Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[N:28][N:29]=4)[N:26]=3)[N:9]=2)=[CH:4][CH:3]=1.NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1.[CH:58]1([C:61](Cl)=[O:62])[CH2:60][CH2:59]1>>[CH:58]1([C:61]([CH2:20][NH:19][C:15]2[CH:14]=[C:13]([C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([CH:27]=[N:28][N:29]=5)[N:26]=4)[CH:11]=3)[CH:18]=[CH:17][N:16]=2)=[O:62])[CH2:60][CH2:59]1
Reactant: CNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Reactant: O=C(Cl)C1CC1
Agent: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(CNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CC1
Yield: 79.4 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 100 mg (0.26 mmol) of 3-(4-fluorophenyl)-4-(2-methylaminopyridin-4-yl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 13-2) in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 81.2 mg (0.78 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 93.8 mg of the title compound as a pale yellow-powder. (Yield: 80%)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[NH:6]2.[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:29][C@@H:28]([NH2:40])[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(O)C>[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:29][C@@H:28]([NH:40][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[NH:6]3)[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc3[nH]c(-c4cccc(Cl)c4)nc23)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 83.5 %

Procedure:
A solution of 6-chloro-8-(3-chlorophenyl)-9H-purine (155 mg, 0.58 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (200 mg, 0.56 mmol) (Example 128, steps a-c), and N,N-diisopropylethylamine (0.20 mL, 1.17 mmol) in ethanol (2.00 mL) was microwaved at 160° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (275 mg, 76%) as a light yellow solid.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCC>[CH2:28]([C:29]1([CH2:30][CH2:31][CH2:32][CH3:33])[C:3]2[NH:2][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH2:11][C@H:12]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH:13]1)[CH2:27][CH2:26][CH3:25]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)cs1
Reactant: CCCCC(=O)CCCC
Agent: Cl
Solvent: CCCCO
Product: CCCCC1(CCCC)N[C@@H](c2nc(-c3ccccc3)cs2)Cc2c1[nH]c1ccccc21
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1,3-thiazol-2-yl)-1-ethanamine hydrochloride (210 mg, 0.59 mmol) in n-butanol (15 ml) was added 0.45 ml (2.5 mmol) of 5-nonanone. The mixture was heated under reflux for about two hours and then 5 ml of n-butanol was removed by Dean-Stark. Reflux was continued for about 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between 15 ml ethyl acetate and 15 ml 10% NaHCO3 solution. After decantation the organic layer was washed with water and dried over MgSO4. Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate 97:3). The pure fractions were collected and concentrated. The residue was dissolved in diethyl ether, and 1N HCl in ethyl acetate was added. The hydrochloride was collected by filtration and washed with diethyl ether to give 85 mg of the title product as an orange powder. Melting point: 134-136° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=4[C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[CH:8]=1)C.[OH-].[K+]>C1COCC1.O>[CH2:22]([C:21]1[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])[CH:16]=[CH:15]2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCc1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1c(-c2ccc3cc(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, [6-(3-Pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.34 g, 0.82 mmol), was hydrolyzed with potassium hydroxide (0.50 g, 8.9 mmol) in THF (20 mL) and water (10 mL). The title compound was obtained as an off-white solid (0.28 g), mp 163-165° C. Mass spectrum (+APCl, [M+H]+) m/z 389. 1HNMR (400 MHz, DMSO-d6): δ13.15 (br s, 1H), 8.24 (s, 1H), 7.99 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.8 Hz), 7.85 (dd, 1H, J=8.5, 1.7 Hz), 7.69-7.66 (m, 1H), 7.59 (d, 1H, J=7.8 Hz), 7.35-7.25 (m, 4H), 4.82 (s, 2H), 2.98 (t, 2H, J=7.6 Hz), 1.72 (p, 2H, J=7.3 Hz), 1.42-1.27 (m, 4H), and 0.83 ppm (t, 3H, J=7.1 Hz). Elemental Analysis for C25H24O4.0.4H2O: Calculated: C, 75.89; H, 6.32; N, 0.00. Found: C, 75.9; H, 6.07; N, 0.17.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:46]=[CH:45][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[C:24]2=O)=[CH:20][CH:19]=1.[OH-].[Na+]>C1(C)C=CC(C)=CC=1.O>[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[C:24]2=[S:2])=[CH:45][CH:46]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cn2c(=S)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Phosphorus pentasulfide (444 mg, 1.0 mmol) was added to a suspension of N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (7) (300 mg, 0.61 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 10 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. The reaction mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 2:1), the desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-thioxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (8) (162 mg, 52% of theory, mp: 167-170° C.) was obtained. After recrystallizing from methanol, there were obtained crystals having a melting point of 175-179° C.
Reaction SMILES: [Br:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]([CH3:17])([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]1[CH:18]([CH3:20])[CH3:19].C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:28]([O:7][C:6]1[N:5]([C:8]([CH3:16])([CH3:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=[C:3]([CH:18]([CH3:20])[CH3:19])[C:2]=1[Br:1])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C1=NN(C(C)(C)Cc2ccccc2)C(=O)C1Br
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nn(C(C)(C)Cc2ccccc2)c(OC(=O)c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
4-Bromo-3-isopropyl-1-(2-methyl-1-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (3.00 g, 8.90 mmol) was dissolved in 39 mL of tetrahydrofuran and cooled with ice to 0° C., and after dropwise addition of 1.80 g (17.8 mmol) of triethylamine and 1.38 g (9.82 mmol) of benzoyl chloride, stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with distilled water, and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 12 g, ethyl acetate:hexane=1:20) to give 3.34 g of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.080 g, 0.17 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.026 mL, 0.19 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD71a, AD71b, and AD71c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD71a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD71b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD71c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([C:25]([C:30]2[N:31]=[CH:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:34]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:19]=[CH:18]3)C2C=CC=CC=2)C=CC=CC=1.NC1C=C2C(=CC=1)C=C(C(C1N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=1)(O)C(C)C)C=C2.[CH3:94][S:95](Cl)(=[O:97])=[O:96].[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[OH:29][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([NH:14][S:95]([CH3:94])(=[O:97])=[O:96])[CH:24]=[CH:23]2)([C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(O)(c1ccc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C(O)(c1ccc2cc(N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1ccc2cc(NS(C)(=O)=O)ccc2c1)c1c[nH]cn1
Reaction time: 0.5 h

Procedure:
In a similar manner to that described in Example 51-(ii), a reaction was carried out by using 1-{6-[(diphenylmethylene)amino]naphthalen-2-yl}-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g) to give crude product containing 1-(6-aminonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol as a pale yellow oily substance. The crude product was dissolved in dichloromethane (10 ml). To the solution were added pyridine (0.71 ml) and methanesulfonyl chloride (0.34 ml) under ice cooling, and the mixture was stirred for 30 min. To the mixture was added 0.1N-aqueous solution of sodium hydroxide, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent, hexane:ethyl acetate=1:1) to give the titled compound (1.16 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH:23]=[CH:22]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:23]2[C:24](=[O:25])[O:26][C:21](=[O:27])[CH:22]2[C:18]2[C:17]3[CH:16]=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)OC(=O)C1C(c1ccccc1Cl)C3

Procedure:
A solution of trans-diene (27) (0.30 g, 1.06 mmol) prepared as described in example 37 and maleic anhydride (0.16 g, 1.59 mmol) in xylene (30 mL) were heated at reflux for 18 hours, before being concentrated in vacuo and chromatographed on silica eluting with ethyl acetatelhexane (1:2). Crystallisation from ethyl acetate/hexane then gave anhydride (286) (0.29 g, 72%) as a pale brown powder, mp 189–191° C. 1H NMR δ (CD3)2SO] 11.16 (br s, 1H), 7.69 (dd, J=7.7, 1.4 Hz, 1H), 7.51 (dd, J=7.7, 1.4 Hz, 1H), 7.43 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.36 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.77 (dd, J=8.6, 2.4 Hz, 1H), 4.70 (d, J=7.7 Hz, 1H), 4.47 (dd, J=7.7, 3.5 Hz, 1H), 3.78 (s, 3H), 3.71–3.66 (m, 1H), 3.36 (dd, J=15.9, 13.0 Hz, 1H), 2.99 (dd, J=15.9, 4.1 Hz, 1H). Found: C, 65.85; H, 3.95; N, 3.70. C21H16ClNO4 requires: C, 66.06; H, 4.22; N, 3.67.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19][C:20]([OH:22])=[O:21])[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](O)([CH3:34])([CH3:33])[CH3:32].C(=NC(C)C)=NC(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][C:20]([O:22][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:21])[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)(C)O
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (400 mg, 0.928 mmol) in CH2Cl2 (2 mL) was added tert-butyl alcohol (3.44 mg, 4.64 mmol) and DMAP (91 mg, 0.744 mmol) at room temperature (about 22° C.). The solution was cooled to 0° C. and N,N′-methanediylidenedipropan-2-amine (172 uL, 1.11 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 h, and then loaded directly onto a SiO2 column and purified by flash chromatography (hexanes/EtOAc gradient) to give the title compound (380 mg, 84%) as a white solid: mp 170-172° C.; 1H NMR (400 MHz, CDCl3) δ 5.44-5.15 (m, 2H), 5.08-4.94 (m, 1H), 4.93-4.75 (m, 2H), 3.74-3.54 (m, 1H), 2.98-2.87 (m, 1H), 2.83-2.71 (m, 1H), 2.61 (hept, J=7.0 Hz, 1H), 2.32-2.21 (m, 1H), 1.44 (s, 9H), 1.40 (s, 9H), 1.27 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 1.6 Hz, 6H); ESIMS m/z 410 ([M+Na]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:12].[C:25](Cl)(=[O:30])[CH2:26][C:27](Cl)=[O:28]>O1CCCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[O:12])[C:25](=[O:30])[CH2:26][C:27](=[O:28])[NH:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(N(C(=O)CNc2ccc(F)cc2N)C(C)C)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3cc(F)ccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A solution of 1.724 g of 2-(2-amino-4-fluoro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (5.20 mmol) in 15 mL of tetrahydrofuran was transferred to an addition funnel. A solution of 0.506 mL of malonyl dichloride (5.20 mmol, 1.0 equiv) in 15 mL tetrahydrofuran was transferred to a separate addition funnel. Each solution of each reagent was simultaneously added dropwise over 30 min. to 100 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring for 20 min. at ambient temperature, an additional 0.506 mL of malonyl dichloride (5.20 mmol, 0.1 equiv) was added in a single portion. The reaction was allowed to stir an additional 2.5 hrs. and then evaporated in vacuo to a residue. The residue was purified on flash grade silica gel with 1:3 ethyl acetate/hexane followed by 3:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a residue and triturated with hexane. The hexane was removed in vacuo and the residual solid was dried under high vacuum to provide 1.061 g of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3) d 8.14 (b, 1H), 7.45 (dd, 1H, J=5.5. 9.2), 7.29 (m, 1H), 7.05 (m, 1H), 6.94 (m, 3H), 6.78 (m, 1H), 4.99 (m, 1H), 4.37 (d, 1H, J=16.4), 3.82 (s, 3H), 3.69 (d, 1H, J=16.0), 3.40 (m, 2H), 1.09 (d, 6H, J=6.8); low resolution MS (FAB)m/e 400 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butoxycarbonylaminophenylacetic acid (4.0 mmol) in CH2Cl2 (8.0 mL) is added morpholine (4.0 mmol), EDCl—H2O (4.8 mmol) and DMAP (0.40 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting solid is triturated with ether-n-hexane to give the title compound; 1H NMR (CDCl3) δ 1.41 (s, 9H), 3.08-3.12 (m, 1H), 3.20-3.28 (m, 1H), 3.39-3.45 (m, 1H), 3.49-3.60 (m, 3H), 3.66-3.76 (m, 2H), 5.54 (d, 1H), 6.01 (d, 1H), 7.29-7.36 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][C:71](=[O:89])[NH:72]/[C:73](/[NH:85][CH2:86][CH:87]=[CH2:88])=[N:74]\[C:75](=[O:84])[O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:77]([O:76][C:75]([NH:74][C:73]([NH:85][CH2:86]/[CH:87]=[CH:88]/[C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([CH3:54])=[CH:42][C:41]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C@@H:13]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C@H:9]3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:45]=2)=[CH:48][CH:49]=1)=[N:72][C:71]([O:70][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:89])=[O:84])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: C=CCN/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Yield: 45.4 %

Procedure:
To an acetonitrile solution (3 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (271 mg, 0.305 mmol) were added dibenzyl[(Z)-(allylamino)methylylidene]biscarbamate (335 mg, 0.914 mmol), palladium(II) acetate (18 mg, 0.0791 mmol), tri-O-tolylphosphine (61 mg, 0.201 mmol) and triethylamine (154 mg, 1.52 mmol), and reacted at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (163 mg, 46%) as a pale yellow amorphous compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][C:41]([CH3:43])=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[O:27]1[C:31]2([CH2:32][CH2:33][CH:34]([N:37]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:39]4[N:40]=[C:41]([CH3:43])[N:42]=[C:38]34)[CH2:35][CH2:36]2)[O:30][CH2:29][CH2:28]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 200 °C
Reaction time: 48 h
Yield: 36.4 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (44 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (15 g) and N,N-diethylaniline (100 mL) was stirred at 200° C. for 48 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (12 g, 36%).