Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10](=[O:23])[CH:11]([N:13]2[CH:16]([S:17][C:18](=[O:20])[CH3:19])[CH:15]([CH3:21])[C:14]2=[O:22])Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([P:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10](=[O:23])[C:11]([N:13]2[CH:16]([S:17][C:18](=[O:20])[CH3:19])[CH:15]([CH3:21])[C:14]2=[O:22])=[P:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)SC1C(C)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)SC1C(C)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
The crude 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acid p-nitrobenzyl ester obtained is dissolved in 12 ml of absolute dioxan, 1 g of poly-Hunig base is added and the mixture is stirred for 30 minutes, then 312 mg of triphenylphosphine are added and the mixture is stirred under nitrogen for 15 hours at 50°. The poly-Hunig base is filtered off, washed with dioxan and the filtrate and washing liquid are together concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate and yields a cis-trans mixture of the title compound having the following physico-chemical properties:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40]>>[CH3:37][N:38]([CH3:47])[C:39]([N:41]1[CH2:42][CH2:43][N:44]([C:31]([N:12]2[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:34][CH2:35][CH3:36])=[O:32])[CH2:45][CH2:46]1)=[O:40]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 664.3 [(M+H)+]
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Cl[C:20]1[N:25]=[C:24]2[CH:26]=[CH:27][N:28](C(OC(C)(C)C)=O)[C:23]2=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:28]1[C:23]2[C:24](=[N:25][C:20]([C:6](=[O:8])[CH3:7])=[CH:21][CH:22]=2)[CH:26]=[CH:27]1
Reactant: CC(C)(C)OC(=O)n1ccc2nc(Cl)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2[nH]ccc2n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
A high-pressure tube was charged with tributyl(1-ethoxyvinyl)stannane (7.75 g, 21.45 mmol) and tert-butyl 5-chloropyrrolo[3,2-b]pyridine-1-carboxylate (4.17 g, 16.50 mmol) in degassed DMF (64.0 mL) and Pd(PPh3)4 (1.9 g, 1.65 mmol) was added in one batch. The tube was closely tightly and the reaction mixture was stirred at 100° C. under N2 for 2 d. The reaction mixture was cooled, diluted with EtOAc (350 mL), and filtered through a pad of Celite® to remove solid Pd. The filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in anhydrous THF (80.2 mL), and 2N HCl (41 mL) was added. The reaction mixture was stirred at RT under N2 for 16 h, poured into 10% aq. NaOH solution (100 mL) and then extracted with EtOAc (3×150 mL). The combined organic phases were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2chromatography eluting with EtOAc/heptane to afford 1.69 g (64.1%) of 1-(1H-pyrrolo[3,2-b]-pyridin-5-yl)ethanone as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.54 (t, J=3.0 Hz, 1H), 6.86 (s, 1H), 2.80 (s, 3H); MS (ESI) m/z: 161.3 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:17])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)c(C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1ccc(C(=O)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-acetyl-2-methyl-benzoic acid (1 g, prepared as described in WO2009001942) in dichloromethane (200 ml) and dimethylformamide (0.2 ml) under argon atmosphere at room temperature, was added dropwise oxalyl chloride (0.53 ml) then the resulting mixture was stirred 1 hour at room temperature until the solid was dissolved. The solvent was removed in vacuo to afford crude 4-acetyl-2-methyl-benzoic acid chloride. To a solution of (R)-4-amino-2-ethyl-isoxazolidin-3-one (1.64 g, Example 4, Step B) in dry dichloromethane (10 ml) was added dropwise at room temperature triethylamine (5 ml). The solution of acid chloride in dichloromethane (5 ml) was added dropwise at room temperature. The resulting mixture was allowed to stir 4 hours at room temperature, then quenched with water. The organic phase was washed with 1N aqueous hydrochloric acid solution. The organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure to afford a residue, which was purified by crystallization from diethyl ether to give a beige solid (1 g). LCMS (Method A) 1.23 min, (M+H)+ 291. Chiral HPLC (method H) 30.18 min (98.99%), 33.62 min (1.01%). 1HNMR (CDCl3, 400 MHz): 1.20 (t, 3H), 2.50 (s, 3H), 2.60 (s, 3H), 3.65 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t, 1H), 6.45 (bs, 1H), 7.50 (d, 1H), 7.70-7.90 (m, 2H).
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.CS(O)(=O)=O>O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: CS(=O)(=O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
9α-Hydroxyandrostenedione (280 mg.; 302 mg. of 92.7% purity) is added to a solution of water (3 ml.) and methanesulfonic acid (1 ml.) and stirred at 22° for 2 hours. Additional methanesulfonic acid (1 ml.) is added and stirred for 6 hours with heating to 68°. The reaction mixture is quenched by addition of water (20 ml.) and benzene (20 ml.). Work-up gives androsta-4,9(11)-diene-3,17-dione, 147 mg. (55.7% chemical yield); m.p. 186°-195°. GC (Example 1) shows an androsta-4,9(11)-diene-3,17-dione/androsta-4,8-diene-3,17-dione ratio of greater than 99 to 1.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:17]=[C:18]=S)[CH:14]([CH3:16])[CH3:15]>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:18]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:2][C:3]=2[CH:7]=1
Reactant: CC(C)CN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CC(C)CNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and isobutyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 262°-264° C.; 1H-NMR (DMSO-d6): δ 0.90 (d, 6H), 2.85 (m, 1H), 3.02 (t, 2H), 7.08 (s, 1H), 7.3 (br. s, 1H), 10.9 (br. s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37](O)([C:39]([CH3:42])([OH:41])[CH3:40])[CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:41][C:39]([CH3:42])([CH3:40])[C:37]([CH3:38])([CH3:36])[O:35]2)[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 139.9 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2,3-dimethylbutane-2,3-diol (0.57 g), p-toluenesulfonic acid monohydrate (0.061 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.85 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=[O:23]>CN(C)C=O>[CH:24]1([C:22](=[O:23])[CH2:21][NH:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH2:26][CH2:25]1
Reactant: Cc1cc(F)c(C#N)cc1N
Reactant: O=C(CBr)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)c(C#N)cc1NCC(=O)C1CC1
Temperature: 60 °C
Yield: 76.5 %

Procedure:
5-Amino-2-fluoro-4-methylbenzonitrile (12 g, 80 mmol) was dissolved in anhydrous N,N-dimethylformamide (160 mL) under nitrogen, and potassium carbonate (13.27 g, 96 mmol) and potassium iodide (14.61 g, 88 mmol) were added as solids with stirring. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropylketone (20.24 mL, 180 mmol) was added. The reaction mixture was heated to 60° C. for 3 hours, and then the solvents removed under reduced pressure. The residue was dissolved in EA (400 mL) and washed with 400 mL of water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The residue was re-dissolved in a minimum amount of EA, and hexanes were added to bring the solution to 3:1 hexanes:EA by volume. The product precipitated out of solution and was collected by filtration to provide 5-(2-cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19 g, 61.2 mmol). LC/MS (m/z: 233, M+1)
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][CH:25]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:25]([CH2:24][CH2:23][C:14]3[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=3[F:12])[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (265.1 mg; 1.000 mmol) and 3-(2-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (220.2 mg; 1.000 mmol) afforded 3-ethyl-8-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: B.[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1.[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([NH:24]C1C=CC=C(OC)C=1)=O)(=[O:16])=[O:15].[CH2:34]1[CH2:38]OC[CH2:35]1>>[Br:7][C:8]1[C:9]([CH3:33])=[N:10][O:11][C:12]=1[NH:13][S:14]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[CH:22]([C:34]1[CH:38]=[CH:3][CH:2]=[C:6]([O:5][CH3:4])[CH:35]=1)[NH2:24])(=[O:15])=[O:16]
Reactant: C1CCOC1
Reactant: COc1cccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Agent: B
Product: COc1cccc(C(N)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 12 %

Procedure:
BH3THF (15 ml, 1 M in THF) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide (Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture was refluxed for 8 hours and cooled. THF was evaporated on a rotavap and MeOH was added to the residue. The resulting solution was concentrated. The final residue was purified by HPLC to give N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)-aminomethyl]thiophene-3-sulfonamide (113 mg., 12% yield) as a grey powder, m.p. 70-73° C.
Reaction SMILES: [C:1]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][C:28]4=[O:36])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][NH2:41]>>[CH3:39][O:40][N:41]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]4[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[O:29][C:28]4=[O:36])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: O=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]([O-])=O.[Na+]>S(=O)(=O)(O)O>[C:7]1([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][N:16]=[N:1][C:2]=3[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2cc(-c3ccccc3)sc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To an ice cold solution (0° C.) of 3-amino-5-phenylthiophene-2-carboxamide (0.37 g, 1.7 mmol) in concentrated sulfuric acid (20 mL) was added a cold (0° C.) solution of sodium nitrite (120 mg, 1.86 mmol) in concentrated sulfuric acid (8 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 1 h. The reaction mixture was cooled and poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (3×50 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an off-white color solid (200 mg, 39%), my 178-180° C. 1H NMR (400 MHz, CDCl3): δ 12.30 (1H, br s), 7.86 (1H, s), 7.73-7.75 (2H, m), 7.49-7.54 (3H, m); LC-MS (negative ion mode): m/z 228 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([CH3:37])[C:25]=1[CH3:38])#[N:7]
Reactant: C1CCNC1
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Solvent: C1CCOC1
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H](O)CN4CCCC4)c(C#N)cc23)c1C
Temperature: 60 °C

Procedure:
After adding tetrahydrofuran (2.0 ml) and pyrrolidine (0.20 ml) to N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-quinolin-4-yloxy)-2,3-dimethylphenyl)-N′-cyclopropylurea (110 mg), the mixture was heated at 60° C. for 2 hours. After allowing the reaction solution to cool, the precipitated crystals were filtered out to obtain the title compound (18 mg) as light brown crystals.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=S)[CH2:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[OH:15][N:14]=[C:3]1[NH:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2]1
Reactant: S=C1CSc2ccccc2CN1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CSc2ccccc2CN1

Procedure:
A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (1.56 g), hydroxylamine hydrochloride (0.83 g) and sodium acetate (0.98 g) in dry ethanol (100 ml) was heated under reflux for three hours. The mixture was cooled, and the precipitated solid was collected by filtration and washed with water. Purification of the precipitate by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol. Yield 1.2 g (m.p. 208°-210° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:24][NH:25][C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c(CC)c1Cc1cncn1Cc1ccccc1

Procedure:
To a solution of 140 mg (0.47 mmol) 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione in 1.5 ml ethanol was added a solution of 24 mg (0.48 mmol) hydrazine monohydrate in 0.5 ml ethanol and the mixture heated to reflux for 10 min. The reaction mixture was evaporated under reduced pressure, the residue dissolved in 1N aqueous HCl solution and extracted three times with t-butyl methyl ether. The aqueous phase was adjusted to pH 12 and extracted three times with t-butyl methyl ether, the combined extracts washed with brine, dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash-chromatography on silica gel with ethyl acetate as eluent provided 4-(3-benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1H-pyrazole as colourless viscous oil: MS (ISP): 295.3 ((M+H)+.).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH3:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[CH2:12]([NH:19][C:5]1[N:4]([CH3:11])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: O
Solvent: CCO
Product: Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 80.6 %

Procedure:
2 g (7.02 mmoles) of 3,5-dibromo-1-methyl-4-nitropyrazole are heated in a solution of 11 g (0.1 mole) of benzylamine in 50 ml ethanol for 10 hours at boiling temperature. After cooling, the reaction mixture is poured on 100 ml water, the separated product is filtered and washed with water (20 ml). After vacuum drying, 1.76 g (81 percent of theory) of 5-benzylamino-3-bromo-1-methyl-4-nitropyrazole are obtained in the form of yellow needles with a melting point of 133° C.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])=N)=O)(C)(C)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]=[N:29]O)=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:8]=[N:9][C:10]([C:12]3[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=3[F:18])=[N:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NNC(=N)c1c(F)cccc1F
Reactant: O=C(C=NO)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(F)c1-c1ncc(-c2ccc(Br)cc2)nn1
Temperature: 10 °C

Procedure:
A mixture of 200 mg of N′-[(2,6-difluorophenyl)-iminomethyl]-hydrazinecarboxylic acid tert-butyl ester, 114 mg of (4-bromophenyl)-oxoacetaldehyde oxime and 123 mg of sodium acetate in 1.5 ml of glacial acetic acid is heated at 10° C. for 3 h. After cooling to room temperature, the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed in succession with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified by means of flash chromatography (1% methanol in dichloromethane). In this way the title compound having a melting point of 180-181° C. is obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Cl[C:10]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[O:12][N:11]=1>O1CCCC1>[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][C:10]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[O:12][N:11]=1
Reactant: CC(C)(N)CO
Reactant: Clc1ccc2onc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(N)COc1noc2ccc(Cl)cc12
Yield: 73.6 %

Procedure:
To a suspension of 0.43 g of 60% (w/w) sodium hydride in 15 ml of tetrahydrofuran is added a solution of 0.80 g of 2-amino-2-methyl-1-propanol in 20 ml of tetrahydrofuran at 20°-25° C., and they are refluxed for two hours. To the reaction mixture is added a solution of 2.36 g of 3,5-dichloro-1,2-benzoisoxazole in 20 ml of tetrahydrofuran under reflux, and they are refluxed for a further one hour. After cooling, the solvent is removed by distillation under reduced pressure, and ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then purified by a column chromatography [eluant:chloroform:methanol=20:1], to obtain 1.59 g of oily 3-(2-amino-2-methylpropoxy)-5-chloro-1,2-benzoisoxazole.