Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(OB(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
After obtaining the supported metal nanoparticles, the catalytic activity was examined using a very popular cross coupling reaction—Suzuki reaction, which is commonly used in the pharmaceutical industry, as shown in FIG. 8. Still referring to FIG. 8, Iodobenzene (0.5 mmol), phenyl boric acid (0.8 mmol) and K2CO3 (1.0 mmol) were added to a 4 mL mixture of a water:ethanol (1:1) solution. Then, the supported nano-Pd on XAD-4 (100 mg) was added, and the reaction mixture was heated to 60° C. for 12 hours. The supported catalyst was recovered by filtration, and the filtrate was extracted by ether. The evaporation of ether furnished the crude product, which was purified by regular flash column chromatography, as known to those of ordinary skill in the art, to yield pure biphenyl in 90% yield. The supported metal nanoparticles could be reused three times without significant activity loss.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:13])[NH:11][CH3:12])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([N:11]([CH3:12])[N:10]([C:8]([C:6]1[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH3:13])=[O:33]
Reactant: COC(=O)Cl
Reactant: CNN(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Solvent: c1ccncc1
Product: COC(=O)N(C)N(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N,N′-dimethyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (250 mg) was dissolved in pyridine (3 mL), methyl chloroformate (150 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 75 μL) was added. After 1 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=1:1, Rf=0.20) to afford 223 mg of compound (9) of the present invention of the formula
Reaction SMILES: [CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][SH:4].[N:15]([O-])=[O:16].[Na+].[OH-].[Na+]>Cl>[CH3:1][C@@H:2]([C:5]([N:7]1[C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8]1)=[O:6])[CH2:3][S:4][N:15]=[O:16]
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](CSN=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
50 mg of Captopril (0.236 mMoles) was dissolved in 10 ml of 0.1 M HCl at room temperature and cooled briefly in an ice bath. A total of 0.25 ml of 1 M NaNO2 was then added in several small portions with rapid swirling. After 2 min on ice, 1.0 ml of 0.5 M Na2HPO4 was added and the solution was adjusted to pH 7.3 with 0.1 M NaOH. The solution displayed absorption maxima at 542 nm (E=19.8 M-1 cm-1) and 330 nm (E=995 M-1 cm-1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([NH:20][NH2:21])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=S)OC2C(F)=C(F)C(F)=C(F)C=2F)[CH:29]=[CH:30][CH:31]=1)[CH3:24].C1N=CN(C(N2C=NC=C2)=O)C=1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:18]3[O:19][C:33]([NH:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=4)=[N:21][N:20]=3)=[O:22])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOc1cccc(NC(=S)Oc2c(F)c(F)c(F)c(F)c2F)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOc1cccc(Nc2nnc(C(=O)Nc3ccc(N4CCN(C(C)=O)CC4)cc3)o2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
N-[4-(4-Acetylpiperazin-1-yl)phenyl]-2-hydrazino-2-oxoacetamide (Intermediate 21, 153 mg, 0.5 mmol) was added to a solution of O-(pentafluorophenyl) (3-ethoxyphenyl)thiocarbamate (Intermediate 48, 182 mg 0.5 mmol) in DMF (7 mL). The mixture was stirred at 60° C. for 30 min then PS-CDI (500 mg 1.0 mmol) was added and stirring was continued for a further 2 hours. The mixture was allowed to cool then filtered to remove the resin, which was washed with a further 2×10 mL DMF. The combined filtrates were concentrated by evaporation to give a solid that was then triturated with 1:1 acetonitrile:water to give the title compound (220 mg) as a solid; 1H NMR δ 10.95 (1H, s), 10.85 (1H, s), 7.67 (2H, d), 7.33-7.22 (2H, m), 7.12 (1H, d), 6.97 (2H, d), 6.64 (1H, d), 4.04 (2H, q), 3.65-3.51 (4H, m), 3.11 (4H, d), 2.07 (3H, s), 1.35 (3H, t); MS m/e MH+ 451.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.[Cl-]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC

Procedure:
A mixture of 13.7 g of 2-amino-4,5-dimethoxybenzamide, 8.1 g of triethylamine, 13.8 g of 4-chlorobenzoyl chloride and 300 ml of methylene. chloride was stirred for 2 h without cooling. The precipitate was filtered off with suction, stirred with water, filtered off with suction and dried under reduced pressure. Yield: 22.5 g. M.p.: 243° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[N:26][C:25]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[C@H:30]([CH3:41])[CH2:29]2)=[CH:24][CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[N:27]=[N:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][C@H:30]([CH3:41])[CH2:29]5)=[CH:24][CH:23]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nn2)CCN1
Yield: 12 %

Procedure:
Compound 408 was prepared from compound 245 and compound 11 using chemistry similar to that described in example 4. The two step yield is 12%. 1H NMR (500 MHz, CD3OD) δ ppm 9.48 (1 H, s), 8.10-8.14 (2 H, m), 8.00 (1 H, d, J=10 Hz), 8.05 (1 H, d, J=10 Hz), 5.66 (1 H, t, J=9.0 Hz), 4.43-4.49 (2 H, m), 3.52-3.62 (2 H, m), 3.29-3.48 (2 H, m), 3.20 (1 H, dd, J=14.4, 10.8 Hz), 2.45 (2 H, ddd, J=9.2, 7.0, 4.5 Hz), 2.13-2.27 (4 H, m), 1.87-1.88 (2 H, m), 1.46 (3 H, d, J=6.6 Hz); LCMS-ESI (POS), M/Z, M+1: Found 448.1, Calculated 448.2
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CO>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:15]([CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
Into a round bottom flask was combined 5-nitro-isochromen-1-one (3.50 g, 0.0165 mol), (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (4.12 g, 0.0206 mol) and methanol (100.0 mL, 2.469 mol). The mixture was heated at reflux for 2 hours. The mixture was allowed to cool and the volatiles were removed under reduced pressure. The crude oil was chromatographed using a methylene chloride:methanol (0-10%) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([NH:16][S:17]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)(=[O:19])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)COc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To the mixture of 6-chlorooxindole (3.05 g, 10 mmol) and N-tert-butyl-C-(4-chloro-2-formyl-phenoxy)-methanesulfonamide (1.65 g, 10 mmol)) in methanol (20 mL) was added pyrrolidine (1.41 g, 20 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound (4 g).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH2:17][CH2:18][CH2:19][CH:20]([N:21]=[C:22]=[O:23])[C:13]1=2>C(Cl)Cl>[CH3:2][O:3][NH:4][C:22]([NH:21][CH:20]1[C:13]2[S:12][CH:16]=[CH:15][C:14]=2[CH2:17][CH2:18][CH2:19]1)=[O:23]
Reactant: O=C=NC1CCCc2ccsc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCCc2ccsc21

Procedure:
A mixture of methoxyamine hydrochloride (5 g.) in 60 ml. of methylene chloride is stirred and 6 g. of triethylamine in 15 ml. of methylene chloride is added slowly. After half an hour of stirring, 5.4 g. of 4,5,6,7-tetrahydrobenzo[b]thien-7-yl isocyanate is added dropwise. The mixture is stirred at room temperature for an hour and filtered. The filter cake is washed with water and dried to afford the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(Cl)Cl>[SH:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCOCC
Product: O=c1c2ccccc2nc(S)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500-ml, three-neck round bottom flask, equipped with magnetic stirrer, 25 g (0.17 moles) methyl anthranilate in 100 ml methylene chloride was placed. Into that mixture 23.0 g (0.17 moles) phenyl isothiocyanate in 50 ml methylene chloride was dropped in. The reaction mixture was stirred overnight (at ambient temperature). The reaction mixture was refluxed at 40° C. for one hour. Ether (about 50 ml) was added; a precipitate formed which was removed by suction filtration to give the above-identified product.
Reaction SMILES: Cl.CN(C)[CH2:4][CH2:5][CH2:6][N:7]=C=NCC.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N)CC1>C(Cl)Cl.CCOCC>[CH:6]1([NH:7][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:22])[CH2:4][CH2:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CNC(=O)OCc1ccccc1)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
23.1 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) are added while stirring to 24 g of N-benzyloxycarbonyl-glycine and 8 ml of cyclopropylamine in 240ml of methylene chloride and the mixture is stirred at room temperature for 4 hours. The mixture is taken up in ether and washed with 1N hydrochloric acid, with bicarbonate solution and with water. After drying and evaporating the ether phase there are obtained 23 g of benzyloxycarbonylamino-acetic acid cyclopropylamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][NH:13]1)=[O:11].O([CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])S(C(F)(F)F)(=O)=O>O.C(Cl)Cl>[C:33]1(=[O:42])[N:32]([CH2:31][CH2:30][N:13]2[CH2:14][C@@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C@@H:12]2[C:10]([O:9][CH3:8])=[O:11])[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]12
Reactant: O=C1c2ccccc2C(=O)N1CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(=O)OC)N(CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a well-stirred bi-phasic mixture consisting of sodium carbonate (500 g, 4.72 mol) in water (3 liters) and trans-2,5-piperidine dicarboxylate dimethyl ester hydrochloride (280 g, 1.18 mol) in methylene chloride (4.5 liters), a solution of 2-phthalimido-ethyl triflate (417 g, 1.29 mol) in methylene chloride (3 liters) was added in a steady stream over a 3 hour period. The organic layer was separated, and the aqueous layer was extracted with fresh methylene chloride (3 liters). The combined organic extracts were washed with water (3 liters), then with brine (3 liters), dried with anhydrous magnesium sulfate and finally, concentrated in vacuo to a solid. The entire residue was triturated in refluxing ether (3 liters), with vigorous stirring, for 15 minutes. After cooling to ambient temperature, the solution was poured into hexanes (3 liters), and the resulting mixture was stirred for 18 hours. The resulting colorless solid was collected by filtration, and the filter cake was washed with hexanes (1 liter). In vacuo drying afforded 437.3 g (99.1% yield) of the title compound as a colorless solid. TLC Rf (ethyl acetate/methylene chloride=1:1 in volume; iodoplatinate spray): 0.5.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16].O>CN(C)C=O>[C:2](=[N:4][O:5][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16])([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: COCOc1cccc(F)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cccc(ON=C(C)C)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Acetone oxime (11.14 g, 0.1524 mole) was dissolved in 300 ml of dry dimethyl formamide (DMF) and then potassium t-butoxide (17.0 g, 0.152 mole) was added portionwise. The reaction mixture was allowed to stir for 30 minutes at room temperature and the 2-fluoro-6-methoxymethoxybenzonitrile of Example 1(b) (23.0 g, 0.127 mole) was added in 150 ml of DMF. After 30 minutes the reaction mixture was poured into 1000 ml of water and stirred well as the product crystallized. The product was filtered off, washed well with water, and then taken up in CH2Cl2 and dried with magnesium sulfate. Concentration and recrystallization from methanol-water gave 20.5 g (69%) of 2-[(isopropylideneamino)oxy]-6-methoxymethoxybenzonitrile as fine needles, mp 62°-64° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:20])[NH:11][O:12][CH:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:14].O.[OH-].[Li+]>C1COCC1>[CH2:16]([O:15][CH:13]([O:12][NH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])[CH3:14])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)CCCCCCC(=O)NOC(C)OCC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(C)ONC(=O)CCCCCCC(=O)O
Yield: 828.3 %

Procedure:
7-(1-Isobutoxy-ethoxycarbamoyl)-heptanoic acid methyl ester (36.6 g, 12.1 mmol, 1.0 eq) was stirred in THF (200 mL) and water (200 mL) in the presence of lithium hydroxide (8.68 g, 36.2 mmol, 3.0 eq) for 3 h at 50° C. THF was evaporated under vacuum and to the mixture water (100 mL) and ethyl acetate (200 mL) were added. The mixture was acidified cautiously to pH 3 by addition of 1N HCl. The organic phase was isolated and the aqueous layer re-extracted with ethyl acetate (150 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as a white solid (29.0 g, 83% yield), m/z 288 [M++H]+ and used in stage 4 without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:10]([N+:28]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:31])[CH2:3]1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:10]([NH2:28])[CH:9]=2)=[N:6][NH:5][C:4](=[O:31])[CH2:3]1
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1N

Procedure:
10 gm of 5-methyl-6-(3-nitro-4-undecane carbonylamino-phenyl)-4,5-dihydro-2H-pyridazine-3-one were dissolved in 100 ml of dimethylformamide, and the solution was treated in the presence of 1 gm of 10% palladium charcoal with hydrogen for 1.2 hours at a pressure of 5 bar. After filtering off of the catalyst, the mixture was poured on ice and extracted with methylene chloride, and the organic phase was evaporated. The oily residue was further processed directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C=O)=[CH:8][CH:7]=[CH:6]2.[CH2:15]1COC[CH2:16]1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:15]=[CH2:16])[CH:7]=[CH:6]2
Reactant: C1CCOC1
Reactant: COc1ccc2c(C=O)cccc2c1
Solvent: CCOCC
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
6-Methoxy-naphthaldehyde (432 mg, 2.35 mmol) is added to a solution of instantaneous ylide (Ph3P+Br−+NaNH2, 1.48 g, 2.4 mmol) in anhydrous THF (5 ml). After one hour of stirring at ambient temperature, it is diluted with ether, it is filtered on Celite, and it is chromatographed (hexane/AcOEt 5:1) to obtain 6-methoxy-2-vinyl-naphthalene (390 mg, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2].B(Br)(Br)Br>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6])#[N:2]
Reactant: COc1ccc(C#N)c(C(N)=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(O)cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-cyano-5-methoxybenzamide (5.2 g, 0.027 mol) in methylene chloride is cooled to 0° C., treated dropwise with boron tribromide (54 mL of a 1M solution in methylene chloride), stirred at 0° C. for 30 minutes, stirred at room temperature for 1 hour, refluxed for 4 hours, cooled to 0° C., treated with additional boron tribromide (54 mL of a 1M solution in methylene chloride), refluxed for 17 hours, cooled to room temperature and diluted with water. The aqueous mixture is filtered to obtain a solid which is washed sequentially with water and ether and dried to give the title product as a beige solid, mp 268°-270° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[CH:28]=[N:27][N:26]([S:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:23]4=[N:24][CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[O:9])[N:7]=1.[CH3:47][C@H:48]1[O:53][C@@H:52]([CH3:54])[CH2:51][NH:50][CH2:49]1>>[CH3:54][C@H:52]1[O:53][C@@H:48]([CH3:47])[CH2:49][N:50]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[C:22]5[CH:28]=[N:27][N:26]([S:29]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)(=[O:31])=[O:30])[C:23]5=[N:24][CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][N:15]4[S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])=[O:9])[N:7]=2)[CH2:51]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Product: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cnc5c(cnn5S(=O)(=O)c5ccccc5)c4)cc4c3cnn4S(=O)(=O)c3ccccc3)cs2)C[C@H](C)O1
Temperature: 90 °C
Yield: 167.2 %

Procedure:
2-(Chloromethyl)-N-{1-(phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-yl}-1,3-thiazole-4-carboxamide (53 mg, 0.077 mmol) and (2R,6S)-2,6-dimethylmorpholine (0.5 ml, 0.077 mmol) were placed in a microwave vial and heated in a microwave at 90° C. for 15 min, allowed to cool, then heated again in the microwave at 90° C. for 15 min. A further portion of (2R,6S)-2,6-dimethylmorpholine (0.3 ml) was added and the mixture was heated in the microwave at 90° C. for 30 mins. Volatiles were removed under a stream of nitrogen to give the title compound as a pale yellow solid (99 mg). The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([OH:17])[CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([O:17][CH3:35])[CH2:15][CH2:14][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(OC[C@H]2OCC[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2OCC[C@@H]2OC)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
The product from Example 22C (620 mg, 1.47 mmol) in DMF (5 mL) was treated with NaH (60%)(88 mg, 2.2 mmol). The mixture was stirred for 10 min at rt. To the mixture was added dropwise iodomethane (251 mg, 1.57 mmol). The reaction was stirred at rt for 12 hrs. The reaction mixture was quenched with water and extracted with EtOAc. The organic was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 574 mg (90%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.91-2.02 (m, 2H) 3.09 (dd, J=9.82, 5.52 Hz, 1H) 3.15 (dd, J=9.82, 4.91 Hz, 1H) 3.31 (s, 3H) 3.78 (s, 6H) 3.81-3.93 (m, 2H) 3.94-4.06 (m, 2H) 6.77-6.87 (m, 4H) 7.16-7.23 (m, 1H) 7.26-7.37 (m, 6H) 7.40-7.48 (m, 2H).