Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18](Cl)=[O:19].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:10]2[O:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:11]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To 1.72 g of 4-bromoaniline was added to 1.89 g of benzofuran-2-carboxylic acid chloride in 35 mL of dichloromethane cooled in ice bath, followed by the addition of 4.9 mL of triethylamine. The reaction was stirred at room temperature overnight and then diluted with dichloromethane. The dichloromethane layer was washed with water, 1N HCl, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide 2.61 g of N-(4-bromophenyl)-1-benzofuran-2-carboxamide as a yellow solid. Yield 72%. m.p. 178-180° C.; MS: 314.1(M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[C:7]([Cl:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1>O1CCCC1>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=2)=[O:13])=[C:7]([Cl:16])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Cl)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Cl)c1
Yield: 7.2 %

Procedure:
A mixture of (4-tert-butyl-2-chlorophenoxy)acetic acid (121 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (90 mg, 0.55 mmol), triethylamine (0.30 ml), tetrahydrofuran (3.0 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (127 mg, 0.5 mmol) was treated in the same procedure described in Example 2(b) to give 16 mg (7% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-(piperidin-3-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.26 g, 0.89 mmol) was dissolved in EtOH (15 ml), and then 5-bromo-2-chloropyrimidine (0.33 g, 1.33 mmol) and DIPEA (0.77 ml, 4.43 mmol) were added, followed by stirring at 50° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.28 g, 70%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carboxylic acid (2.00 g, 9.00 mmol) in anhydrous tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (4.67 mL, 27.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.41 g, 12.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes, followed by the addition of 1-hydroxybenzotriazole (1.70 g, 12.60 mmol) and (4-fluorophenyl)methanamine (2.50 g, 12.60 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was concentrated to half in vacuo. The residue was diluted with ethyl acetate (200 mL), washed sequentially with 10% aqueous hydrochloric acid (50 mL), saturated bicarbonate solution (50 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized in ethyl acetate and hexane to afford the title compound as a colorless solid (2.38 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.05-7.00 (m, 2H), 5.99-5.87 (m, 1H), 4.54 (d, J=5.7 Hz, 2H), 2.63 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:2].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:18][CH2:19][O:20][CH:1]1[C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Yield: 70.2 %

Procedure:
To a solution of 1.8 g (6.3 mmol) of 2-formyl-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 70 mL of benzene was added 3.5 mL of ethylene glycol (63 mmol) followed by p-toluenesulfonic acid monohydrate (180 mg, 0.9 mmol). The reaction mixture was heated at reflux for about 3 hours and is then concentrated under reduced pressure. The residue was partitioned between ether and saturated sodium bicarbonate solution. The ether layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography 1.4% ethyl acetate/) on a Biotage 40M SiO2 cartridge to afford 1.5 g (72%) of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(C(C)C)C(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 3-aminoacetophenone in 20 mL of CH2Cl2 was added 5 mL of ethyl-di-iso-propylamine. To the stirred reaction mixture was then added 1 mL of 2-furoyl chloride which was allowed to stir at 25° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2) to yield 900 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.11 (1 H, br s), 8.09 (1H, t, J=2 Hz), 7.93 (1 H, m), 7.66 (1H, m), 7.47 (1 H, m), 7.20 (1 H, m), 6.52 (1 H, m), 2.56 (3H, s) ppm.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:17]([C@@H:18]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH3:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:31])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1.C1(C)C=CC=CC=1>[Cl:31][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([C:6]1[S:41][C:1]([CH3:2])=[N:4][N:5]=1)[C:17]([C@@H:18]([N:20]1[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]1=[O:30])[CH3:19])=[CH:16]2
Reactant: CC(=O)NNC(=O)c1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)s1
Temperature: 120 °C

Procedure:
To a stirred solution of (S)—N′-acetyl-8-chloro-3-(1-(1,3-dioxoisoindolin-2-yl)-ethyl)quinoline-2-carbohydrazide (85 mg, 0.19 mmol) in THF (1.5 mL) and toluene (3.0 mL) was added Lawesson's reagent (118 mg, 0.29 mmol). The reaction was heated in the microwave at 120° C. for 20 minutes and then cooled to room temperature and purified by column chromatography (SiO2, 12 g, hexanes:ethyl acetate, 1:0 to 1:1) to give 2-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (1H, s), 7.77-7.84 (4H, m), 7.70 (2H, dd, J=5.3, 2.9 Hz), 7.46-7.51 (1H, m), 7.06 (1H, q, J=7.0 Hz), 2.85 (3H, s), 2.11 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:28][NH:29][CH2:30][CH3:31].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:30]([N:29]([CH2:28][C:27]1[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=1[F:25])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:31]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
[4-(2-{[2-(Methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.250 g, 0.722 mmol) was dissolved in DCM (10 ml), N-(2-fluorobenzyl)ethanamine (0.105 g, 0.686 mmol) was added. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.255 g, 0.0.794 mmol) and N-ethyl-N,N-diisopropylamine (0.187 g, 1.443 mmol) were added. The solution was stirred for 2 hours at room temperature. The crude was purified by flash chromatography (started with isocratic DCM 100% and then the MeOH concentration was increased from 0.5% to 20%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation. The substance needed to be purified once more and it was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. The ammonium acetate was removed by freeze drying the product overnight to give 0.1 g of methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}benzoate (yield 29.1%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[CH2:1]([N:8]1[C:12]([NH:22][CH2:21][CH2:19][OH:20])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2ccccc2)c1Br
Reactant: NCCO
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(Cc2ccccc2)c1NCCO

Procedure:
3.61 (10 mmoles) of 1-benzyl-3,5-dibromo-4-nitropyrazole are heated at 80° C. in 15 ml ethanolamine for 2 hours. After cooling, the reaction mixture is poured on 30 ml water and the separated precipitate is collected by filtration. After recrystallizing once from toluene, 2.5 g (74 percent of theory) of 1-benzyl-3-bromo-5-(2'-hydroxyethyl)amino-4-nitropyrazole are obtained in the form of pale yellow crystals with a melting point of 110° to 112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:17][C:10]1[N:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
A solution of 2-methoxypyrazolo[1,5-a]pyridine (Reference; Bull. Chem. Soc. Japan, vol. 49(7), 1980–1984(1976)) (7.15 g) in tetrahydrofuran (140 mL) was cooled to −78° C. under a nitrogen stream, and after adding n-butyllithium (1.6M hexane solution: 46 mL) dropwise thereto, the reaction mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at −78° C., and stirring was continued for 1 hour. The reaction mixture was raised to room temperature, water was added, and then extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (7.1 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (50:1) fraction.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]CS([O-])(=O)=O)[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:23]([CH2:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[CH2:12][CH2:13]1)=[N+:24]=[N-:25]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CCS(=O)(=O)[O-])CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
In 50 ml of dry dimethylformamide was suspended 2.0 g of trans-4-(1-t-butyldimethylsilyloxyethyl)cyclohexylmethylmethanesulfonate and 1.85 g of sodium azide, and the resulting mixture was stirred at 110° C. for 45 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.7 g of the desired compound as a pale yellow oil. This oil was used for the subsequentareaction without purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:30]([Cl:40])[CH:29]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)=[C:30]([Cl:40])[CH:29]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(-c3noc(=O)[nH]3)c(Cl)c2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc(-c3noc(=O)[nH]3)c(Cl)c2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
560 mg [1-[3-Chloro-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-6-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid tert-butyl ester were dissolved in 7 ml dichloromethane. 1 ml trifluoroacetic acid were added and the reaction mixture stirred at room temperature for one hour. The solvents were removed in vacuo and the residue purified by chromatography on reversed has to obtain 7 mg 3-{4-[4-Amino-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinolin-1-yl]-2-chloro-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3-n3cccn3)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 58 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine (57.74, 58% yield) as a red glass. 1H-NMR (CDCl3) δ 10.17 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.02 (m, 2H), 7.82 (d, J=18.3 Hz, 2H), 7.38 (m, 3H), 7.19 (m, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.60 (m, 1H), 6.52 (m, 2H), 5.82 (m, 1H), 3.70 (s, 3H), 3.21 (m, 1H), 3.02 (m, 2H), 2.98-2.30 (m, 6H), 2.06 (m, 2H), 1.23 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.O1CCCC1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCOCC>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (1.6 g) in refluxing tetrahydrofuran (40 ml) was treated with morpholine (0.7 ml) under nitrogen for 3 hr and then poured into ether. The ethereal solution was washed successively with 5% aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated. The residue was partitioned between a mixture of 2N-hydrochloric acid (6 ml), water (200 ml), acetone (20 ml) and methylene chloride (120 ml). The aqueous phase was treated with 2N-sodium hydroxide (6 ml) and sodium chloride (20 g) and the resulting mixture was extracted with methylene chloride. The extracts were washed with water, dried (Na2SO4) and evaporated to give title compound (1.5 g) as a white foam, [α]D + 81° (c 1.1).
Reaction SMILES: [C:1](O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24]>C(OCC)(=O)C.CCCCCCC>[C:1]([NH:21][CH:22]([CH:25]([OH:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:23][OH:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(O)CCCCCCCCCCCCCCC
Yield: 72 %

Procedure:
6.2 g (0.022 mol) of stearic acid and 6 g (0.022 mol) of 2-aminooctadecane-1,3-diol were mixed in a tube and irradiated with the apparatus used in Example 1, under the same frequency and power conditions. After an irradiation of 18 minutes at 140° C.±5° C., the reaction mixture was solubilized in a mixture of 80 ml of ethyl acetate and 40 ml of heptane. The precipitate obtained was recrystallized from ethanol and 8.1 g of expected pure product were obtained with a yield of 72%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:15][C:13]([CH2:12][O:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:14])[CH3:17]
Reactant: NC(=O)c1ncccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccnc1C(N)=O
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A mixture of 3-hydroxy picolinic amide (10 g, 72 mmol), ethyl bromoacetate (12.02 g, 72 mmol) and anhydrous potassium carbonate (10.9 g, 79.2 mmol) in 250 ml of dry 2-butanone is heated at 80° C. for 20 hours. After cooling, the inorganic salts are filtered off and the filtrate is reduced to approximately 120 ml. After addition of cold t-butyl methyl ether the resulting precipitate is filtered off, rinsed with cold t-butyl methyl ether and dried to give 8.6 g of 3-(ethoxycarbonylmethoxy)picolinamide (53%).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:46]=[CH:45][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:47][CH3:48])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:41]1[CH:42]=[CH:43][CH:44]=[C:40]1[C:36]1[O:37][C:38]([CH3:39])=[C:34]([CH2:33][O:32][C:31]2[CH:45]=[CH:46][C:28]([CH2:27][O:1][C:2]3[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:15][CH:14]=4)[N:3]=3)=[CH:29][C:30]=2[O:47][CH3:48])[N:35]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (3.00 g), potassium carbonate (2.52 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.30 g, yield: 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[Li]CCCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:27]=[O:28])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 8 c], 1-bromo-2-trifluoromethyl-4-(phenylmethoxy)-benzene was treated with n-BuLi and N,N-dimethylformamide in dry tetrahydrofuran to yield 4-benzyloxy-2-trifluoromethyl-benzaldehyde as colorless liquid.