Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.Cl.[CH3:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([N:50]2[CH2:53][C:52]4([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH2:51]2)[CH2:45][CH2:44]3)[CH:36]=1.[OH-].[Na+]>ClCCl.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:56]2[CH2:57][CH2:58][C:52]3([CH2:51][N:50]([C@H:46]4[C:47]5[C:43](=[CH:42][C:41]([C:37]6[CH:36]=[C:35]([CH3:34])[N:40]=[CH:39][N:38]=6)=[CH:49][CH:48]=5)[CH2:44][CH2:45]4)[CH2:53]3)[CH2:54][CH2:55]2)=[O:12])=[N:7][CH:8]=1
Reactant: Cc1cc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)ncn1
Reactant: COc1ccc(CC(=O)O)nc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CC(=O)N2CCC3(CC2)CN([C@@H]2CCc4cc(-c5cc(C)ncn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 8.90 g, 53.2 mmol) in dichloromethane (225 mL) was added 1,1′-carbonyldiimidazole (8.63 g, 53.2 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (28.3 mL, 203 mmol) was added to a mixture of 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 22.5 g, 50.7 mmol) in dichloromethane (113 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature for 2 hours. Aqueous sodium hydroxide (1N, 80 mL) and 100 mL of water were added and mixture was stirred for 10 minutes. The aqueous layer was washed with 150 mL of dichloromethane. The combined organic layers were washed with aqueous NH4Cl (3×) to remove the residual amine starting material. The organic solution was concentrated to a light green-amber oil and was stirred at 50° C. in EtOAc (150 mL) until a solution was obtained. The solution was cooled to room temperature with stirring. A solid formed and the thick slurry was diluted with 50 mL of EtOAc and 50 mL of heptanes. The slurry was stirred for 1 hour and filtered under nitrogen to afford 2-(5-methoxy-pyridin-2-yl)-1-{2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]non-7-yl}-ethanone (22 g, 89.7%) as an off-white solid. MS (ES+) 484.4 (M+H)+. 1H NMR (CDCl3) δ 1.74 (dt, 4H), 1.95-1.99 (m, 1H), 2.25-2.36 (m, 1H), 2.59 (s, 3H), 2.89-2.99 (m, 1H), 3.11-3.21 (m, 1H), 3.34-3.46 (m, 4H), 3.51-3.61 (m, 4H), 3.83-3.92 (m, 5H), 4.17 (dd, 1H), 7.29 (d, 1H), 7.38 (dd, 1H), 7.53 (d, 1H), 7.88 (s, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.16 (d, 1H), 9.02 (s, 1H). [α]D20=+55.0 deg (c=1 mg/mL, MeOH).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:15][O:16][CH3:17])[CH:8]=[O:9]
Reactant: CN(C)c1cc(C=O)ccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1N(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 1.90 g, 47.5 mmol) in dry DMF (60 ml) was added dropwise a solution of the compound (3) (5.98 g, 36.2 mmol) obtained above in DMF (40 ml) under nitrogen atmosphere under ice-cooling. The mixture was stirred at 0° C. for 30 minutes, and thereto was added dropwise chloromethyl methyl ether (3.6 ml, 47.4 mmol). The reaction mixture was stirred at 0° C.-room temperature for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The concentrate was purified by column chromatography on silica gel to give the title aldehyde compound (Compound A) as yellow liquid. Yield 7.17 g (95%).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[NH2:10][C:11]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([CH3:28])[N:12]=1.O>FC(F)(F)C(O)=O>[CH2:21]([C:14]1[N:13]([CH3:28])[N:12]=[C:11]([N+:10]([O-:6])=[O:5])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1c(N)nn(C)c1Cc1ccccc1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c([N+](=O)[O-])nn(C)c1Cc1ccccc1
Temperature: 75 °C

Procedure:
A mixture of sodium perborate tetrahydrate (95%, 3.12 g, 19.3 mmol) and trifluoroacetic acid (10 mL) was heated to 75° C. To this was added a solution of ethyl 3-amino-5-benzyl-1-methyl-1H-pyrazole-4-carboxylate (prepared according to the method of Y. Xia et al., J. Med. Chem. 1997, 40, 4372-4377; 1.00 g, 3.86 mmol) in trifluoroacetic acid, and the mixture was allowed to react at 75° C. for 2.5 hours. The reaction was then cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Eluant: 30% EtOAc in heptane) provided C20 as a dark yellow oil. Yield: 333 mg, 1.15 mmol, 30%. LCMS m/z 290.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.1 Hz, 3H), 3.74 (s, 3H), 4.33 (br s, 2H), 4.34 (q, J=7.1 Hz, 2H), 7.14-7.18 (m, 2H), 7.25-7.30 (m, 1H), 7.31-7.36 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:25](=[O:29])[C:26]([NH2:28])=[O:27])=[C:9]([CH3:24])[N:10]2[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23].[OH-].[Na+].CO.C(OCC)(=O)C>O>[NH2:28][C:26](=[O:27])[C:25]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:10]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:9]=1[CH3:24])=[O:29]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A mixture of 420 mg (0.94 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 5 mL of 1N NaOH and 15 mL of MeOH was heated to maintain reflux for 0.17 hours, cooled to room temperature and stirred 0.5 hours. Ethyl acetate and water was added, the aqueous layer separated, made acidic to pH 2-3 with 1N HCl, and the mixture extracted with ethyl acetate two times. The part that was not soluble was filtered. The filtrate was dried (MgSO4) and concentrated. The remaining solid was washed with a small volume of ether/methylene chloride and the insoluble material filtered and combined with the filtered material above to give 351 mg (86% yield) of [[3-(2-amino-1,2-dioxoethyl)1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid, mp, 236-239° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:22][O:23][C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:27]=1)=[O:25]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:33][NH:32][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:35][CH:34]=3)[CH3:16])[C:11]([C:18]([F:19])([F:20])[F:21])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C(F)(F)F)nn(-c2ccc(C)c(C)c2)c1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C(F)(F)F)cc1
Yield: 62 %

Procedure:
1-(1-(3,4-Dimethylphenyl)-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-yl)-ethanone (0.189 mmol, 56.5 mg) and 4-methoxycarbonylbenzhydrazide (0.189 mmol, 36.8 mg) were stirred in DMF at 100° C. for 2.2 hours and at 120° C. for 17 hours. After the solvent was removed by evaporation, the residue was resolved by silica gel thin layer chromatography (CHCl3/MeOH=10/1) to obtain 4-methoxycarbonylbenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide as a yellow solid (55.6 mg, 62%)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)[N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=[O:3])[CH3:2].Cl>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][NH2:28])[N:20]=2)[C:15](=[O:36])[N:14]([CH3:37])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cccc(OCCNC(=O)OC(C)(C)C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3cccc(OCCN)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution 101d (400 mg, 0.56 mmol) in DCM (15 mL) was added dropwise 3M HCl (in dioxane). This mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residual yellow solid was washed with ethyl acetate and dried under vacuum to afford 101e (290 mg, 80%) as a yellow solid. MS-ESI: [M+H]+ 612.3
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:26][C:25]4[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][C:24]=4[CH3:29])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: COc1ccc(N)c(C)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c(C)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with 4-methoxy-2-methylaniline gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.30 (bs, 1H), 9.10 (bs, 1H), 8.22 (d, 1H, J=5.1 Hz), 7.55 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 6.92 (m, 2H), 6.82 (d, 1H, J=8.7 Hz), 4.22 (bs, 4H), 3.80 (s, 3H), 2.15 (s, 3H); LCMS: purity: 94%; MS (m/e): 383 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([C:10]([OH:20])([C:14]#[C:15][Si](C)(C)C)[CH2:11][O:12][CH3:13])[CH2:9][CH2:8]1>CO>[CH:7]1([C:10]([OH:20])([C:14]#[CH:15])[CH2:11][O:12][CH3:13])[CH2:9][CH2:8]1
Reactant: COCC(O)(C#C[Si](C)(C)C)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(O)(COC)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
10.9 mg of potassium carbonate (0.08 mmol) are added to a solution of 1.67 g of (±)-2-cyclopropyl-1-methoxy-4-(trimethylsilyl)but-3-yn-2-ol (7.86 mmol) in methanol, and the mixture is stirred overnight at ambient temperature. The methanol is evaporated off and the residue is taken up with an ethyl acetate/water mixture. The product is extracted 3 times with ethyl acetate and the organic phases are then combined, dried over sodium sulphate, filtered, and concentrated under vacuum. 0.434 g of (±)-2-cyclopropyl-1-methoxybut-3-yn-2-ol is obtained in the form of an oil used without subsequent purification (crude yield=40%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:16].[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([C:28]([OH:30])=[O:29])=[CH:23][CH:22]=[CH:21]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[F:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[O:17][C:18]1[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=1)[C:24]([C:28]([OH:30])=[O:29])=[CH:23][CH:22]=[CH:21]3)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2
Reactant: COc1cc2ncc(F)c(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: CN(C)C=O
Product: COc1cc2ncc(F)c(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 19 h

Procedure:
A resealable tube was charged with 4-chloro-3-fluoro-6,7-dimethoxyquinoline (prepared by the method described in WO 98/13350) (0.610 g, 2.52 mmol), 6-hydroxy-1-naphthoic acid (0.474 g, 2.52 mmol), palladium acetate (0.023 g, 0.101 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (0.086 g, 0.202 mmol), potassium phosphate (2.14 g, 10.08 mmol), and DMF (12.6 mL, Aldrich). The system was flushed with argon and the tube was sealed. The mixture was stirred at 100° C. for 19 h then cooled to RT. Water (13 mL) was added, and the pH was adjusted to 6-7 with aqueous 6 N HCl solution. The resulting precipitate was filtered, washed with water, and purified by column chromatography on silica gel (eluting with 0-100% (50:50:2, EtOAc:hexane:AcOH)) to afford 6-(3-fluoro-6,7-dimethoxyquinolin-4-yloxy)-1-naphthoic acid as an off-white solid. MS (ESI, pos. ion) m/z: 394.0 (M+H). Mass Calc'd for C22H16FNO5: 393.1
Reaction SMILES: I[CH2:2][C:3]([NH2:5])=[O:4].[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>>[C:3]([NH:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:2]
Reactant: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1
Reactant: NC(=O)CI
Product: CC(=O)NN1CCC(c2ccc(-c3cccc(N)n3)cc2)CC1

Procedure:
Prepared from Example 13, using iodoacetamide to alkylate 6-[4-(piperidin-4-yl)-phenyl]-pyridin-2-ylamine, in 55%, mp 224-227° C.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6])C.[OH-].[Na+].[OH-].[K+].Cl>C(O)(=O)C.O1CCOCC1.O1CCCC1.CO>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5](=[O:6])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cccs1

Procedure:
The thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb may be subjected to hydrolysis to provide the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb. The hydrolysis may be carried out under either acidic or basic conditions. Basic hydrolysis can typically be carried out by treating a solution of a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb (1.0 equivalent) in an aqueous mixture of an appropriate solvent such as methanol, tetrahydrofuran or 1,4-dioxane with a suitable base such as aqueous sodium hydroxide or potassium hydroxide (typically 1.5 equivalents) for a period of four to twenty hours at a temperature range of 0° C. to room temperature. The reaction mixture can be worked up by acidification with an appropriate acid such as hydrochloric acid or acetic acid followed by extraction with an appropriate solvent such as ethyl acetate or dichloromethane. The resulting organic layer may then be concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa or IVb, respectively. If desired, the thiophenyl oxo-acetic acid IV, IVa or IVb could then be further purified by recrystallization or preparative HPLC. Alternatively, the hydrolysis of the thiophenyl oxo-acetic acid ethyl ester VII, VIIa or VIIb to the corresponding thiophenyl oxo-acetic acid IV, IVa or IVb may be carried out under acidic conditions. The acidic hydrolysis is typically carried out by refluxing a thiophenyl oxo-acetic acid ethyl ester such as VII, VIIa or VIIb in a mixture of acetone and water in the presence of hydrochloric acid for one to four hours. The reaction mixture is then extracted with an appropriate solvent such as dichloromethane and the organic layer concentrated in vacuo to provide the thiophenyl oxo-acetic acid IV, IVa and IVb, respectively.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[CH:17][CH:18]=[C:13]2[N:12]=[N:11]1.O>C(O)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2=[N:15][C:16]([OH:19])=[C:17]([Br:1])[CH:18]=[C:13]2[N:12]=[N:11]1
Reactant: Oc1ccc2nnn(-c3ccccc3F)c2n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc2c(cc1Br)nnn2-c1ccccc1F
Yield: 91.2 %

Procedure:
Bromine (0.10 ml, 2 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.23 g, 1.0 mmol) in glacial acetic acid (5 ml) at room temperature. After 4 h the solution was poured into water (150 ml). The precipitate was collected, dissolved in 10% methanol-dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.282 g, 91%) as a beige solid. δH (360 MHz; CDCl3) 7.42-7.47 (2H, m), 7.60-7.71 (2H, m) and 8.48 (1H, s); m/z (ES+) 309, 311 (M+H+).
Reaction SMILES: C(O)[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.[C:24]([O:34]C)(=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30].CN(C1C=CC=CN=1)C.C(Cl)(=O)CCCCC(Cl)=O>O1CCOCC1>[C:24]([OH:34])(=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)CCCCC(=O)OC
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)CCCCC(=O)Cl
Agent: 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
Solvent: C1COCCO1
Product: O=C(O)CCCCC(=O)O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Five grams of resin (Mw of 50,000) synthesized from cellobiose and dimethyl adipate were poured into dioxane and then 3.7 g of dimethylaminopyridine and 3.0 g of adipic acid chloride were added dropwise thereto in a nitrogen atmosphere, followed by stirring for 20 hours at 50° C. A white powder, obtained from the resulting reaction mixture, was subjected to GPC. As a result, the molecular weight of the white powder was two to eight times larger than that of the resin measured before the reaction. The infrared absorption spectroscopy of the white powder revealed that the intensity of an absorption peak due to the C═O bond in the ester bond was higher than that shown in FIG. 8. Therefore, it was understood that esterification occurred in the saccharide portions in the resin of Example 1 and resulted in crosslinks by adipic acid.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1)#[N:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(C#N)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(Cc1ccc(C#N)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 61 %

Procedure:
Prepared using General Procedure 7: To a stirred solution of tert-butyl 2-((4-cyanobenzyl)amino)acetate (14.7 g, 47.7 mmol) INT-31 in DCM (150 mL) stirring in a 0° C. in an ice bath was added TEA (9.98 mL, 71.6 mmol) followed by 4-nitrobenzoyl chloride. The reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was diluted with DCM (300 mL) and washed with NaHCO3 (2×200 mL). The organics were dried over dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (MeOH/DCM) followed by evaporation from hexanes to provide 11.5 g (61%) tert-butyl 2-(N-(4-cyanobenzyl)-4-nitrobenzamido)acetate INT-56 as a white powder. LCMS-ESI (m/z) calculated for C21H21N3O5: 395; found 394 [M−H]−, tR=2.33 min broad (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([C:16]([NH:18]C(OC(C)(C)C)=O)=[O:17])[NH2:15])[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][O:12][CH2:13][C@@H:14]([C:16]([NH2:18])=[O:17])[NH2:15])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(COC[C@H](N)C(=O)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(COC[C@H](N)C(N)=O)c1
Temperature: 25 °C

Procedure:
To a solution of O-[[3-(methoxycarbonyl)phenyl]methyl]-N-(t-butoxycarbonyl)-L-serinamide (2.4 g, 6.82 mmol) in EtOAc (50 mL) at 0° C. is bubbled HCl gas at a moderately vigorous rate for 5 minutes, during which time a lot of white precipitate is observed. The mixture is warmed to room temperature over 30 minutes, after which time EtOAc is removed, yielding O-[[3-(methoxycarbonyl)phenyl]methyl]-L-serinamide.HCl as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]([O-])=[CH:8][C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.[F:20][C:21]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][C:22]=1[C:23]#[N:24]>C(O)(=O)C>[C:23]([C:22]1[CH:25]=[C:26]([N:29]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[N:30]2)[CH:27]=[CH:28][C:21]=1[F:20])#[N:24]
Reactant: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Reactant: N#Cc1cc(NN)ccc1F
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1cc(-c2ccco2)n(-c2ccc(F)c(C#N)c2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
Part A. To lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (13 g, 54 mmol; Example 74, Part A) was added 2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL of glacial acetic acid. The resulting orange mixture was maintained at rt for 20 h and then concentrated to dryness. The resulting residue was taken up in 30% chloroform in hexanes and filtered to afford tert-butyl 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (18 g, 95%) as a light brown solid. LC/MS (ESI+): 354.2 (M+H)+. 1H NMR (CDCl3) δ 7.64-7.78(m, 3H), 7.42 (s, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 6.30 (s, 1H), 1.61 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:8]2=[O:23])=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:27][CH3:26])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:8]2=[O:23])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2cccc(C#N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
According to Scheme 2 Step 4: To a stirred solution of 3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile (0.300 g, 0.72 mmol) in DMF (5 ml) was added, dropwise, at 0° C., 2M solution of sodium methoxide (0.72 mmol, 0.359 ml). The mixture was stirred 1 hour at 0° C. then quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, DCM 100%. 150 mg (Yield=57%) of 3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)benzonitrile were recovered and used for the next step.