Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.O.[CH3:26][N:27](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=2)[C:26]#[N:27])=[O:9])=[CH:11][CH:12]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)c2cncc(C#N)c2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (284 mg, 0.246 mmol) to a solution of (5-bromo-pyridin-3-yl)-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanone (1.0 g, 2.46 mmol) and zinc cyanide (578 mg, 4.92 mmol) in dimethylformamide (25 mL) and stir. Purge solution with nitrogen and heat to 80° C. After 18 hours, add water (100 mL) and extract with ethyl acetate. Combine organic layers, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue with flash chromatography eluting with 12.5% ethyl acetate:hexanes to yield the title compound as a white solid (550 mg, 63%): 1H NMR (DMSO-d6) δ 0.11 (s, 6H), 0.93 (s, 9H), 4.84 (bs, 2H), 7.53 (d, 2H), 7.83 (d, 2H), 8.61 (t, 1H), 9.09 (d, 1H), 9.26 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][CH:21]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CCOCC>[C:29]([C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][CH:21]=2)[C:12]([O:14][CH3:15])=[O:13])(=[O:31])[CH3:30]
Reactant: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1ccc(OC)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)C(Cc1cnc2cccc(OC)c2c1)c1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of methyl 2-(3,4-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate CCH 34144-5 (46 mg, 121 μmol) in acetic anhydride (2.0 mL, 21.2 mmol) at 0° C. in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added HClO4 (ca. 70% solution in water, 0.1 mL, 1.2 mmol). The reaction mixture was then allowed to warm up to RT, stirred for 45 min and diluted with Et2O (40 mL). The solid was filtered and washed several times with Et2O giving a brown residue. The residue was then suspended in CH2Cl2 (40 mL) before neutralisation with saturated aqueous NaHCO3 solution. The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave methyl 2-(2-acetyl-4,5-dimethoxyphenyl)-3-(5-methoxyquinolin-3-yl)propanoate CCH 34154 as a yellow solid (30 mg, 59% yield).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([Cl:12])[C:4]=1[F:13].[B:14](OC)([O:17]C)[O:15]C.Cl>C1COCC1.C(O)(=O)C>[Cl:12][C:5]1[C:4]([F:13])=[C:3]([B:14]([OH:17])[OH:15])[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1ccc(Br)c(F)c1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOc1ccc(B(O)O)c(F)c1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4.79 g of well dried magnesium and 50 mL of THF were added to a reactor in a nitrogen atmosphere and heated to 50° C. 50.0 g of the compound (C2) dissolved in 200 mL of THF was added dropwise thereto over 60 minutes in a temperature range of 43 to 48° C., followed by stirring for 60 minutes. The resulting reaction mixture was cooled to 25° C. Thereafter, the reaction mixture was added dropwise to a solution of 24.6 g of trimethyl borate and 100 mL of THF cooled to −50° C. over 60 minutes in a nitrogen atmosphere in a temperature range of −60 to −40° C. The reaction mixture was warmed to 0° C. and then poured into 400 mL of 3N hydrochloric acid at 0° C. 700 mL of acetic acid was added to the solution, followed by mixing, and the mixture was then left to rest to separate into an organic layer and an aqueous layer, followed by extracting. The resulting organic layer was collected and washed with a saturated sodium hydrogen carbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue. The residue was recrystallized from heptane. The recrystallization operation was repeated to obtain 35.9 g of 3-chloro-4-ethoxy-2-fluorophenylboronic acid (b58). The resulting compound (b58) was a yellowish solid.
Reaction SMILES: [O:1]=[C:2]1[NH:15][C:5]2=[N:6][CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH2:3]1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17].C(OCC)C>C(O)(=O)C>[CH2:16]([O:19]/[CH:20]=[C:3]1\[C:2](=[O:1])[NH:15][C:5]2[C:4]\1=[CH:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=2)[CH3:17]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCO/C=C1\C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.040 g, 0.19 mmol) and diethoxymethyl acetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature, and diethyl ether was added to precipitate the title compound as a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 MHz (DMSO-d6): δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: II.[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH:27]=[CH:28]N(C)C)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]2=[O:40])=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:41][C:42]([NH2:44])=[S:43]>C(Cl)Cl.O1CCCC1.O.C(OCC)(=O)C>[NH2:41][C:42]1[S:43][C:27]([C:26]2[CH2:25][S:24][CH:23]3[N:20]([C:21](=[O:40])[CH:22]3[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]=2[C:17]([O:16][CH:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:18])=[CH:28][N:44]=1
Reactant: NC(N)=S
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Agent: II
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reaction time: 2 h

Procedure:
A suspension of iodine (2.54 g) in dry methylene chloride (20 cc) is added, in 5 minutes, to a solution, cooled to -55° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, E-form (5.35 g) in dry tetrahydrofuran (20 cc). The reaction mixture is stirred for 2 hours, whilst allowing the temperature gradually to return to 0° C., and is then treated with distilled water (0.36 cc) and stirred for 2 hours at 5° C. A solution of thiourea (0.57 g) in a mixture of tetrahydrofuran (5 cc) and water (2 cc) is added to 25 cc of this reaction mixture and this mixture is stirred for 16 hours at 25° C. Thiourea (0.57 g) is added, stirring is continued for 3 hours at 25° C., and the mixture is then diluted with ethyl acetate (150 cc). The organic phase is washed successively with distilled water (100 cc), saturated sodium bicarbonate solution (100 cc), distilled water (100 cc) and a half-saturated sodium chloride solution (100 cc). After having dried the mixture over magnesium sulphate, the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is chromatographed on a column (height: 30 cm; diameter: 2 cm) of silica (0.04-0.06 mm), elution being carried out under 0.4 bar (40 kPa) with a 45:55 (by volume) mixture of cyclohexane and ethyl acetate. After evaporation of the solvents, 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (0.08 g) is obtained in the form of an orange froth, whose characteristics are identical to those of the product described below, in Example 2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]([OH:26])=[O:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=1.CCOC(C)=O>CN1C(=O)CCC1>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:37]4[N:42]=[CH:41][C:40]([CH2:43][CH2:44][CH3:45])=[CH:39][N:38]=4)[CH2:22][CH2:23]3)[C:12]([C:24]([OH:26])=[O:25])=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)c1nn(-c2ccc(Cl)c(Cl)c2)c(=O)cc1OC1CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(Cl)c(Cl)c4)nc3C(=O)O)CC2)nc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
To a stirring solution of 1-(3,4-dichlorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid HCl (83 mg, 0.217 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (84 mg, 0.651 mmol) and 2-chloro-5-propylpyrimidine (51 mg, 0.326 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give 1-(3,4-dichlorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylic acid (57 mg, white solid, 52%). MS (ESI) 504 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12](Cl)Cl.[CH2:15]([NH2:19])[CH2:16][CH2:17][NH2:18]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]1[NH:19][CH2:15][CH2:16][CH2:17][NH:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C(Cl)Cl)c1
Reactant: NCCCN
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCN2)c1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(2-Chloro-5-nitrophenyl)carbonimidic dichloride (35.5 g, 140 mmol) was dissolved in tetrahydrofuran (135 mL). The solution was added dropwise within 30 min to a solution of 1,3-propanediamine (58 mL, 700 mmol) in tetrahydrofuran (335 mL) which was kept at 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. another 2 hr at room temperature. The suspension was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The residue was taken up in water, filtered, and washed with water and diisopropyl ether. After drying at 50° C. under vacuum, the title compound (35.0 g, 137.4 mmol, 98%) was obtained as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Yield: 96 %

Procedure:
The title compound is prepared in 96% yield (270 mg, pale brown solid) from 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and 2-chloroacetyl chloride (90 mg, 0.79 mmol) in a similar manner to Example-18 (Method-D).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]2[O:12][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=2)[O:3]1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C@@H:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=2)[O:3][C:2]([CH3:19])([CH3:1])[C@H:11]1[OH:12]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C2OC21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O

Procedure:
A mixture containing 1.9 g of 2,2-dimethyl-3,4-epoxy-6-trifluoroacetylchromane (PREPARATION II), 1.4 g of 2-hydroxypyridine, 5 ml of dioxane and 0.2 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide is refluxed for 20 hours. The residue obtained after concentration under vacuum is taken up with 20 ml of water and the insoluble material is then filtered off and washed with water and boiling isopropyl ether. It is chromatographed on a column of 50 g of silica using a methylene chloride/ethyl acetate mixture (7/3) as the eluent. This gives 0.3 g of dry product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]N(C=O)C>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and Mel (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:49])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:49][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]([CH3:48])[CH:45]=[CH:46][N:47]=3)[S:42][C:35]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 54.9 %

Procedure:
To a solution of the acid (27) (75 mg, 0.36 mmol) and HOBt (54 mg, 0.40 mmol) in DMF (6 mL), was added amine 9 (135 mg, 0.40 mmol). After stirring for 5 min, EDC (84 mg, 0.42 mmol) was added and the reaction mixture was stirred for additional 4 hrs at room temperature. The reaction mixture was poured into NaHCO3 solution, extracted with EtOAc; the organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC (Aquasil C-18 column, gradient MeOH/water from 60:40 to 95:5) to afford 28a (105 mg, 55% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.80 (s, 1H), 9.62 (s, 1H), 8.66 (d. 1H), 8.33 (s, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (m, 2H), 6.89 (m, 2H), 4.03 (s, 3H), 3.84 (s, 3H), 3.66 (s, 2H). MS (m/z): 532.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N+:18]([O-])=O)[C:14](=[O:21])[NH:13][C:12]2=[O:22].O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:18][C:17]1[CH:16]=[C:15]2[C:11]([C:12](=[O:22])[NH:13][C:14]2=[O:21])=[CH:10][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:3][C:2]=1[Cl:1]
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2[N+](=O)[O-])C(=O)NC3=O)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2N)C(=O)NC3=O)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 30.1 (162 mg, 0.42 mmol) in 10 mL of EtOAc was added SnCl2.2H2O (469 mg, 2.1 mmol). The mixture was heated to reflux for 3 h. After cooling to room temperature, the mixture was poured into 20 mL of water. Saturated NaHCO3 was added to adjust the pH value of the mixture to 3. The mixture was filtered through Celite to remove solid precipitates. The filtrate was extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 30.2. MS ESI (pos.) m/e calcd for (M+H)+ 361.1. found 361.0.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](Cl)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[CH:20][CH:21]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 82 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 3-methylpiperazine-1-carboxylate (2.00 g, 9.99 mmol, 1.00 equiv), 1-chloro-4-[chloro(4-chlorophenyl)methyl]benzene (5.46 g, 20.1 mmol, 2.01 equiv), potassium carbonate (6.90 g, 49.9 mmol, 5.00 equiv), acetonitrile (30 mL). The resulting solution was stirred overnight at 82° C. in an oil bath. The resulting solution was diluted with H2O (50 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to yield 1.70 g (53% yield) of tert-butyl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate as a light yellow solid. LCMS: (ESI, m/z): 435 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.C(O[C@@:55]([N:64]=C=O)([CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])[C:56]([NH2:58])=[O:57])C1C=CC=CC=1.Cl.NCC(N)=O>>[NH2:64][C@H:55]([C:56](=[O:57])[NH2:58])[CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42]
Reactant: NCCCC[C@](N=C=O)(OCc1ccccc1)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NCCCC[C@H](N)C(N)=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-benzyloxy-carbonylamino-6-aminohexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CC(C)c1cc(NN)nc2ncccc12
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: CC(C)c1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ncccc12

Procedure:
A 100 mg (0.5 mmol) sample of 2-hydrazinyl-4-isopropyl-1,8-naphthyridine and 94 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate were reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.74 Hz, 6 H) 3.56 (d, J=6.74 Hz, 1 H) 6.82 (s, 1 H) 7.04 (t, J=1.76 Hz, 1 H) 7.23 (dd, J=8.20, 4.40 Hz, 1 H) 7.59 (br. s., 2 H) 8.31 (d, J=1.47 Hz, 1 H) 8.54 (br. s., 1 H) 8.66 (d, J=1.17 Hz, 1 H) 8.99 (br. s., 1 H) 9.25 (br. s., 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.ClCCl.FC(F)(F)C(O)=O>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)[N:10]=3)=[CH:17][C:18]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Yield: 92 %

Procedure:
A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (25 g, 32.6 mmol) in dichloromethane (150 mL, 32.6 mmol) and trifluoroacetic acid (150 mL, 2019 mmol) was stirred at room temperature for 1 h. The solution was concentrated and the residue was dissolved in DCM and carefully neutralized with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (20 g, 30.0 mmol, 92% yield). The crude product was taken on to the next step without purification.