Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-chloro-4-fluorobenzaldehyde and 3-(trifluoromethyl)phenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:24][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C1COCC1>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:15]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]=[CH:27][N:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)[NH:24][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1
Reactant: COC(OC)N(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1ccc(-c2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
0.2 g (0.56 mmol) of 6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (see stage 19.5), 0.097 ml (0.67 mmol) of N,N-dimethylformamide dimethyl acetal and 0.112 ml (0.73 mmol) of triethylamine are stirred at RT for 24 h in 10 ml of THF until all the starting material has disappeared in the TLC. The reaction solution is concentrated to dryness in vacuo and the residue is chromatographed on a silica gel column. Crystallization from THF/hexane or ethyl acetate/hexane gives 4-(3-chloroanilino)-6-(4-[dimethylamino-methylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine; m.p.>300° C.; MS: (M)+=390.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])([OH:3])=O.[O:59]=[C:60]1[CH:64]=[CH:63][C:62](=[O:65])[N:61]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][NH2:74])=[O:72]>>[O:65]=[C:62]1[CH:63]=[CH:64][C:60](=[O:59])[N:61]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:71]([NH:73][NH:74][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][N:7]([CH3:58])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:54]([CH3:57])[CH2:55][CH3:56])[C@H:24]([O:52][CH3:53])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:50][CH3:51])[C@@H:34]([CH3:49])[C:35]([NH:37][C@@H:38]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:39]([NH2:41])=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:72]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 152, from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([N:5]2[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1n[nH]cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nn(-c2cccc(OC)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.9 g, 46%) as a pale-yellow oil.
Reaction SMILES: Br[CH2:2][C:3](=[O:34])/[C:4](=[N:31]/[O:32]C)/[C:5](N[C@@H]1C(=O)N2[C@@H]1SCC(CSC1N(C)N=C(O)C(=O)N=1)=C2C(O)=O)=[O:6].[C:35]([O:39]C(=O)CC(C)=O)([CH3:38])([CH3:37])[CH3:36].N([O-])=O.[Na+]>C(O)(=O)C.O>[C:35]([O:39][C:5](=[O:6])/[C:4](=[N:31]\[OH:32])/[C:3](=[O:34])[CH3:2])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CO/N=C(/C(=O)CBr)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The (6R,7R)-7-[4-bromo-2-[(Z)-methoxyimino]-3-oxobutyramido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid used as the starting material can be prepared as follows: 592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1C(=O)N([Br:22])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C/c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C/c1ccccc1CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a suspension of ethyl(E)-3-(2-methylphenyl)-2-propenoate (20.0 g; 105 mmol) and NBS (19.64 g; 110.3 mmol) in refluxing CCl4 was added benzoyl peroxide (1.27 g) and the mixture was stirred for 12 h. The solution was cooled to r.t., filtered and concentrated. Flash chromatography with EtOAc:hexane 5:95 yielded the title compound (14.18 g, 50%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[OH:17].Cl[C:19]([F:29])([F:28])C(C1C=CC=CC=1)=O>CC#N>[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[O:17][CH:19]([F:29])[F:28]
Reactant: Oc1c(Br)cc(Br)nc1Cl
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: FC(F)Oc1c(Br)cc(Br)nc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Potassium carbonate (K2CO3; 5.01 g, 36.3 mmol) and H2O (4 mL) were added to a microwave reaction vessel. 4,6-Dibromo-2-chloropyridin-3-ol (0.359 g, 1.25 mmol) was dissolved in CH3CN (4 mL) and added to the microwave reaction vessel. 2-Chloro-2,2-difluoro-1-phenylethanone (0.953 g, 5.00 mmol) was then added, and the microwave reaction vessel was sealed. The reaction mixture was heated with vigorous stirring with a large stir bar in a Biotage microwave reactor at 100° C. for 4 h. (The reaction mixture is biphasic, and the reaction will not proceed to completion without vigorous stirring.) The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was washed once more with H2O, dried and concentrated. The product was redissolved in CH2Cl2 and filtered through short plug of silica gel utilizing CH2Cl2 as the eluting solvent. The eluent was concentrated to provide the title compound as a light yellow low-melting solid (0.325 g, 0.963 mmol, 77%): 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 6.63 (t, J=73.1, 1H); EIMS m/z 337.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(N)nc32)cc1OCc1c(OC)ccc(F)c1F
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NC(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 110 °C

Procedure:
A mixture of 2-amino-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (29 mg) and acetic anhydride (3 mL) was stirred at 110° C. in a reaction vessel equipped with a reflux condenser for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution were added sodium methoxide (28% methanol solution, 2 mL) and water (1 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue was added a mixed solvent (n-hexane/ethyl acetate=1/1), and the precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give the title compound (20 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](C)[CH:5]=[CH:4][N+:3]=1[O-].[CH3:10][C:11]([O:13]C(C)=O)=[O:12]>>[C:11]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:12])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c(C)c1
Product: CC(=O)OCc1ccccn1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
Compound 2,4-Dimethylpyridine N-Oxide (4.47 g, 36.3 mmol) was dissolved in Ac2O (11 mL) and added dropwise to acetic anhydride (108 mL) heated to 110° C. The resulting solution was stirred at 110° C. for 1 hour and 15 minutes. Excess reagent was evaporated leaving the corresponding 2-[(acetyloxy)-methyl]pyridine which was used without further purification. To a solution of the protected alcohol in MeOH (5 mL) was added NaOH 2N (15 mL) at room temperature. The mixture was stirred at room temperature for 1.5 hours, extracted with EtOAc and washed with water. The solvent was evaporated giving a residue that was purified by column chromatography (4% MeOH in CH2Cl2) affording 1.54 g (34% overall yield) of colorless oil. 1H NMR (CD3OD) δ 8.29 (d, 1H, J=4.2 Hz, H-6); 7.40 (s, 1H, H-3); 7.11 (d, 1H, J=4.2 Hz, H-5); 5.10 (s, 1H, OH); 4.68 (s, 2H, CH2); 2.38 (s, 3H); 13C NMR (CD3OD) δ 162.4 C-2), 151.0 (C-4), 149.4 (C-6), 125.0 (C-3), 123.3 (C-5), 65.8 (CH2), 21.7 (Me).
Reaction SMILES: [OH-].[NH4+:2].[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>CCOCC>[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:2])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: NC(=O)c1ccc(I)cc1

Procedure:
A total of 20 ml of 15 M ammonium hydroxide was reacted with a solution of 5.4 g p-iodobenzoyl chloride in 25 ml of ether. The crude product was recovered as described in Example 3 and recrystallized from ethanol to yield 3.5 g of p-iodobenzamide as white crystals, m.p. 221°-223°, Rf 0.46.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[OH:1][C:2]1[N:10]=[C:9]([OH:11])[C:8]([I:19])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1ccc(O)nc1O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: NC(=O)c1cc(I)c(O)nc1O
Reaction time: 0.33 h

Procedure:
A mixture of compound 2,6-dihydroxynicotinamide (20 g, 0.13 mol) and NIS (29.2 g, 0.13 mol) in DCM (1000 mL) was stirred at r.t for 20 min. The mixture was concentrated in vacuo to afford crude compound 2,6-dihydroxy-5-iodonicotinamide. (50 g) which was used for the next step directly. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 11.04 (bs, 1H), 8.46 (s, 1H), 2.55 (s, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4](/[N:6]=[C:7](/[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)\SC)=O.[NH2:16][NH2:17].C1COCC1>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[NH:17][N:16]=[C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:6]=1
Reactant: NN
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Solvent: C1CCOC1
Product: CC(C)=Cc1nc(N2CCCC2)n[nH]1
Yield: 22.2 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 2, using (Z)-methyl N-3-methylbut-2-enoylpyrrolidine-1-carbimidothioate (3.69 g, 16.3 mmol, Eq: 1.00) and hydrazine 1M in THF (16.3 ml, 16.3 mmol, Eq: 1.00). Chromatography afforded 5-(2-Methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (695 mg, 22.2%) as white waxy solid. MS: m/z=193.1 (M+H+)
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: NC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)COc2ccccc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a suspension of 5 g (36.5 mmol) of salicylamide in 60 mL of N,N-dimethylformamide, 8.36 g (36.5 mmol) of 2-bromo-1-(3-methoxy-phenyl)-ethanone and 7.57 g (54.7 mmol) of potassium carbonate were added. The mixture was stirred at room temperature overnight. Water was added under stirring and the precipitate was filtered, washed with water and dried in vacuo to yield 9 g of the title compound (90%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([F:8])[C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of 2-chloro-1,3-difluoro-4-nitrobenzene (80 g, 415 mmol) and benzyl alcohol (47 g, 435 mmol) in DMF (500 mL) was treated with K2CO3 (120 g, 870 mmol) and stirred at RT overnight. The mixture was poured into water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (45 g, 39%). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (t, J=9.2 Hz, 1 H), 7.49-730 (m, 6 H), 5.40 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12](Cl)=[C:13]([Cl:16])[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([Cl:16])[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Reactant: Cc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2c(Cl)c(Cl)c(C(O)=NCCO)c(C(=O)O)c2Cl)cc1

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 0.79 g (6.38 millimols) of p-thiocresol, 2.52 g (18.24 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 20 hours. The mixture is acidified with dilute HCl solution and extracted with methylene chloride and the extracts are dried over sodium sulfate. After recrystallisation from toluene, 1.41 g (56% of theory) of the title compound are obtained: melting point 205°-9° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[O:21])[C:3]1=[O:32].[C:33]1([CH3:42])[CH:38]=[CH:37][CH:36]=[C:35]([N:39]=[C:40]=[O:41])[CH:34]=1>>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C:20]([CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:40]([NH:39][C:35]2[CH:34]=[C:33]([CH3:42])[CH:38]=[CH:37][CH:36]=2)=[O:41])[C:3]1=[O:32])=[O:21]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccc3ccccc3c2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3ccc4ccccc4c3)C2=O)c1

Procedure:
3-Amino-1,3-dihydro-1-(2-naphthoylmethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one, and 3-tolyl isocyanate
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C:18]2(OCC[O:32]2)[CH:17]=[CH:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]1[CH2:30][C:29]2[CH:28]=[C:27]([OH:31])[CH:26]=[CH:25][C:24]=2[C@@H:23]2[C@@H:14]1[C@H:15]1[C@@:19]([CH2:21][CH2:22]2)([CH3:20])[C:18](=[O:32])[CH:17]=[CH:16]1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 97.3 %

Procedure:
2.6 g of 7α-(11-hydroxyundecyl)-17,17-ethylenedioxy-1,3,5(10),15-estratetraen-3-ol is stirred in 57 ml of acetone and 6.6 ml of water at 25° with 164 mg of p-toluenesulfonic acid for 2.5 hours. Then the mixture is concentrated to one-third, precipitated with ice/aqueous sodium chloride solution, filtered off, taken up in dichloromethane, washed neutral, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 2.3 g of crude 7α-(11-hydroxyundecyl)-1,3,5(10),15-estratetraen-3-ol-17-one, [α]D =-14.0°, as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.048 mMol) 2-nitrobenzoyl chloride, 0.015 gm (92%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]([O:20]C)=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=1
Reactant: COC(=O)c1cccc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of methyl 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylate (13.6 g, 46.3 mmol), and 1N NaOH (92.5 mL, 92.5 mmol) in 225 mL of ethanol is refluxed for 5 h. Water is added to the mixture and the aqueous layer is washed with ether. The aqueous layer is acidified with 1N HCl and extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate/hexanes to yield 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid melting at 202-203° C. 1HNMR CDCl3:300 MHz): δ 7.87 (1H, d),7.65(2H, d), 7.47(1H, d), 7.35 (1H, t), 7.25 (2H, d), 2.05(3H, s). MS m/z 279 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CO.ClCCl>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:24]=1
Reactant: Oc1cccnc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1cccnc1
Yield: 14 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-hydroxypyridine (12 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 9 mg (14%) of the titled compound. ESI-MS m/z 391 (M+Na+), 367 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[CH2:31]([NH2:34])[C:32]#[CH:33]>C(O)CCC.CO>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]3[C:32]([CH3:33])=[CH:31][N:34]=[C:7]3[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: C#CCN
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Solvent: CCCCO
Solvent: CO
Product: Cc1cnc2n1-c1cc(Cl)c(Cl)cc1N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)C2

Procedure:
A mixture of 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (452 mg, 1.0 mmol), propargylamine (110 mg, 2.0 mmol) and red mercuric oxide (216 mg, 1.0 mmol) in n-butanol (5 ml) was heated at reflux for 10 hours. The mixture was cooled, diluted with methanol (50 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and purified by flash chromatography (eluting with ethyl acetate:methanol=3:1). The product was further purified by trituration with ether to give the title compound as a buff solid, (170 mg, 38%), m.p. 243°-246° C.