Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][N:8]([C:28](=[O:37])[C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[C:5]2=[N:6][CH:7]=1.[NH:38]1[C:46]2[C:41](=[CH:42][C:43](B(O)O)=[CH:44][CH:45]=2)[CH:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[C:28]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:43]3[CH:42]=[C:41]4[C:46](=[CH:45][CH:44]=3)[NH:38][CH:39]=[CH:40]4)[CH:3]=[C:4]2[C:10]([C:11]([C:13]2[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=2[F:19])=[O:12])=[CH:9]1)=[O:37]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(-c4ccc5[nH]ccc5c4)cc23)c1F
Temperature: 70 °C

Procedure:
Propane-1-sulfonic acid {3-[5-bromo-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (11, 113 mg, 0.18 mmol) and 1H-indole-5-boronic acid (14, 44 mg, 0.27 mmol) are dissolved in 4 mL of tetrahydrofuran, then 2 mL of 1M aqueous potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (6.5 mg, 0.018 mmol, 10%) are added. The reaction mixture is heated at 70° C. overnight. The reaction is neutralized with acetic acid and diluted with ethyl acetate and water. The organic layer is washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is dissolved in 1 mL of dimethylformamide and purified by HPLC using a C8 column, eluting with water/acetonitrile and 0.1% trifluoroacetic acid, 40-85% acetonitrile at 15 mL per minute. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI)=[M+H+]+=669.5. This compound is a prodrug of P-0012, or can be further reacted to remove the dichlorobenzoyl protecting group to provide P-0012.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([O:30]C)=O)=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([NH:35][CH3:34])=[O:30])=[CH:25][C:24]=4[CH:32]=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(C(C)(C)C)cc4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N4-(4-tert-butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine with methylamine hydrochloride gave N4-(4-tert-butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.04 (d, 1H, J=2.4 Hz), 7.88 (d, 1H, 4.2 Hz), 7.58-7.30 (m, 7H), 2.94 (s, 3H), 1.33 (s, 9H); LCMS: ret. time: 22.86 min.; purity: 94%; MS (m/e): 434 (MH+).
Reaction SMILES: NC1C=CC(C(OC)=O)=CC=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)(C)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[CH:13]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: COC(=O)c1ccc(N)cc1
Solvent: CC(C)O
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C
Yield: 190.9 %

Procedure:
A solution of methyl 4-aminobenzoate (151 mg, 1.00 mmol) and 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol) in isopropanol (200 ml) was heated at reflux for 3 hours before the reaction was allowed to cool to ambient temperature. The solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×50 ml). Drying of this material yielded 4-(4-carbomethoxy)anilino)-6,7-dimethoxyquinazoline (363 mg, 97% yield) as a white solid:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12](C2C=CC(OC)=C(OC)C=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2].NC1C=C(C(F)=CC=1)C(N)=O.[CH2:37]([O:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[O:46][CH:47]([CH3:49])[CH3:48])[CH3:38].O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:42]2[CH:43]=[CH:44][C:45]([O:46][CH:47]([CH3:49])[CH3:48])=[C:40]([O:39][CH2:37][CH3:38])[CH:41]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Reactant: CCOc1cc(B(O)O)ccc1OC(C)C
Agent: NC(=O)c1cc(N)ccc1F
Agent: O=CC(=O)O
Solvent: O
Product: CCOc1cc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)ccc1OC(C)C
Yield: 55 %

Procedure:
21A was prepared in a procedure similar to that of 13A using 3-amino-6-fluorobenzamide, 3-ethoxy-4-isopropoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 55%. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.28 (s, 3H) 1.29 (s, 3H) 1.37 (t, J=7.03 Hz, 3H) 4.05 (q, J=7.03 Hz, 2H) 4.46-4.55 (m, 1H) 5.00 (s, 1H) 6.78-6.84 (m, 1H) 6.90-6.99 (m, 2H) 7.02 (dd, J=8.35, 2.20 Hz, 1H) 7.07-7.12 (m, 2H), LCMS: 391 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24](N2CC[C@@H](OS(C)(=O)=O)C2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:22]=[CH:23][C:24]([N:37]2[CH2:41][CH2:40][C@H:39]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:38]2)=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](OS(C)(=O)=O)C3)cc2)C1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@H](N4CCCC4)C3)cc2)C1
Temperature: 90 °C
Yield: 58.3 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-methansulfonyloxy-pyrrolidino)phenyl)piperazine (877 mg, 1.64 mmol) in toluene (10 mL) was added pyrrolidine (0.64 mL, 8.19 mmol), and the resulting solution was heated at 90° C. for 8 h. After checking consumption of the starting material with TLC, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 30-100% ethyl acetate-hexane and then 3-10% methanol-ethyl acetate to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazine (479 mg, 58%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>CN(C=O)C.O>[O:37]1[C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:16]3[C:15](=[O:18])[N:4]4[N:5]=[CH:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=5)=[C:2]([Cl:1])[C:3]4=[N:17]3)=[CH:28][CH:29]=2)=[CH:34][CH:35]=[N:36]1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (300 mg, 1.07 mmol), prepared as described in Example 354, in DMF (5 mL) was added K2CO3 (180 mg, 1.3 mmol) followed by 5-(4-(bromomethyl)phenyl)isoxazole (305 mg, 1.28 mmol), prepared as described in Example 250A. The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to RT, diluted with water (25 mL) and a precipitate formed. The solid was collected by filtration. The solid was washed with water (2×25 mL) followed by hexanes (20 mL). The solid was dried in a vacuum oven at 40° C. The title compound 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (450 mg, 96%) was obtained as a yellow solid. HPLC: 3.50 min; M+H=438.
Reaction SMILES: [CH:1]([C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([CH:13]([CH3:15])[CH3:14])[CH:7]=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=1)([CH3:3])[CH3:2]>O1CCCC1.[Ni]>[CH:1]([C:4]1[C:9]([NH2:10])=[C:8]([CH:13]([CH3:15])[CH3:14])[CH:7]=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N

Procedure:
11.9 g of 2,4-diisopropyl-6-(4-chlorophenoxy)-3-nitropyridine are dissolved in 120 ml of tetrahydrofuran and, after the addition of 12 g of Raney nickel (suspended in ethanol), hydrogenated under normal pressure at from +30° C. to +35° C. The reaction mixture is filtered over diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:3). 2,4-Diisopropyl-6-(4-chlorophenoxy)-3-aminopyridine is obtained in the form of a light-yellow crystalline powder, m.p. 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[CH:16][N:15](C3CCCCO3)[N:14]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40].CC#N>Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:17]([CH2:18][N:19]([CH3:31])[CH2:20][CH2:21][NH:22][CH3:23])=[CH:16][NH:15][N:14]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1c(Cl)cc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CNCCN(C)Cc1c[nH]nc1-c1cc(Cl)c(OC(C)C)c(Cl)c1
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A solution of tert-butyl N-[2-[([3-[3,5-dichloro-4-(propan-2-yloxy)phenyl]-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl)(methyl)amino]ethyl]-N-methylcarbamate (210 mg, 0.38 mmol, 1.00 equiv) in 3N hydrochloric acid (20 mL) was stirred at 40° C. overnight. The resulting solution was washed with 3×10 mL of dichloromethane. The aqueous layer was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to yield 106.4 mg (47%) of ([3-[3,5-dichloro-4-(propan-2-yloxy)phenyl]-1H-pyrazol-4-yl]methyl)(methyl)[2-(methylamino)ethyl]amine bis(trifluoroacetic acid) salt as a yellow oil. 1H-NMR (300 MHz, D2O): δ 7.94 (s, 1H), 7.56 (s, 2H), 4.89-4.52 (m, 1H), 4.44 (s, 2H), 3.29 (s, 4H), 2.62 (d, J=4.5 Hz, 6H), 1.32 (d, J=6.3 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.28 min, m/z=371.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S:11]([O-])([O-:14])(=[O:13])=[S:12]>>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:12][SH:11](=[O:14])=[O:13]
Reactant: O=S([O-])([O-])=S
Reactant: CN(C)c1ccc(N)cc1
Product: CN(C)c1ccc(N)c(S[SH](=O)=O)c1

Procedure:
In one embodiment, an N,N-dimethyl-1,4-diamino-benzene, 1, is oxidized in the presence of a thiosulfate to give a thiosulfonic acid S-{2-(amino)-5-(dimethylamino)-phenyl}ester (an amino-(N,N-disubstituted-amino)phenylthiosulfonic acid), 2, as illustrated in the following scheme:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: OCc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccn4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.23 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (5 mL), and 2-pyridinemethanol (62 mg), tributylphosphine (0.21 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.21 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (15 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.19 g, 70%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:13][C:12]([CH3:14])=[CH2:11])=[CH:3][C:2]=1[F:1]
Reactant: C=C(C)CCl
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(F)c(F)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 62.9 %

Procedure:
A mixture of 3,4-difluorophenol (2 g, 15.37 mmol), 3-chloro-2-methylpropene (1.66 mL, 16.91 mmol), and potassium carbonate (3.2 g, 23.06 mmol) in DMF (10 mL) was stirred at 85° C. for 6 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by flash column chromatography eluting with hexanes-EtOAc (2:1) to provide 1,2-difluoro-4-(2-methylallyloxy)benzene (731) (1.78 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.05 (q, J=9.5 Hz, 1H), 6.76-6.71 (m, 1H), 6.63-6.60 (m, 1H), 5.07 (s, 1H), 5.00 (s, 1H), 4.38 (s, 2H), 1.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Cc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(C)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-phenol to give (6-methoxy-1-p-tolyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[CH3:26][N:27]1CCOCC1.Cl.CN.Cl>C1COCC1>[CH3:26][NH:27][C:17](=[O:19])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
N-Benzyloxycarbonyl tert-leucine (24.7 mmol, 6.56 g) was taken up in dry THF (50 ml) and the solution cooled to -40° C. under a nitrogen atmosphere. Ethyl chloroformate (26 mmol, 2.84 g) was added and the solution left to stir for 10 min. N-methylmorpholine (52 mmol, 5.24 g) was added and the solution stirred for 50 min between -20° C. and -40° C. before adding neat methylamine hydrochloride (24.7 mmol, 1.67 g). The solution was allowed to warm to RT and stirred at this temperature for 18 hr. The solution was poured into 10% HCl (50 ml), extracted with EtOAc (50 ml×3), the combined organic layer washed with saturated sodium bicarbonate solution (1×55 ml), then brine (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give the title compound (5.72 g) as an off-white solid. δH (CDCl3) 1.0 (9H, s), 2.75 (3H, d), 3.6 (1H, d), 5.0-5.1 (2H, m), 5.65 (1H, d), 6.25 (1H, s), 7.25-7.4 (5H, m) and 8.0 (1H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:14])[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC(=N)C(Cl)(Cl)Cl)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:12][C:11](=[O:13])[C:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC(C)(COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(COCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of the N-Boc carboxylic acid 7 (1.6 g, 5.17 mmol) in 15 mL of CH2Cl2 at room temperature was added a 3 eq portion of tert-butyl-2,2,2-trichloroacetimidate (3.4 g). After overnight stirring at room temperature, the solvent was evaporated under reduced pressure. Purification via silica gel column chromatography (15% EtOAc in hexane) afforded 8 as a colorless oil (1.71 g, 90%): 1H NMR (CDCl3) δ 1.44 (9H, s), 1.45 (9H, s), 1.48 (3H, s), 3.66 (1H, d, J=8.8), 3.79-3.82 (1H, broad d), 4.48-4.58 (2H, m), 5.51 (1H, broad s), 7.28-7.35 (5H, m). Anal. (C20H31NO5) C, H, N.
Reaction SMILES: [F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:26][NH:27][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CNS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-aminomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.30 mmol) with methane sulfonyl chloride (1.40 mmol) and triethylamine (2.08 mmol) in dichloromethane (10 ml) at a temperature 25° C. for 2 hours followed by purifification of the compound using silica gel column chromatography in 75% yield.
Reaction SMILES: [N+:1]([C:4]([C:16](=[O:18])[CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)[CH2:21][CH2:20]1>C(O)C>[CH3:17][C:16]1[O:18][C:25]2([N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:30]([CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([F:13])([F:14])[F:15])[C:4]=1[N+:1]([O-:3])=[O:2])[CH2:29][CH2:28][CH2:27][CH2:26]2
Reactant: CC(=O)C(=Cc1ccccc1C(F)(F)F)[N+](=O)[O-]
Reactant: C1=C(N2CCOCC2)CCCC1
Solvent: CCO
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)C2CCCCC2(N2CCOCC2)O1

Procedure:
10.4 g (40 mmol) of 2-nitro-1-(2-trifluoromethylphenyl)-but-1-en-3-one and 6.7 g (40 mmol) of 1-morpholinocyclohexene are brought together in 20 ml of ethanol at room temperature. An exothermic reaction takes place and after a short time the product crystallizes in pale yellow crystals as an isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:4]=1[CH2:5][NH:6][C@H:7]1[C@H:11]([C:12]([O:14]C)=[O:13])[C@@H:10]([CH3:16])[NH:9][C@H:8]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:32]>>[ClH:32].[ClH:32].[C:12]([C@@H:11]1[C@@H:10]([CH3:16])[NH:9][C@@H:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:7]1[NH:6][CH2:5][C:4]1[CH:23]=[C:24]([O:27][C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:3]=1[O:2][CH3:1])([OH:14])=[O:13]
Reactant: COC(=O)[C@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N[C@@H]1C
Agent: Cl
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1[C@H](C(=O)O)[C@@H](C)N[C@H]1c1ccccc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of (2S,3S*,4R*,5R*)-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (162 mg, 0.37 mmol) in 6M HCl aq. solution (2.5 ml) was stirred and heated at a gentle reflux for 30 min. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo to give crude title compound as a dark red amorphous solid. This was recrystallized from ethanol-ether to give the pure title compound (133 mg, 72.5%) as a white solid. mp 137-140 ° C. ##STR9##
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:55])([CH3:57])[CH3:56])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (165 mg) in dry methylene chloride (4 ml) was added an excess of 2,6-lutidine (41 μl) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (49 μl) was added via syringe. After 1 hour the reaction mixture was diluted with ethyl acetate, extracted from saturated sodium bicarbonate, washed with brine and the organic phase dried over magnesium sulfate. Removal of the solvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:4)+1% methanol) gave the title compound (130 mg).