Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1>CCO.CO.[Pd]>[CH3:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccncn2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.7 %

Procedure:
To a solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.186 mmol) and TEA (52 μL, 0.371 mmol) in EtOH (5 mL) and MeOH (1 mL) was added 10% (w/w) palladium on carbon (50 mg, 0.048 mmol). The suspension was transferred to a hydrogenation bottle, and installed in a Fisher-Porter hydrogenation apparatus. The bottle was charged with H2 (50 psi) and stirred at rt for 72 h. The reaction mixture was filtered through Celite and concentrated to generate 90 mg (0.178 mmol, 96%) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.10 (s, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.53-7.57 (m, 1H), 7.40-7.50 (m, 4H), 7.30 (t, J=7.6 Hz, 1H), 6.89 (d, J=5.3 Hz, 1H), 1.43 (s, 9H). MS (ESI): 504.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 106.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 1-methanesulfonyl-piperazine (0.109 g, 0.55 mmol) and triethylamine (0.38 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.139 g, 0.55 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methanesulfonyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 22a (0.2 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](OC)=[CH2:4].[C:8]([O:12][C:13]([NH:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH3:37])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH:37]=[C:3]([N:2]([CH3:7])[CH3:1])[CH3:4])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(COC(=O)C2=C(C)CSC3C(NC(=O)OC(C)(C)C)C(=O)N23)cc1
Reactant: C=C(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(C=C(C)N(C)C)CSC3C(NC(=O)OC(C)(C)C)C(=O)N23)cc1
Temperature: 80 °C

Procedure:
1-Dimethylamino-1-methoxyethylene (4 cc) is added, in the course of 55 minutes, to a solution of 7-t-butoxycarbonylamino-2-(4-methoxybenzyloxycarbonyl)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.75 g) in dimethylformamide (25 cc), heated to 80° C., the temperature being kept at 80° C. This yields a solution of 7-t-butoxycarbonylamino-3-(2-dimethylaminoprop-1-en-1-yl)-2-(4-methoxybenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is poured into a mixture of iced water (20 cc) and ethyl acetate (150 cc). The organic phase is washed with water (2×200 cc), dried over sodium sulphate and filtered in the presence of decolorising charcoal and the filtrate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (45 g) (diameter of the column: 3 cm, height: 15 cm). Elution is carried out with a 20/80 (by volume) ethyl acetate/cyclohexane mixture (500 cc) and 40 cc fractions are collected. Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) and this yields a mixture (70/30) of 3-acetonyl-7-t-butoxycarbonylamino-2-(4-methoxybenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene (0.25 g) in the form of an ochre solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[OH:18][CH2:19][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>CCOCC>[C:29]([O:28][C:27](=[O:33])[NH:26][C:20]([CH3:25])([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(C)CC(C)(COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Yield: 111.3 %

Procedure:
8-Chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.613 mmol), prepared as described in Example 2, Part C, and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.284 g, 1.226 mmol) were subjected to ether synthesis as described in Example 2, Part D, to afford tert-butyl(2,4-dimethyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.3 g, 28% yield) as pale yellow solid. LC/MS (ESI) m/e 440.2 [(M+H)+, calcd for C25H34N3O4 440.2]; LC/MS retention time (method C): tR=2.67 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7](F)(F)F)[N:6]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:14]=1[C:15](Cl)=[O:16].Cl>C1COCC1.N1C=CC=CC=1>[Br:11][C:4]1[S:3][C:2]([NH:1][C:15](=[O:16])[C:14]2[C:13]([F:12])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[N:6][C:5]=1[CH3:7]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1nc(C(F)(F)F)c(Br)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1Br
Temperature: 0 °C
Yield: 83 %

Procedure:
2-Amino-5-bromo-4-trifluoromethylthiazole (0.8 g) was dissolved in 3 mL of 1:1 mixture of THF and pyridine. 2,6-difluorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on silica gel gave the title compound as a white solid. Yield 83%.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4]I.[CH2:6]([O:13][C:14]1[C:15](=[O:20])[NH:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[CH2:6]([O:13][C:14]1[C:15](=[O:20])[N:16]([CH2:4][CH2:3][CH2:2][I:1])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ICCCI
Reactant: O=c1[nH]cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(OCc2ccccc2)cccn1CCCI
Temperature: 70 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 1,3-diiodopropane (7.1 mL, 63 mmol) in tetrahydrofuran (50 mL) was added 3-(benzyloxy)pyridin-2(1H)-one (1.28 g, 6.3 mmol) and Na2CO3 (0.67 g, 6.3 mmol). The mixture was then stirred at 70° C. for 1 day. Reaction progress was monitored by ES-MS. After ESMS showed essentially complete consumption of the starting material 3-(benzyloxy)pyridin-2(1H)-one, the reaction was stopped. Then the reaction mixture was filtered, concentrated, and subjected to flash column chromatography (eluent: hexane:ethylacetate 1:1). Compound 7 was obtained (240 mg, 10% yield). Analysis: ES-MS (positive ion in MeOH/H2O): m/z=370.2, ([M+H]+, calculated: 370.03).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([NH:17][C:18]([N:20]3[CH2:23][CH:22]([CH2:24][NH:25]C(=O)OC(C)(C)C)[CH2:21]3)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][CH2:24][CH:22]1[CH2:21][N:20]([C:18]([NH:17][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[N+:14]([O-:16])=[O:15])=[O:19])[CH2:23]1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl (1-(4′-fluoro-4-nitrobiphenyl-3-ylcarbamoyl)azetidin-3-yl)methylcarbamate (2.0 g, 4.5 mmol) in DCM (60 mL) was added TFA (8 mL, 104 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. The residue was basified with a saturated aqueous solution of NaHCO3 and extracted with a 15% MeOH in DCM. The organic layer was dried over Na2SO4 and concentrated to afford 3-(aminomethyl)-N-(4′-fluoro-4-nitro-[1,1′-biphenyl]-3-yl)azetidine-1-carboxamide (1.6 g, 100% yield) as yellow syrup which is used in the next step as such without any further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)C1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclohexanone (0.11 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 90 mg (96%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[C:5]=2[CH:6]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([O:11][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[C:5]=2[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCCc2sc(Br)cc21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(Br)cc21
Yield: 91 %

Procedure:
To a solution of 2-bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (5.0 g, 21 mmol) that was obtained in Example 8 (8a) in N,N-dimethylformamide (30 ml) were added successively imidazole (2.9 g, 43 mmol) and t-butyldimethylchlorosilane (3.5 g, 24 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (6.8 g) in a yield of 91% as a colourless oily product.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C(#N)C>[N:1]1[CH:6]=[C:5]([NH:7][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc2c(c1)CCC2
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cnc2c(c1)CCC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridin-3-amine (D) (250 mg, 1.86 mmol) was dissolved in acetonitrile. The reaction mixture was added pyridine (0.18 mL, 2.23 mmol) and phenyl chloroformate (0.26 mL, 2.05 mmol) and stirred at room temperature for 3 h under N2. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylcarbamate (E). (372 mg, 78%)
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH2:3][CH2:4][C:5]#[N:6].[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:7]1[N:8]=[CH:9][C:10]([NH:13][C:27]([C:25]2[N:26]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:23][C:24]=2[C:30]([F:32])([F:33])[F:31])=[O:28])=[CH:11][CH:12]=1)#[N:6]
Reactant: CN(CCC#N)c1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCC#N)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 34.7 %

Procedure:
3-[Methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile (103 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (108 mg, 0.423 mmol), Et3N (297 uL, 2.11 mmol) and BOP (196 mg. 0.444 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a solid (61 mg). ES-MS calcd for C20H16F3N5O2 (m/e) 415.38, obsd 416.1 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26](Br)[CH:27]=[CH2:28]>C1(C)C=CC=CC=1>[CH2:28]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
8 parts of 2-(4-phenoxyphenyl) pyrrolidine, 3.3 parts of triethylamine, 4 parts of allyl bromide and 70 parts of toluene were refluxed for 5 hours. After cooling and filtration, there were obtained by distillation 7.7 parts of 1-allyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.2 mm Hg: 148°-150° C., nD26 =1.5695, M.P. of its acid fumarate: 115°-116° C. (isopropanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[CH:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Prepared according to Procedure B using ethyl 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoate (11.4 g, 44.3 mmol; described herein) in THF (40 mL), and sodium hydroxide (1.22 g, 53.2 mmol) in water (10 mL). The reaction was stirred at rt for 2 h, affording 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=230.0 (M+1).
Reaction SMILES: [CH3:1][CH2:2]/[C:3](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1)\[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33](O)=[O:34]>>[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:2][CH3:1])=[CH:10][CH:9]=1)=[O:34]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Product: CCC(=C(c1ccc(OCCN(C)C)cc1)c1ccc(OC(=O)c2c(C)cc(C)cc2C)cc1)c1ccccc1

Procedure:
This was prepared using 4-OH tamoxifen (Example 19) and 2,4,6-trimethylbenzoic acid following the procedure described in Example 30.
Reaction SMILES: S(O[C@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C)C=O>[N:26]([C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13]([O:15][CH3:16])=[O:14])[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of 1-[2-deoxy-3-O-mesyl-5-O-methoxycarbonyl-β-D-threopentofuranosyl]-thymine (5.0 g, 13.2 mmoles) from Example A13 and sodium azide (1.07 g, 16.5 mmoles) in dimethylformamide (40 mL) was heated at 85°-90° C. for 4 h. The suspension was cooled to ambient temperature poured into 300 mL of water and the aqueous solution extracted with 3×100 mL portions of ethyl acetate. The combined organic extracts were washed with 2×100 mL portions of water and concentrated by rotary evaporation affording 3.88 g (90.2%) of 3'-azido-3'-deoxy-5'-O-(methoxycarbonyl)thymidine as a colorless oil: 1H NMR (CDCl3) δ1.91 (d, J=1.15 Hz, 3H, C-5-CH3), 2.30-2.49 (m, 2H, C-2'H), 3.83 (s, 3H, CO2CH3), 3.97-4.44 (m, 4H, C-3'H, C-4'H and C-5'H), 6.21 (t, J=6.26 Hz, 1H, C-1'H), 7.29 (q, J=1.15 Hz, 1H, C-6H) and 8.75 (broad, 1H, NH); 13C NMR (CDCl3) δ12.42, 37.57, 55.28, 60.04, 66.39, 81.56, 84.94, 111.38, 135.28, 150.45, 155.18 and 164.03; TLC, Rf =0.78, silica gel, CHCl3 :CH3OH/90:10.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[Br:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(16-bromohexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.I[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[N:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3)CC2)nc1C
Yield: 55 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (90 mg) described in Preparation Example 4 and (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (193 mg) described in Preparation Example 120 and by the reaction and treatment in the same manner as in Example 4, the title compound (108 mg) was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:16]2[N:17]=[C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>>[C:3]1([S:9][C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:21]([CH:23]4[CH2:24][CH2:25]4)=[O:22])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1nc2cccc(Sc3ccccc3)n2n1)C1CC1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
A microwave tube was charged with sodium hydride (0.036 g, 0.889 mmol) in anhydrous well-degassed dioxane (1 mL). Thiophenol (0.091 mL, 0.889 mmol) was added dropwise and the mixture allowed to stir for 5 min. Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol) was added and the mixture was heated to 160° C. for 20 min in a microwave. The crude product was purified by preparatory HPLC. LCMS method: 2, RT: 4.32 min, MI: 311 [M+1]. NMR (1H, DMSO, 300 MHz): 11.17 (s, 1H), 7.70 (m, 2H), 7.57 (m, 3H), 7.49 (d, 2H), 6.28 (t, 1H), 2.03 (brs, 1H), 0.83 (d, 4H)