m/z 363 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H) 1.78 (quin, J=6.6 Hz, 2 H) 3.25 (s, 3 H) 3.30-3.37 (m, 2 H) 3.39 (t, J=6.3 Hz, 2 H) 4.14 (s, 3 H) 4.27 (q, J=7.1 Hz, 2 H) 7.79 (dd, J=8.5, 0.6 Hz, 1 H) 8.03 (s, 1 H) 8.39 (dd, J=8.5, 2.4 Hz, 1 H) 8.76 (t, J=5.6 Hz, 1 H) 8.98 (dd, J=2.4, 0.6 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O-:9])=[O:8])=[CH:5][S:4][N:3]=1.[OH-].[Na+].Cl.[CH2:13]1COCC1.CO.O>>[CH2:1]([C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1)[CH3:13]
Reactant: Cc1nscc1C(=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nscc1C(=O)O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylate (G-3) (4.73 g, 30.1 mmol) in THF-MeOH-H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40° C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3 ethylisothiazole-4-carboxylic acid (G-4).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(CCN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
4-Methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (60 mg, 0.31 mmol, 1.2 mmol) and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (68 mg, 0.26 mmol, 1.0 eq) were suspended in ethanol (5 ml) in a microwave tube. The tube was capped, degassed under vacuum, and purged with nitrogen gas. The mixture was heated to 150° C. for 30 min under microwave irradiation. The mixture was then concentrated and purified by flash column chromatography (0-10% MeOH/DCM).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[C:37]([F:38])=[CH:36][C:35]([F:39])=[C:34]([F:40])[C:33]=1[CH2:41][CH:42]([NH2:44])[CH3:43].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:20][C:19]1[C:18]2[C:17](=[O:21])[N:16]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:15](=[O:29])[C:14]=2[CH:13]=[C:12]2[NH:30][C:9]([C:3]3[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=3[NH:44][CH:42]([CH3:43])[CH2:41][C:33]3[C:34]([F:40])=[C:35]([F:39])[CH:36]=[C:37]([F:38])[C:32]=3[F:31])=[N:10][C:11]=12
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Yield: 78.5 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.54 g, 2.58 mmol), Hunig's base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.10 g of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H, NH), 11.35 (d, J=6.0 Hz, 1H, NH), 11.02 (d, J=8.5 Hz, 1H, NH), 7.93 (s, 1H, ArH), 7.81-7.77 (m, 1H, ArH), 7.42 (t, J=7.0 Hz, 1H, ArH), 6.22 (d, J=8.0 Hz, 1H, ArH), 4.34-4.29 (m, 1H, CH), 4.12 (m, 1H, CH), 3.17 (m, 2H, CH2), 3.08 (d, J=5.5 Hz, 21-1, CH2), 2.72 (s, 3H, CH3), 2.48 (s, 3H, CH3), 1.77-1.76 (m, 2H, CH2), 1.37 (d, J=6.5 Hz, 3H, CH3), 1.29-1.24 (m, 6H, 2×CH2); Mass (ESI, positive) m/z 597.2 [M+H]+.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18]>C(O)C.[H][H].[C].[Pd]>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:18])=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15]
Reactant: [H][H]
Reactant: Cc1cc(C)c(-c2cccc([N+](=O)[O-])c2C)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(-c2cccc(N)c2C)c(C)c1
Yield: 84.6 %

Procedure:
Palladium-carbon (10%, 1.1 g) was added to a solution of 1-mesityl-2-methyl-3-nitrobenzene (11.0 g, 43 mmol) in ethanol (220 mL) at room temperature, followed by stirring for one day in hydrogen atmosphere. The mixture was filtered through Celite and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (8.2 g) as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.ClCCl.CCN(C(C)C)C(C)C>[N:30]1([C:36]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (200 μL of a 0.19 M solution in acetonitrile, 36 μmole) was added 220 μL of a 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 48 h at 25° C. under N2, and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford trifluoro-methanesulfonic acid 7-{[1-(morpholine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (12.8mg) 106[M+H]+=548.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Brc1ccc(OC2CCCC2)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC3CCCC3)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 1-bromo-4-cyclopentoxybenzene (see Example 48(a)), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:42][CH2:41][CH2:40][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:29])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=2[CH3:30])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:32])[CH:17]=[CH:16][N:15]=1)([CH3:20])[CH3:21]
Reactant: ClCCBr
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 252j, 7.08 g) dissolved in acetonitrile (150 mL) was treated with potassium carbonate (22.42 g) and 1-bromo-2-chloroethane (13.50 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h. The reaction mixture was evaporated to dryness, diluted with water (300 mL), and extracted with dichloromethane. The organic layer was dried (MgSO4) and evaporated. The crude product was triturated with 50% diethyl ether in iso-hexane to afford subtitle compound (7.58 g).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:16][CH2:17][CH3:18])[N:6]=1.O.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1>[CH2:17]([O:16][C:7]1[N:6]=[C:5]([CH:4]=[O:22])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:8]=1[C:9]#[N:10])[CH3:18]
Reactant: CCOc1nc(C=CN(C)C)c([N+](=O)[O-])cc1C#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc(C=O)c([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of the compound prepared in Example 445 (1.07 g) in tetrahydrofuran (20 mL) at ambient temperature was added water (20 mL), and to the resulting mixture was added sodium periodate (2.62 g). The resulting mixture was stirred at ambient temperature for 18 hours. There was a significant amount of precipitate present in the reaction mixture, and it was collected by filtration and washed with 50% aqueous tetrahydrofuran. The combined filtrate and wash were concentrated to remove most of the tetrahydrofuran, and the residue was extracted with chloroform. The organic layers were combined and dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 1/1 hexanes/ethyl acetate, to provide the title compound (0.61 g) with the following physical data.
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[Cl:17][C:18]1[N:19]=[C:20]([C:27]2[CH:48]=[CH:47][C:30]([O:31][CH2:32][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[C:29]([C:49]([F:52])([F:51])[F:50])[CH:28]=2)[C:21]2[CH:26]=[CH:25][NH:24][C:22]=2[N:23]=1.[O:53]1[CH2:58][CH2:57][CH:56](O)[CH2:55][CH2:54]1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[N:19]=[C:20]([C:27]2[CH:48]=[CH:47][C:30]([O:31][CH2:32][CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:36][CH2:35]3)=[C:29]([C:49]([F:50])([F:51])[F:52])[CH:28]=2)[C:21]2[CH:26]=[CH:25][N:24]([CH:56]3[CH2:57][CH2:58][O:53][CH2:54][CH2:55]3)[C:22]=2[N:23]=1
Reactant: OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4[nH]ccc34)cc2C(F)(F)F)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(Cl)nc4c3ccn4C3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanomethylenetributylphosphorane (1.1 mL) was added to a mixture of tert-butyl 4-{2-[4-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (1.0 g), tetrahydro-2H-pyran-4-ol (0.36 mL), and toluene (30 mL) at room temperature in a nitrogen atmosphere, and the reaction mixture was stirred overnight while heating to reflux. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=67:33 to 33:67), whereby tert-butyl 4-(2-{4-[2-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (1.04 g) was obtained as a yellow amorphous material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.BrC1C=CC(NC(=O)CC2C=CC=CC=2)=C(C=1)C([O-])=O.BrC1C=C2C(=CC=1)NC(=O)C(C1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:22])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[C:7]2[OH:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1Cl
Agent: O=C(Cc1ccccc1)Nc1ccc(Br)cc1C(=O)[O-]
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1Cl

Procedure:
The title compound was prepared using methyl 5-bromo-2-(2-(2-chlorophenyl)acetamido)benzoate (Intermediate 2: step a) in place of 5-bromo-2-(2-phenylacetamido)benzoate using the procedure described for Intermediate 1: step b.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][O:31][NH2:32])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][O:31][NH:32][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCON
Product: CC(C)(C)OC(=O)NCCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 63 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and tert-butyl(3-(aminooxy)propyl)carbamate (730 mg) described in Reference Example 20, the title compound 398.1 mg was afford (yield 63%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:22]=[C:10]3[N:11]=[C:12]([CH3:21])[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:14](O)[N:9]3[N:8]=2)[CH:2]=1.P(Cl)(Cl)([Cl:31])=O.C([O-])(O)=O.[Na+]>>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:22]=[C:10]3[N:11]=[C:12]([CH3:21])[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:14]([Cl:31])[N:9]3[N:8]=2)[CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)Cc1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1Cl
Yield: 87.1 %

Procedure:
A suspension of methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (748 mg, 1.998 mmol) in phosphoryl trichloride (15 ml, 1.998 mmol) was heated to reflux for 16 hrs. Concentrated to remove most of phosphoryl chloride to leave an oil, which was carefully neutralized w/sat'd NaHCO3 to PH=˜7. The precipitates was filtered and washed w/water, dried in vacuo to afford methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (720 mg, 1.741 mmol, 87% yield). The crude was used for the next reaction directly. 1H-NMR (500 MHz, CDCl3) δ ppm 2.75 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 7.43-7.44 (1H, m), 7.49-7.52 (2H, m), 7.62-7.63 (1H, m), 7.74-7.78 (3H, m), 8.36-8.38 (1H, m), 8.65 (1 H, s).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([OH:35])[C@H:14]1[O:19][C@H:18]([O:20][C@H:21]2[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[O:23][C@@H:22]2[CH2:30][OH:31])[C@H:17]([OH:32])[C@@H:16]([OH:33])[C@@H:15]1O.OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N.C(N[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:15]2[C@H:16]([OH:33])[C@@H:17]([OH:32])[C@@H:18]([O:20][C@H:21]3[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@@H:24]([OH:29])[O:23][C@@H:22]3[CH2:30][OH:31])[O:19][C@@H:14]2[CH2:13][OH:35])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
D-Glucose (10 mg), D-maltose (10 mg) maltotriose (25 mg), D-glucosamine (10 mg) or N-acetyl-D-mannosamine (10 mg) were reacted with O-(3-thiolpropyl)hydroxylamine (6 mg) in 1 ml D2O adjusted to pH 5.5 with 30% solution of NaOD at 37° C. for 15 hours. Progress of reaction was monitored by 1H NMR. Maltotriose-SH (30 mg) was separated from linker by passing through BioBel P-2 column in 0.05 M pyridine acetate buffer as above and freeze-dried. Next 30 mg of maltotriose-SH was reacted with bromoacetamido-derivatized BSA (15 mg), prepared as above to form maltotriose-BSA conjugate by thioether linkages. Reaction was done in buffer A, pH 7.4, 3 hours and solution was purified on Sephadex G-100 column as above. Extent of conjugation was evaluated by MALDI-TOF. Molecular mass of bromoacetamido-BSA was 73545 Da, while maltotriose-BSA conjugate was 81673 Da, indicated incorporation of 16 maltotriose molecules per BSA.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:16]=[CH:17][CH:18]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][NH:21][C:20]2=[O:25])[CH:14]=1)(=[O:29])=[O:28]
Reactant: O=C1CNC(=O)N1c1cccc(CCCCOCCCCCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOCCCCc1cccc(N2C(=O)CNC2=O)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
3-(3-{4-[(6-Hydroxyhexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione (2.67 g) in CH2Cl2 (50 ml) and triethylamine (1.2 ml) was treated with methanesulfonyl chloride (1.22 ml) and the mixture was stirred at 20° C. for 1.5 h. The mixture was diluted with CH2Cl2 and washed with 2M HCl, NaHCO3, dried and purified by chromatography on Biotage (40 g) eluting with EtOAc-petroleum ether(1:1) and then with 2% MeOH—CH2Cl2 to give the title compound (1.186 g) ES+ve 427 (MH)+.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ncccn1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N[C@H]1CCN(c2ncccn2)C1)c1cccc2ccccc12
Yield: 70.4 %

Procedure:
To a suspension of 156.6 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in 5 ml of dioxane were added 87.4 mg of 2-bromopyrimidine and 207 mg of diisopropylethylamine, and the mixture was stirred under reflux for 16 hours. The reaction mixture was evaporated, and to the residue were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→0:1) to obtain 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine. (2) In 10 ml of ethyl acetate was dissolved 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine, and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate was added to the mixture and the resulting mixture was stirred. The reaction mixture was concentrated under reduced pressure, to the residue was added diethyl ether, precipitates were collected by filtration and washed with ethyl acetate, to obtain 68.3 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine dihydrochloride (the following Table A2, Example 2.010).
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH2:15][Cl:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCCCCON=C(C(=O)CCl)C(=O)OCC

Procedure:
Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer) (57.5 g.) and sulfuryl chloride (20.9 ml.) were reacted in acetic acid (58.5 ml.) according to a similar manner to that of Preparation (6-10) to give an oil of ethyl 2-pentyloxyimino-3-oxo-4-chlorobutyrate (syn isomer) (51.1 g.).