Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[NH:40][C:41](=[O:43])[CH3:42]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:29]4[CH:28]=[CH:27][C:26]([NH:40][C:41](=[O:43])[CH3:42])=[C:25]([O:24][CH3:23])[CH:30]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(C)=O
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2ccc(N3CCN(C4CC4)CC3)nn2)ccc1NC(C)=O

Procedure:
The title compound was prepared from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine (4.6 g, 19.3 mmol), 1 M sodium carbonate solution (50 mL, 100.5 mmol), acetonitrile (50 mL), bis(triphenylphosphine)palladium(II)chloride (0.68 g, 0.96 mmol) and N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (6.73 g, 23.1 mmol), yield 3.39 g (40%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=O.C1(NC(C2C=CC3NC(N4C=C(C(O)=O)C=N4)=NC=3C=2)=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O.C1COCC1>[Cl:12][C:10]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]2[CH:19]=[CH:20][C:5]([CH2:3][OH:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COCCOCn1c(Cl)nc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: O=C(O)c1cnn(-c2nc3cc(C(=O)Nc4ccccc4)ccc3[nH]2)c1
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2cc(CO)ccc21
Temperature: 23 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a stirred solution of 2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (Intermediate from EXAMPLE 120, product of Step C) (0.500 g, 1.67 mmol) and THF (30 mL) was added lithium aluminum hydride (2M in THF, 0.836 mL) dropwise over 10 min at 0° C. The reaction mixture was stirred for 48 h, warming to 23° C. The reaction mixture was cooled to 0° C. water (20 mL) was added and the resulting mixture was acidified with 1M HCl. The product was extracted with EtOAc (3×40 mL) and the combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-80% EtOAc/hexanes) to yield the titled compound (0.356 g, 78%) as a 1:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C12H15ClN2O3, 270.1; m/z found, 271.1 [M+H]+. 1H (600 MHz, CDCl3): 7.65-7.61 (m, 2H), 7.52 (s, J=0.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.3 Hz, 1.5 Hz, 1H), 7.27 (dd, J=8.2 Hz, 1.5 Hz, 1H), 5.63 (s, 2H), 5.62 (s, 2H), 4.81 (s, 2H), 4.77 (s, 2H), 3.64-3.60 (m, 4H), 3.49 (dd, J=5.4 Hz, 3.6 Hz, 4H), 3.35 (s, 3H), 3.34 (s, 3H), 2.59 (s, 1H), 2.50 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][CH:5]([N:7]([C@@H](C2C=CC=CC=2)C)C(=O)OCC2C=CC=CC=2)[CH:4]([NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH2:3]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:7][CH:5]1[CH2:6][C:2]([F:1])([F:34])[CH2:3][CH:4]1[NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28]
Reactant: C[C@H](c1ccccc1)N(C(=O)OCc1ccccc1)C1CC(F)(F)CC1NS(=O)(=O)C(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1N

Procedure:
A solution of benzyl N-[4,4-difluoro-2-(2-methylpropane-2-sulfonamido)cyclopentyl]-N-[(1R)-1-phenylethyl]carbamate (130 mg, 0.26 mmol) and palladium hydroxide on carbon (20%, 100 mg, 0.14 mmol) in methanol (3.5 ml) was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:24]>>[CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]([Cl:24])=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(C3CCCCC3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc2nc(Cl)n(C3CCCCC3)c2n1
Temperature: 80 °C

Procedure:
3-Cyclohexyl-2-hydroxy-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate (0.4 g, 1.285 mmol) and POCl3 (2.395 ml, 25.7 mmol) were placed in a sealed tube and heated to 80° C. for 48 h. The volatiles were removed under reduced pressure. The residue was dissolved in aqueous NaHCO3 giving a basic solution. The solution was further diluted with water and extracted with EtOAc. The combined organics was dried over MgSO4 and concentrated to give the title compound without further purification. LCMS m/z=330.30 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:24])[C:20]([CH3:23])([CH3:22])[CH3:21].O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)CN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NCC(C)(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
In 0.5 ml of acetonitrile were dissolved 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 740 mg (8.49 mmol) of neopentylamine, and the resulting solution was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 215 mg (yield: 72.2%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[NH2:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23].O1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
6 g (30 mmol) of 1-chloro-2,6-dinitrobenzene and 4.8 g (30 mmol) of 4-aminoresorcinol hydrochloride were added to 300 ml of a mixture of tetrahydrofuran with dimethylformamide (1:1). After adding 7.8 g (60 mmol) of N,N-diisopropylethylamine thereto, the obtained mixture was stirred at room temperature for 24 hours. Then the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then it was dried over magnesium sulfate and concentrated and the residue was purified by silica gel column chromatography. Thus 6.95 g of 4-((2,6-dinitrophenyl)amino) resorcinol was obtained. This product was dissolved in 125 ml of dimethylformamide and 25 ml of N,N-diisopropylethyl-amine was added thereto. After heating at 100° C. for 2 hours, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus 5.4 g of the title compound was obtained.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:19]([Si:16]([CH3:18])([CH3:17])[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (15.3 g, 225 mmol) was added to a solution of 4-hydroxyindole (20 g, 150 mmol) in 300 mL of anhydrous methylene chloride at ambient temperature. The resulting mixture was treated with tert-butyldimethylsilyl chloride (25 g, 165 mmol). After stirring overnight at ambient temperature, the reaction mixture was poured into 300 mL of water. The layers were separated, and the aqueous phase was extracted with methylene (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to a black oil. The crude residue was purified on a Prep 500 (silica gel; 0% to 5% ethyl acetate/hexanes) to give the title compound as a light purple waxy solid in quantitative yield. MS (ion spray, NH4OAc) m/e [M+1]+ 248, [M−1]− 246.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 4-nitrobenzenesulfonyl chloride 40 g 0.181 mole in dichloromethane 400 ml was added over 30 mins a solution of pyridine 15 g 15.3 ml and piperidine 16.15 g 18.8 ml in dichloromethane 100 ml. The mixture was stirred at room temperature for 2 h and then washed with water, 2M hydrochloric acid and brine, dried MgSO4 and evaporated in vacuo to give 1-(4-nitro-benzenesulfonyl)-piperidine 44.5 g. 1HNMR CDCl3 7.76 (2H, d), 7.40 (2H, d), 3.21 (6H, q), 1.07 (6H, t).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(F)cc1F
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,4-difluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=435.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1C=CC=CC=1.ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:21][CH:18]1[CH2:20][CH2:19]1)=[O:7]
Reactant: NC1CC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred, cooled (ice bath) solution of 3-bromo-4-methyl-benzoic acid (Aldrich, 5 g, 23.25 mmol) in benzene (50 mL), dichloromethane (10 mL) and N,N-dimethylformamide (0.5 mL) was treated with oxalyl chloride (4 mL, 46.5 mmol). The reaction mixture was allowed to warm to ambient temperature over 3 h. The volatiles were then distilled off in vacuo, the residue was diluted with anhydrous dichloromethane (50 mL) under argon, cooled (ice bath) and treated with 4-(dimethylamino)pyridine (5.67 g, 46.5 mmol) followed by cyclopropyl amine (1.93 mL, 27.9 mmol). After 3 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title product that was used as such for the next step (6.0 g, ˜100%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[CH2:13]([S:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:20])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)[N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(SCc2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(SCc2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 212B and (3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 8.32-8.35 (m, 1H), 7.91-8.02 (m, 3H), 7.39-7.41 (m, 2H), 7.24-7.27 (m, 3H), 7.14-7.18 (m, 3H), 4.34 (s, 2H), 3.79 (s, 2H); MS (DCI+) M/Z 455 (M+NH4)+.
Reaction SMILES: [ClH:1].[O:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)=[CH:9][CH:8]=2)=[N:3]1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[O:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:18][NH:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(-c3ncon3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1nc(-c2ccc([C@H]3CNCCN3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Hydroxylamine hydrochloride (1.3 g, 20.2 mmol) and sodium carbonate (3.4 g, 32.1 mmol) were added to a solution of di-tert-butyl (2S)-2-(4-cyanophenyl)piperazine-1,4-dicarboxylate (2.5 g, 6.45 mmol) in ethanol (15 ml) and water (15 ml) at the room temperature and the solution was stirred at 80° C. for 2 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Triethyl orthoformate (9.6 g, 64.8 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added to a solution of the residue in toluene (25 ml) and stirred at 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)-piperazine-1,4-dicarboxylate (1.94 g, 70%) as a colorless oil. Hydrogen chloride in ethyl acetate (4N) was added to a solution of di-tert-butyl (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine-1,4-dicarboxylate (1.94 g, 4.51 mmol) in methanol and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure to give white solid, which was washed with ethyl acetate to afford (2S)-2-(4-([1,2,4]oxadiazol-3-yl)phenyl)piperazine dihydrochloride (1.3 g, 95%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 48 h
Yield: 44.4 %

Procedure:
To a solution of (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g, 4.73 mmol) in THF (24 mL) was added 4-fluorophenol (795 mg, 7.10 mmol), triphenylphosphine (1.86 g, 7.10 mmol), and DEAD (1.12 mL, 7.10 mmol). After 48 h, the mixture was diluted with 1 M NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. Purification by FCC provided the desired product (969 mg, 44%). MS (ESI): mass calcd. for C25H36FN3O4, 461.27; m/z found, 462.6 [M+H]+. 1H NMR (CDCl3): 6.98-6.89 (m, 2H), 6.79 (dd, J=8.5, 4.1 Hz, 2H), 4.81-4.74 (m, 1H), 4.71-4.51 (m, 1H), 4.03-3.90 (m, 1H), 3.79-3.59 (m, 2H), 3.59-3.41 (m, 3H), 2.88-2.73 (m, 1H), 2.68-2.29 (m, 5H), 2.18-2.06 (m, 1H), 2.04-1.94 (m, 2H), 1.93-1.70 (m, 4H), 1.69-1.53 (m, 2H), 1.46-1.40 (m, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[C:8](I)[CH:9]=1)(=[O:3])[CH3:2].[C:27](=O)([O-:29])[O-:28].[K+].[K+].[OH-].[Na+]>C(#N)C.[Cu](I)I>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[O:13])=[C:8]([CH:9]=1)[C:27]([OH:29])=[O:28])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Agent: I[Cu]I
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a stirring solution of 5-acetyl-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-1-iodobenzene (4.5 g, 9.53 mmol) in acetonitrile (150 mL) was added potassium carbonate (6.6 g, 47.7 mmol), followed by tetrakis-(triphenylphosphine)palladium(0) (0.55 g, 0.48 mmol), and copper iodide (91 mg, 0.48 mmol). The mixture was placed under an atmosphere of carbon monoxide and heated to 80° C. After 3 h, 1 N aqueous sodium hydroxide (50 mL) was added to the hot reaction solution. The solution was stirred for 10 min and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was filtered, acidified to pH 3 with citric acid, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1.4 g (38%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C1C(=O)N([Br:33])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:15])([F:14])[F:16])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:25][Br:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c(CBr)c2)=NO1
Yield: 42.5 %

Procedure:
A mixture of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (100 mg, 0.221 mmol), NBS (62.8 mg, 0.35 mmol) and AIBN (cat.) in 1,2-dichloroethane (10 mL) was refluxed for 3.5 h and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel to give crude 3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (50 mg, yield 42%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.B(F)(F)F.CCOCC.[CH2:26]([SH:29])[CH2:27][SH:28]>C(Cl)Cl>[CH2:12]([C:11]1([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)[S:29][CH2:26][CH2:27][S:28]1)[CH2:13][CH2:14][CH3:15]
Reactant: SCCS
Reactant: CCCCC(=O)c1cc(OC)cc(OC)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a stirred solution of Compound 5 (3.52 g, 15.9 mmol) in anhydrous CH2Cl2 (58 ml); was added BF3-Et2O (0.58 ml, 4.8 mmol) and ethane-1,2-dithiol (2.71 g, 28.8 mmol) and stirred at room temperature for 16 h. The organic phase was then extracted with 10% NaOH (20 ml) followed by water and brine. The organic phase was dried, concentrated and the residue resolved over silica gel eluting with EtOAc/hexanes (5:10) to yield 4.50 g (95.2%) of Compound 9 as a colorless oil. Rf=0.51 (hexane:ethyl acetate 9:1); IR (neat) 2955, 1205, 1067 694 cm−1; 1H NMR δ 6.89 (d, J=2.22 Hz, 2H), 6.34 (t, J=2.21 Hz, 1H), 3.81 (s, 6H). 3.40–3.20 (m, 4H), 2.33 (t, J=7.53 2H), 1.31–1.20 (m, 4H), 0.85 (t, J=6.78 Hz, 3H). 13C NMR δ 160.56, 148.04, 106.01, 98.74, 74.58, 55.60, 45.92, 39.33, 30.23, 23.03, 14.13; MS: (ESI, Pos.) m/z 299 (M+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:29][CH2:30]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C21H24N6O3, 408.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])C(=O)C)[CH3:2].[ClH:19]>>[ClH:19].[ClH:19].[CH2:1]([NH:3][CH2:7][CH:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])[CH3:2]
Reactant: CCN(CC(C)Nc1c(C)cccc1C)C(C)=O
Agent: Cl
Product: CCNCC(C)Nc1c(C)cccc1C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 0.3 g (1.2 mmoles) of 1-(N-ethyl-acetamido)-2-(2,6-dimethylphenyl-amino)-propane and 5 ml of a 20% aqueous hydrochloric acid solution is boiled for 3 hours. The solvent is evaporated, and the residue is dissolved in 30 ml of water. The solution is washed five times with 5 ml of chloroform, each, and then the solvent is evaporated. The residue is crystallized from a mixture of chloroform and diethyl ether to obtain 0.14 g (56%) of 1-ethylamino-2-(2,6-dimethylphenyl-amino)-propane dihydrochloride; m.p.: 155°-157° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11](N)[S:12][CH:13]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[O:24])[S:12][CH:13]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-c2csc(C(=O)c3ccncc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 4-mesitylthiazol-2-amine (7.8 g, 37 mmol)4 in CH2Cl2 (200 mL) was added DMAP (9.0 g, 74 mmol) followed by isonicotinoyl chloride hydrochloride (8.5 g, 48 mmol). Then the mixture was stirred at room temperature for 2 hr. After that, the concentrated mixture was subjected to purification by silica gel chromatography followed by recrystallization from ethanol to give INH41 (10.2 g, 85%) as a white solid; mp 202-203° C. 1H NMR (400 MHz, CDCl3) δ 12.71 (br, 1H), 8.65 (dd, 2H, J=1.6, 4.8 Hz), 7.47 (dd, 2H, J=1.6, 4.8 Hz), 6.79 (s, 1H), 6.54 (s, 2H), 2.15 (s, 3H), 1.87 (s, 6H). 13C NMR (100.5 MHz, CDCl3) δ 164.0, 159.4, 150.2, 148.4, 138.7, 138.0, 136.8, 130.8, 128.5, 121.2, 112.3, 21.1, 20.4. MS (ESI) m/z 324.1 (M+H+), 346.1 (M+Na+). HRMS calculated. for C18H18N3OS (M+H+): 324.1171. found: 324.1167; calculated. for C18H17N3OSNa (M+Na+): 346.0990. found: 346.0984.