Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(Br)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
A solution of 0.05 m of 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(p-bromophenyl)ethane (DE 3317597) and 0.05 m of p-trifluoromethylphenylboric acid (prepared from p-bromotriflurotoluene by consecutive reaction with n-BuLi/B(OCH3)3 and H+ /H2O) in 100 ml of toluene and 50 ml of ethanol is refluxed for 4 hours after 0.0001 m of Pd(Ph3)4 and 50 ml of Na2CO3 solution (2M) have been added. Conventional extractive work-up and subsequent purification by chromatography and crystallization give 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(4-trifluoromethylbiphenyl-4'-yl)ethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:19][CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:20])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CCOc1cnc(Cl)cc1I
Reactant: C=CC(O)C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3H), 1.55-1.87 (m, 8 H), 2.75 (m, 2 H), 2.86 (m, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 7.09 (s, 1 H), 7.89 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:20](Cl)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:20]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 89.3 %

Procedure:
Production Example 1 was repeated using 20.0 g (0.072 mols) of α-glutamylglutamic acid and 21.9 g (0.072 mols)of stearoyl chloride to give 34.9 g of N-(N'-stearoyl-α-glutamyl)glutamic acid in a yield of 89%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,650 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]=O)=[CH:42][CH:41]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:38][C:39](=[O:50])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][C:16]2[C:17]3[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:29])=[O:28])=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Reactant: O=S(=O)(Cc1ccccc1)NCCc1cc2ccc(Cl)cc2n1C(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
To N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamide (0.033M, 1 equiv.) in DCM at 0° C. were added 4-(2-oxo-ethoxy)-benzoic acid methyl ester (3.3 equiv.), triethylsilane (6 equiv.), and TFA (5 equiv.). The reaction mixture was stirred at rt for 2 d 20 h before aqueous workup. Purification by silica gel chromatography followed by reverse phase HPLC gave 4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester in 35% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:30][CH2:31][CH2:32][C:33]2=[O:34])=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCCC2=O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (1.0 g, 3.5 mmol) in THF (15 ml) was added triethylamine (0.59 mL, 4.3 mmol). The mixture was cooled in an ice bath and a solution of 4-chlorobutyryl chloride (0.48 mL, 4.3 mmol) in THF (5 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (20 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane/ethyl acetate=100:0 to 60:40) afforded the title compound (250 mg, 20%) (as the most polar component of two formed in the reaction) which was obtained as a white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[N:7]([C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])=[CH2:3]>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH2:17])=[CH:25][CH:26]=2)[N:7]([C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])=[CH2:3]
Reactant: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)nc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C(C)c1cc(-c2ccc(OCCN)cc2)n(-c2ccc(OC)nc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4M solution of HCl in dioxane (2 ml) was added to a solution of ter-butyl (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate (269.7 mg) in CH2Cl2 (2 ml) . The reaction mixture was stirred at ambient temperature for 2 hours, then, was concentrated in vacuo to give (2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)amine dihydrochloride (259 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4-methyl piperazine (7.68 mL, 70 mmol, 4 equiv) was added to a stirred solution of tert-butyl 3-bromopropionate (3.0 mL, 18 mmol) in ethyl acetate (15 mL) at 0° C. The solution was stirred at 25° C. for 1 h with evolution of a white precipitate, then heated on an oil bath to 55° C. for 2 h. TLC analysis (20% EtOAc in Hexanes, Rf=0.9 (starting material), 0.1 (product)) indicated complete consumption of the bromide reagent. The reaction was diluted with EtOAc (100 mL) and transferred to a separatory funnel, and the organic phase was washed with water (100 mL), NaHCO3 (sat'd, 2×100 mL), and brine (100 mL), dried over MgSO4 and concentrated to give a slightly yellow oil. The oil was dissolved in methylene chloride (20 mL), loaded on to a pre-equilibrated plug of silica gel (20% EtOAc in Hexanes, 150 mL SiO2) and the desired product was eluted from the silica with increasingly polar eluent (EtOAc in hexanes, starting at 20%, 200 mL volumes increasing in 15% increments to 100%). Fractions containing the desired material were concentrated to give tert-butyl 3-(4-methylpiperazin-1-yl)propanoate (4.1 g, quantitative). 1H NMR (400 MHz, CDCl3) δ (ppm)=3.45 (d, J=3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.47 (br s, 6H), 2.38 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][C:5]([CH3:18])=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:23])=[C:6]2[C:5]([CH3:18])=[N:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of N-(1-ethyl-3-methylpyrazol-5-yl)anthranilic acid (7.0 g, 28.57 mmol) and POCl3 (20 ml) was refluxed for 24 hours. The reaction mixture was cooled to room temperature and then was poured into ice-water. The mixture was neutralized with concentrated NH4OH to a pH of about 8 and the resulting gum crystallized slowly to afford a solid which was collected by filtration, washed with water and dried to afford 6.7 g (95%) of 1-ethyl-3-methyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C([N:24](CC)CC)C.O.NN>C(O)C>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:16])[NH:17][NH2:24])=[N:7]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCN(CC)CC
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.000 g (163.535 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride were dissolved in 700 ml of ethanol, and 66.192 g (654.141 mmol) of triethylamine and 10.233 g (163.535 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and the solution was washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether, filtered off with suction and dried under high vacuum. 46.49 g (46% of theory, 68% pure) of the title compound were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.1 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and acetic anhydride (5.13 g), and the mixture was stirred at room temperature for 21 hrs. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed with water (100 mL), an aqueous copper sulfate solution (40 mL), water (60 mL) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (8.34 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[O:14][CH2:13][CH:12]([OH:15])[CH2:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:15][CH:12]1[CH2:13][O:14][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COC2COC(c3ccccc3)OC2)cc1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of about 19.63 g of about 50% sodium hydride in about 450 ml of dimethylformamide was added, portionwise, over about 15 minutes about 67 g of 2-phenyl-m-dioxan-5-ol. After stirring about 20 minutes, the mixture was cooled in ice and about 69.95 g of benzyl bromide was added dropwise over about 20 minutes. The mixture was stirred at room temperature overnight, water was added and the solid collected. This solid was dissolved in hot toluene, dried, filtered and diluted with an equal volume of petroleum ether. After standing about 4 hours at about 0° C. the solid was collected, giving about 90.5 g of the desired title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH2:13][NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)[CH3:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH2:13][NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH3:2]
Reactant: CCc1ccc(C(=O)[O-])c(O)c1CNC(=O)CCCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(C(=O)O)c(O)c1CNC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl(N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethyl-2-hydroxybenzoate (0.58 g, 1.41 mmoles) was dissolved in dichloromethane (5 mL) and the solution was cooled in an ice/water bath. Trifluoroacetic acid (5 mL) was added, and the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was evaporated to dryness to give the product as an oil, which was dried in vacuo over potassium hydroxide pellets to afford 0.59 g (99% yield) of ethyl (6-aminohexanoyl)aminomethyl-2-hydroxybenzoate trifluoroacetate.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:27]([NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:3])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: CC(C)N
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC(C)C)nn1
Yield: 39 %

Procedure:
As described for example 52, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using isopropylamine instead of ethanolamine, to the title compound (58 mg, 39%) which was obtained as a white solid after recrystallisation from heptane:ethyl acetate. MS: m/e=371.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:14]=2[CH3:23])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to the general procedure 3 as described hereinabove. 2-Chloro-4-(2-methyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine (220 mg, 0.71 mmol) was dissolved in 5 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.61 ml, 1.22 mmol) was added, and the mixture stirred for 15 min at −75° C. Iodomethane (0.08 ml, 1.14 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→0:100 gradient) and by recrystallization from dichloromethane and diisopropylether. The desired compound was obtained as a light yellow solid (30 mg, 13%), MS: m/e=322.3 (M+H+).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH3:22])[C:11]([C:20]#[N:21])([CH:17]1[CH2:19][CH2:18]1)[C:12](OCC)=[O:13])=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH:17]1([C:11]2([C:20]#[N:21])[CH:10]([CH3:22])[CH2:9][NH:8][C:12]2=[O:13])[CH2:19][CH2:18]1
Reactant: CCOC(=O)C(C#N)(C(C)CNC(=O)OC(C)(C)C)C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CNC(=O)C1(C#N)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropyl-3-methylbutanoate (5.3 g) obtained in Step A of Example 357 was added 4 M hydrogen chloride in ethyl acetate (30 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, to a solution of the residue in acetonitrile (150 mL) was added potassium carbonate (9.4 g), and the mixture was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[C:9]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C1=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCNC1=O

Procedure:
A solution of 6-2 (28.0 g, 98 mmol), Mg(CIO4)2 (4.3 g, 20 mmol), and CH3CN (400 mL) was heated at 50° C. for 3 hr. The cooled solution was diluted with CHCl3 and then washed with 1N HCl, sat. naHCO3, and brine, dried (Mg S4), and concentrated. Flash chromatography (silica, 50% EtOAc/hexanes→EtOAc) gave 6-3 as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26]([CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:24][CH2:23][C:22]=4[CH:36]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)O)C4)no2)cc1C#N
Temperature: 50 °C

Procedure:
1,1-Dimethylethyl [7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]acetate (Preparation 10) (85 mg, 0.174 mmol) was treated with HCl (1305 μl, 5.22 mmol) (4N soln in dioxan) and warmed at 50° C. for 2 hours. A white crystalline product formed. The reaction was cooled to RT and the solid filtered off and washed with ether. On drying the title compound was obtained (65 mg) as a white solid. δH (400 MHz, d6DMSO) 1.39 (6H, d), 1.91-2.00 (2H, m), 3.11-3.12 (2H, m), 3.59 (2H, m), 4.00 (2H, s), 4.60 (2H, s), 4.94-5.02 (1H, m), 7.53-7.59 (2H, m), 7.99-8.06 (2H, m), 8.41 (1H, dd), 8.52 (1H, d); MS (ES) C24H24N4O4 requires 432; found 433 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[N:26]([CH2:37][CH3:38])[N:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:30])[CH:29]=2)[CH:22]=[CH:23][CH:24]=1>>[CH2:37]([N:26]1[C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[CH:29][C:28](=[O:30])[N:27]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:38]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: CCn1c(-c2cccc(N)c2)cc(=O)n1-c1ccccc1
Product: CCn1c(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)cc(=O)n1-c1ccccc1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-(3-aminophenyl)-2-ethyl-1-phenyl-3-pyrazolin-5-one (54 mg, 0.193 mmol) similar to Example 58 and isolated as a dark yellow solid (52 mg, 54%). 1H NMR (DMSO-d6): 10.61 (s, 1H), 9.52 (s, 1H), 8.83–8.81 (m, 1H), 8.65 (dd, J=1.2, 7.5 Hz, 1H), 8.38 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.68–7.48 (m, 7H), 7.37–7.33 (m, 1H), 7.22 (s, 1H), 5.97 (s, 1H), 3.63 (q, J=6.6 Hz, 2H), 0.634 (t, J=6.6 Hz, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[O:11]=[C:10]1[NH:6][CH2:7][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:9]1
Reactant: COc1ccc(CN2C[C@@H](C(=O)O)CC2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C1C[C@H](C(=O)O)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To (S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (5.3 g) were added anisole (3.1 ml) and trifluoroacetic acid (26.5 ml) at room temperature, and the mixture was stirred for 4 hours at reflux. This reaction solution was cooled to room temperature, concentrated under reduced pressure, azeotropic-dried with toluene. To the resulting residue was added diisopropyl ether (53 ml), and the mixture was stirred at room temperature. A solid was collected from this suspension by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the titled compound (2.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29](C(OC(C)(C)C)=O)[C:28]([CH3:38])([CH3:37])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:21]=[C:22]2[NH:29][C:28]([CH3:38])([CH3:37])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccnc(F)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3cc(F)c(Oc4ccnc(F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.