Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:34][I:35]>C(Cl)Cl>[I-:35].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:3][N+:2]([CH3:34])([CH3:1])[CH3:33])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CI
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Solvent: ClCCl
Product: C[N+](C)(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Product: [I-]
Reaction time: 8 h

Procedure:
To a solution of (R)-benzyl 4-(dimethylamino)-3-(6-phenoxypyridine-3-sulfonamido)butanoate in CH2Cl2 (2 mL) was added methyl iodide (100 pit). The reaction was stirred overnight and concentrated to dryness to give the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H), 7.39-7.29 (m, 5H), 7.13 (d, J=8.1 Hz, 2H), 6.99 (d, 1H, J=8.8 Hz, 1H) 5.14-5.03 (m, 2H), 4.49-4.41 (m, 1H), 4.36-4.30 (m, 1H), 3.74-3.71 (m, 1H), 3.42 (s, 9H), 2.91-2.84 (m, 1H), 2.46-2.42 (m, 1H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([N:27]2[CH2:28][CH2:29][C:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:33]([F:34])=[C:20]([F:19])[CH:21]=3)([OH:30])[CH2:25][CH2:26]2)=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1-c1ccncc1
Reactant: OC1(Cc2ccc(F)c(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (0.30 g), 4-(3,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.38 g), HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.32 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Li+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:3][CH2:2][Cl:1])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1CCCl
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
1.4 g of 5-(2-chloroethyl)-2'-deoxyuridine and 1.3 g of triphenylphosphine were dissolved in 20 ml of dimethylformamide and stirred while 1.2 g of lithium azide were added to give a solution within 5 minutes at room temperature. 1.7 g of carbon tetrabromide were added portionwise during 5 minutes to give a hazy orange colored solution which was stirred at room temperature for 17 hours. 5 ml of methanol were added to give a clear solution. After 0.5 hour, the solvents were removed by evaporation under an oil pump vacuum to give a gum which was partitioned between 30 ml of ethyl acetate and 20 ml of water. The white solid which formed was removed by filtration to give 0.64 g of crude product of melting point 179°-182° C. (decomposition). This crude product was stirred with methanol and then removed by filtration to give 0.48 g of pure 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)-uridine of melting point 197°-199° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.Cl.[C:49](Cl)(=[O:59])[O:50][C@@H:51]1[CH:56]2[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]2)[CH2:52]1.N1C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:47])[CH:5]=[C:6]([Cl:46])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]([C:49]([O:50][C@@H:51]2[CH:56]3[CH2:57][CH2:58][N:53]([CH2:54][CH2:55]3)[CH2:52]2)=[O:59])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[CH:33][CH:32]=1)(=[O:29])=[O:30])=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CNc3ccccc3F)cc2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3F)cc2)cc1OC
Temperature: 80 °C
Yield: 16.3 %

Procedure:
To a stirred solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[4-[(2-fluoroanilino)methyl]phenyl]sulfonylpyrrolidine-2-carboxylate (105 mg, 0.15 mmol) in acetonitrile (3.2 mL) was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (131 mg, 0.6 mmol) and pyridine (0.12 mL), and the mixture was heated to 80° C. in a microwave for 6 minutes. Further (R)-quinuclidin-3-yl carbonochloridate hydrochloride (34 mg, 0.15 mmol) was added, and the mixture was heated to 80° C. in a microwave for 6 minutes. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The layers were separated and the water was removed in vacuo. Purification of the residue from the aqueous layer was achieved by preparative HPLC to afford the title compound as a white solid (21 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([NH2:9])=[C:4]([NH2:10])[N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:9]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[NH:10]2)=[C:6]([OH:8])[N:7]=1
Reactant: Nc1nc(N)c(N)c(O)n1
Reactant: O=Cc1ccc(F)cc1
Product: Nc1nc(O)c2nc(-c3ccc(F)cc3)[nH]c2n1
Yield: 60 %

Procedure:
This compound was synthesized from commercially available 2,5,6-triamino-4-hydroxypyrimidine (40 mmol) and 4-fluorobenzaldehyde (40 mmol), yielding the title compound in 60% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].CO>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-chloropropanesulfonyl chloride (commercially available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an ice-water bath was added t-butylamine (commercially available, for example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and the cartridge eluted with methanol (2 column volumes). The methanol fraction was concentrated in vacuo to give the title compound as a white waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151°-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 487 (M+ +1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]#[N:31])[CH2:21][C:20](=[O:32])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccco4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K5) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown powder (73 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 7.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.362 g, 1.14 mmol) in DMSO (1.5 mL) was added 4-(2-chloroethyl)morpholine (0.466 g, 2.50 mmol) and Cs2CO3 (1.85 g, 5.67 mmol). After stirring at ambient temperature for 5.5 h, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×40 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) yielded the title compound (37.3 mg, 7%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=1.0 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 6H), 7.29 (d, J=7.5 Hz, 1H), 6.09-6.06 (m, 2H), 5.06 (s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.68 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.5 Hz, 2H) 2.52 (t, J=4.5 Hz, 4H); ESI MS m/z 431 [M+H]+; HPLC (Method A) 98.9% (AUC), tR=14.0 min.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>O.CO>[NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4]([NH:20][NH2:21])=[O:5]
Reactant: CCOC(=O)c1c(N)nc(C)c(NC(C)=O)c1C
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(=O)Nc1c(C)nc(N)c(C(=O)NN)c1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-amino-5-acetamido-4,6-dimethylnicotinate (45.3 g., 0.18 mole) and hydrazine hydrate (100 ml.) is heated in an oil bath with stirring at 120° C. for two hours. The mixture is cooled, the solid collected, and a second crop of solid obtained by evaporating the mother liquor to about half its initial volume. The combined solids melt at 293° C. (dec.), yield 38.1 g. (89%). Analytically pure compound is obtained by dissolving the solid in about six and one-half parts (volume by weight) of hot water and diluting the filtered solution with methanol. The purified product decomposed at about 309° C. with only partial melting.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.OO.C=CCCCC.C(=O)([O-])[O-:35].[Na+].[Na+]>CO>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:35])[NH2:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Agent: OO
Agent: [Na+]
Solvent: C=CCCCC
Solvent: CO
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.293 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 4 ml of methanol. 1.1 ml of hydrogen peroxide (30%), 0.32 ml of 1-hexene and 22 mg of sodium carbonate are added and the reaction mixture is stirred for 16 hours at RT. The product is isolated by filtration and washed (methanol/water) to give N-(3-trifluoromethyl-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 240°-242°, FAB-MS: 360 (M+ +H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29][NH2:30].[H][H]>C(O)C.[C].[Pd].O>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: COCCN
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COCCNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 31 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (176 mg, 1.28 mmol) and 2-methoxyethylamine (105 mg, 1.39 mmol), and this was heated to reflux for 3.5 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (7 mL) of the crystals obtained was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 6 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (102 mg, 31% yield).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:33][N:34]([CH:43](Br)[C:44](N)=O)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[O:48]1CCCC1>>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:44][C:43]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:48])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: CN(CCc1ccccc1)C(Br)C(N)=O
Reactant: C1CCOC1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: [H-]
Agent: [Na+]
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
998 mg of 6-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-1-methylethyl-ester (2.4 mmol) is introduced into 10 ml of dry tetrahydrofuran and deprotonated at 0° C. with 72 mg of sodium hydride (80% suspension in oil) (2.4 mmol). Then, it is stirred for 20 minutes at room temperature, mixed with 630 mg of 2-[N-methyl-N-(2-phenylethyl)-amino]-2-bromoacetamide (2.4 mmol)--dissolved in 10 ml of tetrahydrofuran--stirred for another 5 hours at room temperature, filtered on diatomaceous earth, and then the solvent is drawn off in a vacuum. The crude product that is obtained is recrystallized from dichloromethane/diethyl ether, and 1.22 g of 6-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)amino]-2-oxoethyl}-9H-pyrido-[3,4-b]indole-3-carboxylic acid-(1-methyl-ethyl)-ester is obtained.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[N:3]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([CH:4]([CH3:5])[CH3:6])=[CH:23][CH:22]=2)[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:16]
Reactant: CC(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CNN
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(-c2nn(C)c(=O)c3ccccc23)cc1
Yield: 67 %

Procedure:
Methyl hydrazine (8.05 g, 0.175 mol) was added to a mixture of 2-(4-isopropylbenzoyl)benzoic acid (40.2 g, 0.15 mol) in toluene (350 mL) and the mixture was heated to reflux for 3 hours with the removal of water with a Dean Stark trap. The reaction mixture was hot filtered through celite, the filtrate was concentrated to 125 mL and the filtrate was diluted with hexane (100 mL) and cooled. A solid was collected by filtration to afford 27.97 g (67%) of 2-methyl-4-(4-isopropylphenyl)-1-(2H)-phthalazinone, m.p. 107°-107.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:19]
Reactant: NCCCC(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[C:16]([NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].C(N(CC)CC)C.ClC1C=CC=C(F)C=1CN1C2C=CC=CC=2S(=O)(=O)N(C2C=CC(=O)N(C)C=2)C1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:32](=[O:33])[N:21]([CH2:22][C:23]3[C:24]([F:31])=[CH:25][C:26]([F:30])=[CH:27][C:28]=3[F:29])[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]2(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(NS(=O)(=O)c2cccnc2NCc2c(F)cc(F)cc2F)cc1OC
Agent: Cn1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)ccc1=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC
Yield: 59.1 %

Procedure:
The title compound (63 mg, 0.13 mmol) was prepared from N-(3,4-dimethoxyphenyl)-2-[(2,4,6-trifluorobenzyl)amino]pyridine-3-sulfonamide (98 mg, 0.22 mmol), 1,1′-carbonyldiimidazole (143 mg, 0.88 mmol) and triethylamine (0.06 mL, 0.44 mmol) using the methods of (132).
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](OC)([O:21]C)[CH2:13][C:12]=1[CH2:11][CH2:10]3)#[N:2].O.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(C)(C)C>[C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH2:16][CH2:15][C:14](=[O:21])[CH2:13][C:12]=1[CH2:11][CH2:10]3)#[N:2]
Reactant: COC1(OC)CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C#N)CC[C@@H]32)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2C#N)CC(=O)CC4

Procedure:
3 g of 17β-cyano-3,3-dimethoxyestr-5(10)-ene are suspended in a mixture of 24 ml of dichloromethane and 70 ml of t-butanol. After addition of 28 ml of water and 0.11 ml of 60% perchloric acid, the batch is stirred until fully reacted, admixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered and the filtrate is evaporated to dryness to leave 17β-cyanoestr-5(10)-en-3-one which is further processed without purification.