Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([SH:56])[CH2:52]1.C(NC(C)C)(C)C>C(#N)C>[CH3:50][N+:51]1([CH3:57])[CH2:55][CH2:54][C@H:53]([S:56][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([O-:37])=[O:36])[CH2:52]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: C[N+]1(C)CC[C@H](S)C1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CC[N+](C)(C)C3)C[C@H]12
Reaction time: 1 h
Yield: 18.4 %

Procedure:
183 μl of diisopropylethylamine and 218 μl of diphenylphosphoryl chloride were simultaneously added, whilst ice-cooling, to a solution of 348 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2oxo-1-carbapenam-3-carboxylate dissolved in 4 ml of dry acetonitrile, and the mixture was stirred at the same temperature for 1 hour. At the end of this time a solution of 338 mg of the crude (3S)-1,1-dimethyl-3-mercaptopyrrolidinium salt prepared as described in Example 5-(1) in 4 ml of dry acetonitrile and 201 μl of diisopropylamine were added to the mixture, whilst ice-cooling. The mixture was then allowed to stand at the same temperature for 1 hour and then for two days in a refrigerator. At the end of this time, the reaction mixture was washed by decantation with diethyl ether. The resulting product was dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of a 0.1M phosphate buffer (pH 7.0) and hydrogenated at room temperature for 2.5 hours in the presence of 400 mg of 10% w/w palladium-on-charcoal. At the end of this time, an insoluble material was removed by filtration and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure and then subjected to column chromatography through Diaion HP-20AG (Mitsubishi Chemicals Industries Inc.). The title compound was prepared as a crude product from the fractions eluted with water. The crude compound was then further purified by chromatography through a Lobar column (Merck, LiChroprep RP-8, size B) and the fractions eluted with 5% by volume aqueous methanol were collected, concentrated by evaporation under reduced pressure and lyophilized to afford 60 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(C=O)ccc1Oc1ccc([N+](=O)[O-])cn1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-(5-nitropyridin-2-yloxy)benzaldehyde (600 mg, 2.32 mmol) in toluene (35 mL) were added 2,4-thiazolidinedione (270 mg, 2.31 mmol) and piperidine acetate (135 mg, 0.93 mmol). The resulting solution was attached to a Dean Stark, and stirred under reflux for 1.5 hours. After being left to cool for 17 hours at room temperature, the precipitated yellow powder was filtered, to thereby yield 600 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][N:10]2[C@@H:14]([CH3:15])[C@@H:13]([C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=3)[O:12][C:11]2=[O:27])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:3]([CH2:9][N:10]2[C@@H:14]([CH3:15])[C@@H:13]([C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=3)[O:12][C:11]2=[O:27])=[N:4][C:5]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[CH:6][CH:7]=1
Reactant: C[C@H]1[C@@H](c2cc(F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ccc1Br

Procedure:
(4S,5R)-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (1.0721 g, 2.293 mmol), 3,3-difluoroazetidine hydrochloride (1.336 g, 10.32 mmol), triethylamine (3.20 ml, 22.93 mmol) and THF (10 ml) were sealed in a microwave vessel and subject to microwave irradiation at 150° C. for 8 hrs. Volatiles were removed under reduced pressure. The resulting pot residue was worked up with brine/ethyl acetate. The combined extracts were dried over Na2SO4, filtered and evaporated to afford a dark mixture. This dark mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford a light amber glass of 530.8 mg as the titled compound. LCMS calc.=523.03. found=525.99.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:27])[C:15](=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C[O:29][C:30](=O)[CH2:31][N:32]([CH3:34])[CH3:33]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[C:15](=[O:26])[N:14]([CH3:27])[C:8]2[N:9]([CH3:13])[C:10]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:30](=[O:29])[CH2:31][N:32]([CH3:34])[CH3:33])=[CH:12][CH:11]=3
Reactant: COC(=O)CN(C)C
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Product: CN(C)CC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in Example 80 above, with the compound from preparation 1.10E, 6-acetyl-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and dimethylglycine methyl ester.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH2:31]Br)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:18]([C@H:23]1[CH2:24][CH2:25][C@H:26](/[CH:29]=[CH:30]/[CH2:31][O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:27][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@H]1CC[C@H](O)CC1
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/CO[C@H]2CC[C@H](CCC)CC2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 g of sodium hydride and 25 ml of tetrahydrofuran was treated with 0.5 g of trans-4-propylcyclohexanol while gassing with nitrogen, stirred for a further 2 hours, then treated with 1.0 g of (E)-3-(trans-4-pentylcyclohexyl)allyl bromide and subsequently heated to 70° C. overnight. Thereafter, the reaction mixture was treated with 500 ml of water and extracted four times with 50 ml of hexane each time. The combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, filtered and then concentrated. The residue was purified by chromatography on silica gel with toluene. The trans-4-propylcyclohexyl (E)-3-(trans-4-pentylcyclohexyl)allyl ether obtained was recrystallized from acetone at -25° C.. This gave 1.2 g of pure product with m.p. (C-I) 26° C..
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.[SH:59][C@@H:60]1[CH2:64][N:63]([CH3:65])[C@H:62]([C:66]([N:68]2[CH2:73][CH2:72][N:71]([C:74]([O:76][CH2:77][C:78]3[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=3)=[O:75])[CH2:70][CH2:69]2)=[O:67])[CH2:61]1>C(#N)C>[N+:84]([C:81]1[CH:82]=[CH:83][C:78]([CH2:77][O:76][C:74]([N:71]2[CH2:72][CH2:73][N:68]([C:66]([C@@H:62]3[CH2:61][C@H:60]([S:59][C:32]4[C@H:33]([CH3:34])[C@@H:29]5[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]5[C:31]=4[C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])[CH2:64][N:63]3[CH3:65])=[O:67])[CH2:69][CH2:70]2)=[O:75])=[CH:79][CH:80]=1)([O-:86])=[O:85]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 39.2 %

Procedure:
7.0 g of diphenylphosphoryl chloride and 3.4 g of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 8.6 g of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 120 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 6.7 g of diisopropylethylamine and a solution of 13.8 g of (2S,4S)-4-mercapto-2-[4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-methylpyrrolidine trifluoromethanesulfonate in dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was allowed to stand overnight, whilst ice-cooling. At the end of this time, the reaction mixture was worked up and purified in a similar manner to that described in Example 49(a), to give 7.0 g of the title compound, as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].Br[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8]2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccccc2OC1c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
To a solution of 2-aminophenol (13.5 g) in ethyl acetate (150 ml) is added a solution of sodium hydrogen carbonate (15 g) in water (300 ml), and to the mixture is added dropwise a solution of α-bromo-4-chlorophenylacetyl chloride (32.2 g) in toluene with vigorous stirring under ice cooling. After the mixture is stirred at room temperature for one hour, the solvent in the organic layer is distilled off and the residue is dissolved in acetone. To the solution is added potassium carbonate (20 g), and the mixture is stirred at room temperature overnight. The solvent is distilled off and to the residue is added water. The mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(4-chlorophenyl)-3-oxo-3,4-dihyro-2H-1,4-benzoxazine (24.0 g) as crystals. M.p. 180.5°-181.5° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH:1]1([C:4]2[N:5]([S:18]([N:17]([CH3:22])[CH3:16])(=[O:20])=[O:19])[CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1c[nH]c(C2CC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) in dichloromethane (60 mL). Triethylamine (31.4 mL, 225.3 mmol), N,N-dimethylsulfamoyl chloride (13.2 mL, 121.87 mmol, 1.10 equiv) were added to the reaction. The reaction mixture was stirred for 4 h at room temperature, then quenched with 20 mL of water. The aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 16 g (67%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][CH:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:35][CH2:36][CH:37]([NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH2:38][CH2:39]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CS(=O)(=O)NC1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CS(=O)(=O)NC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC1

Procedure:
N—(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-4-yl)-methanesulfonamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and N-piperidin-4-yl-methanesulfonamide following General Procedure B.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1>>[Cl:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][NH:17][CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]2[O:9][C:8](=[O:10])[CH:7]=[C:6]2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:24][CH:23]=1
Reactant: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Reactant: NCc1ccc(Cl)nc1
Product: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1

Procedure:
If, in the preparation process 2 according to the invention for preparing the novel compounds of the general formula (I), the compound of the formula (III) used is, for example, 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one and the compound of the general formula (IV) is 3-aminomethyl-6-chloropyridine, this can be reacted in a first reaction step to give 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one as compound of the general formula (V) which is then subjected to an intramolecular cyclization in the second reaction step (reaction scheme VI):
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15](=[N:22]C(OC(C)(C)C)=O)[N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl.O>[N:16]1([C:15]([NH2:22])=[NH:14])[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCSCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N=C(N)N1CCSCC1
Reaction time: 72 h

Procedure:
Trifluoroacetic acid (50 mL, 0.073 mol) was added dropwise to a stirred mixture of (tert-Butoxycarbonylimino-thiomorpholin-4-yl-methyl)-carbamic acid tert-butyl ester (21 g, 0.0723 mol) in DCM (200 mL) and water (10 mL). After 3 days at rt, the solvent was evaporated and re-evaporated with 2-propanol. The resulting semi-solid was triturated with 10% 2-propanol/Et2O. The solid was filtered off and was washed with 10% 2-propanol/Et2O and then with Et2O. The product was dried in vacuo over phosphoric oxide, to give 15.72 g as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>C(O)C>[NH2:30][CH2:29][C@@H:27]1[CH2:26][C@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9]2)[CH2:28]1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reaction time: 20 h

Procedure:
To a solution of 3.84 g (7.25 mmol) of cis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione in 100 ml of dry ethanol are added dropwise at RT and under argon 3.75 g (3.64 ml; 74.96 mmol) of hydrazine monohydrate. After 2 h most of the starting material is not yet dissolved, and additional 1.6 ml of hydrazine monohydrate are added thereto (total amount: 14.8 equivalents). The reaction is complete after 20 h. The colorless precipitate is filtered off, and washed with ethanol. The filtrate is evaporated to dryness and the crude compound is purified by chromatography on silicagel (dichloromethane:methanol:aqueous concentrated ammonia=90:10:1) to provide cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=7.47 min (Grad 1); ES-MS: m/eo=400; 1H-NMR (CDCl3): 8.31/s (1H); 7.3-7.5/m (6H); 7.12/s (1H); 7.05-7.08/2 peaks (2H); 6.99/m (1H); 5.17/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.87/d (2H); 2.75-2.65/m (2H); 2.2-2.1/m (2H); 1.55/broad s (2H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].C(O)C.[F:16][C:17]([F:31])([F:30])[C:18](=O)[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=O>>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:1]([C:3]3[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:4]=3)[N:2]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=2)=[CH:27][CH:26]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Solvent: CCO
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)O)cc2)cc1
Yield: 82.2 %

Procedure:
To a stirred suspension of p-hydrazino-benzenesulfonic acid (42 g, 0.223 mol) in ethanol (450 ml) 6N hydrochloric acid (74 ml, 0.446 mol) was added at room temperature, followed by addition of 4,4,4-trifluoro-1-(4-methyl-phenyl)-butane-1,3-dione (51.45 g, 0.223 mol). The obtained suspension was refluxed for 8 h, then concentrated in vacuo. The residue was dissolved in water (300 ml) and extracted with ethyl acetate (2×200 ml). The combined organic layers were washed with water (1×100 ml) and brine (1×100 ml), dried over MgSO4, decolorized, filtered and concentrated in vacuo. The obtained crystalline product was recrystallized from diisopropyl ether (300 ml) to yield 70.12 g (82%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (4) (101 mg, 0.268 mmol), TMS-acetylene (0.045 mL, 0.31 mmol), Pd(PPh3)2Cl2 (18.7 mg, 0.0261 mmol), CuI (5.1 mg, 0.027 mmol), and i-Pr2NH (0.075 mL, 0.53 mmol) in THF (1.5 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl and brine, dried over MgSO4, and concentrated. Purification by flash column chromatography using the Biotage system (100% hexane to 1% EtOAc in hexane) gave 81.3 mg (77% yield) of the desired product (5).
Reaction SMILES: [CH3:1][N:2]([C:24]1[S:25][C:26]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1.[ClH:48]>O.CO>[ClH:48].[CH3:1][N:2]([C:24]1[S:25][C:26]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:28]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[CH:6][CH:5]=1
Reactant: COC(=O)CCc1sc(N(C)Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CN(C)c2nc(-c3ccccc3)c(CCC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of methyl 3-[2-[N-methyl-N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]amino]-4-phenyl-5-thiazolyl]propionate (570 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in diethyl ether (40 ml) and 10% hydrochloric acid-methanol (0.5 ml) was added. The precipitated solid was collected by filtration and recrystallized from methanol-diethyl ether to give 3-[2-[N-methyl-N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]amino]-4-phenyl-5-thiazolyl]propionic acid hydrochloride (270 mg, yield 46%) as colorless crystals. melting point: 106–108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:50]=[CH:49][N:48]=[C:47]([C:51]([OH:53])=O)[C:46]2=[O:54])=[CH:41][CH:40]=1>>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[C:46](=[O:54])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=3)[CH:50]=[CH:49][N:48]=2)=[O:53])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][N:20]([CH:23]([CH3:24])[CH3:25])[CH2:21][CH2:22]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: CC(C)N1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 64 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy) N-(1-isopropylpiperidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in Example 101, Step A except using 1-isopropylpiperidin-4-amine) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (Example 125, Step E) according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 4.6 mg (64%) of the desired product. The desired product was treated with 2N HCl (Et2O solution) in a solution of MeOH and EtOAc to afford HCl salt compound. LRMS (APCIpos) m/e 601.3 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.17 (d, 1H), 8.06 (dd, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.55 (m, 2H), 7.49 (d, 1H), 7.34 (t, 3H), 6.14 (d, 1H), 3.93 (m, 1H), 3.52 (m, 2H), 3.17 (m, 2H), 2.47 (m, 2H), 1.96 (m, 2H), 1.40 (d, 6H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −111.0, −127.6.