Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:35][C:36]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:39]4[CH2:40][CH2:41][C:36]([F:42])([F:35])[CH2:37][CH2:38]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: FC1(F)CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC(F)(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (50 mg) in 1-methyl-2-pyrrolidinone (3 mL) is added N,N-diisopropylethylamine (0.03 mL) and 4,4-difluoropiperidine from Preparation No. 37 (50 mg). The reaction mixture is stirred at room temperature overnight and then heated at 50° C. for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude solid is recrystallized from CH2Cl2/hexanes to afford 51.5 mg (84%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.CCOC(C)=O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-bromo-7-(1-bromo ethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11.1 g, 31.5 mmol) and sodium azide (6.15 g, 94.6 mmol) in dimethyl formamide (DMF) (100 mL) was stirred at room temperature for 2 h. After diluting with EtOAc, the mixture was washed with water, brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to provide the product (8.68 g, 87.6%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z=314.0. Found: 313.9. 1H NMR (DMSO-d6, 300 MHz) δ 7.15 (1H, s), 4.83 (1H, q, J=6.6 Hz), 2.69 (3H, s), 1.48 (3H, d, J=6.6 Hz) ppm.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH:15]([C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[O:21][CH:22]=1>S(=O)(=O)(O)O.CC(C)=O>[O:14]=[C:15]([C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([Si:23]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:28][CH3:29])[O:21][CH:22]=1
Reactant: CCCCCCCCCCCC#CC(O)CCc1coc([Si](CC)(CC)CC)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC#CC(=O)CCc1coc([Si](CC)(CC)CC)c1
Reaction time: 0.42 h

Procedure:
Jones reagent (a 2.67M solution in sulfuric acid; 50 μl, 0.14 mmol) was added to a solution of 4-(3-hydroxy-4-hexadecynyl)-2-triethylsilylfuran (53.6 mg, 0.13 mmol) in acetone (5 ml) at 0°. After 25 minutes, the mixture was quenched with ethanol, diluted with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by preparative silica plates to give the titled ketone.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:37])[CH2:27][CH2:26]3)[N:20]=[N:19][C:18]=2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OCC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 4-(4-benzyloxy-phenyl)-3-butyl-6-(piperidin-4-ylmethoxy)-pyridazine dihydro chloride (0.37 mmol, 190 mg) and paraformaldehyde (6.7 mmol, 611 mg) in DCM was stirred for 20 min then sodium triacetoxyborohydride (6.7 mmol, 1.41 g) was added. Stirring was continued overnight. Solvent was evaporated, and to the residue was added saturated NaHCO3. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant product was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-ylmethoxy)-pyridazine.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([N:6]([C:22](=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[CH3:31])[N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)=[O:5].[I-:33].[Na+]>CC(C)=O>[I:33][CH2:2][O:3][C:4]([N:6]([C:22](=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=1[CH3:31])[N:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)=[O:5]
Reactant: COc1cccc(C(=O)N(C(=O)OCCl)N(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C(=O)N(C(=O)OCI)N(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 30 °C

Procedure:
A solution of N′-tert-butyl-N′-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine carboxylic acid chloromethyl ester (15.0 g, 32.5 mmol) in 40 mL of acetone was added sodium iodide (9.8 g, 65.1 mmol)and heated to 30° C. for 3 h. The acetone was removed and the resulting slurry was treated with ether. The resulting white precipitated solids were filtered off, and the ether was then concentrated to afford yellow solids. Recrystallization from ether/hexanes afforded tannish crystals (20 g, 96%). 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.64 (s, 9H), 1.97 (bs, 3H), 2.25 (s, 6H), 3.79 (s, 3H), 5.76 (s, 2H), 6,78-7.1 (m, 6H). Mp=70-72° C.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21](=[O:42])[CH2:22][N:23]1[C:28](=[O:29])[C:27]([Cl:30])=[C:26]([NH:31][C@@H:32]2[CH2:37][C@@H:36]3[CH2:38][C@@H:34]([C:35]3([CH3:40])[CH3:39])[C@H:33]2[CH3:41])[CH:25]=[N:24]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[Cl:30][C:27]1[C:28](=[O:29])[N:23]([CH2:22][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[O:12][CH2:11][CH2:10][OH:9])=[O:42])[N:24]=[CH:25][C:26]=1[NH:31][C@@H:32]1[CH2:37][C@@H:36]2[CH2:38][C@@H:34]([C:35]2([CH3:40])[CH3:39])[C@H:33]1[CH3:41]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3OCCOC(=O)c3ccccc3)c(=O)c1Cl)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3OCCO)c(=O)c1Cl)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
2-({4-[({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]pyridin-3-yl}oxy)ethyl benzoate (23.8 mg, 0.04 mmol) in methanol (2 mL) was mixed with 1 M aqueous sodium hydroxide (0.12 mL, 0.12 mmol) at room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated azeotropically with ethanol, and the resulting residue was purified by silica gel chromatography (ethyl acetate/methanol=10/1 to 8/1) to give the desired product (19.7 mg, 100% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:22][CH2:23][CH2:24][O:25]C(=O)C)[CH:21]=[C:14]3[C:15]=2[C:10](=[CH:11][CH:12]=[CH:13]3)[C:9]1=[O:29].Cl>CO>[OH:7][N:8]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:21]=[C:14]3[C:15]=2[C:10](=[CH:11][CH:12]=[CH:13]3)[C:9]1=[O:29]
Reactant: CC(=O)OCCOc1cc2c3c(cccc3c1)C(=O)N(O)C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1c2cccc3cc(OCCO)cc(c23)C(=O)N1O
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of potassium carbonate (0.4 g, 2.9 mmol) and 2-hydroxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione (0.3 g, 1.0 mmol, from Example 23) in methanol (20 mL) was stirred for 2 hours. The mixture was acidified with 1N HCl to pH 4. The precipitate formed was filtered, washed with water, and dried to give 0.2 g of the title compound, mp 242-244° C.;
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].Cl.[O:15]1[C:19]([CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18][CH:17]=[N:16]1>CO>[C:7]([NH:22][CH:21]([C:23]([OH:25])=[O:24])[CH2:20][C:19]1[O:15][N:16]=[CH:17][CH:18]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(Cc1ccno1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)NC(Cc1ccno1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
20 ml of pyridine and 20 ml of acetic anhydride were added to a solution of 12.45 g of 3-(5-isoxazolyl)-DL-alanine hydrochloride (prepared as described in Preparation 6) dissolved in 100 ml of methanol, whilst ice-cooling. The mixture was then stirred at room temperature for 8 hours, after which it was allowing to stand overnight. The mixture was then freed from the solvent by evaporation under reduced pressure. The residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 10.39 g (82.3%) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH:28]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[C:39]([CH:42]=O)[CH:38]=[CH:37]2)([CH3:30])[CH3:29]>C(O)C>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:42]/[C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[C:32]([O:31][CH:28]([CH3:30])[CH3:29])[CH:33]=[CH:34][CH:35]=4)[N:40]=3)=[CH:16][CH:17]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Solvent: CCO
Product: CC(C)Oc1cccc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 3.34 mmol) in Ethanol (25 mL) was added 8-isopropoxyquinoline-2-carbaldehyde (0.719 g, 3.34 mmol) and stirred at ambient temperature overnight. The reaction was concentrated and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.33 g, 2.27 mmol, 67.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[N:12]3[N:19]=[CH:20][C:21]([CH:22]=[C:30]4[NH:24][C:25](=[O:26])[NH:27][C:28]4=[O:29])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cccc(Cl)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 70 °C

Procedure:
To 5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (26 mg, 0.08 mmol) in EtOH was added hydantoin (8 mg, 0.08 mmol) and piperidine (8 μl, 0.08 mmol). The mixture was stirred at 70° C. over the weekend. Insolubilities were filtered off, and filtrate was concentrated under reduced pressure. Filtrate was then dissolved in MeOH and, isolated by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=410)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.ClCCl.C(N(CC)CC)C>CO>[C:13]([O:12][C:11]([NH:10][CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]([O:12][CH3:13])=[O:17])[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc(C(C)NC(=O)OC(C)(C)C)c1
Reaction time: 17 h
Yield: 150.4 %

Procedure:
To a solution of tert-butyl 1-(3-bromophenyl)ethylcarbamate (300 mg, 1 mmol) in methanol (10 mL) was added [1,1′-bis(diphenyl-phosphino)ferrocene]palladium [II]chloride, 1:1 complex with dichloromethane (146 mg, 0.2 mmol) then triethylamine (0.28 mL, 2 mmol). The mixture was evacuated and backfilled with carbon monoxide four times and was then heated to reflux and stirred under an atmosphere of carbon monoxide for 17 hours. After this time the mixture was filtered through Celite to give a brown solid which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give methyl 3-{1-[(tert-butoxycarbonyl)amino]ethyl}benzoate (210 mg, 75%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:25][CH3:26])=[C:7]([CH:12]=[C:13]([NH:15][C:16]([NH:18][C:19](=[O:24])/[CH:20]=[CH:21]/[O:22][CH3:23])=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:28].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CO.O>[C:1]([C:5]1[C:6]([O:25][CH3:26])=[C:7]([CH:12]=[C:13]([N:15]2[CH:21]([O:22][CH3:23])[CH:20]([F:28])[C:19](=[O:24])[NH:18][C:16]2=[O:17])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: CO/C=C/C(=O)NC(=O)Nc1cc(C(=O)OC)c(OC)c(C(C)(C)C)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(N2C(=O)NC(=O)C(F)C2OC)cc(C(C)(C)C)c1OC
Temperature: 90 °C
Yield: 29 %

Procedure:
The fluorination procedure was performed as described in Lal, G S, et al. J. Org. Chem., 60:7340-7342 (1995). The product from Example 41A, Part B (0.42 g, 1.26 mmol) and Selectfluor™ (0.672 g, 1.9 mmol) were combined in a mixture of acetonitrile (8 mL) and methanol (1 mL) and heated at 90° C. under N2 for 5 h. The solution was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and purified by column chromatography on silica gel to give the title compound (0.138 g, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][O:31][C:35](=[O:37])[CH3:36])=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (100 mg) and acetic anhydride (34 mg) in pyridine (5 ml) was stirred at ambient temperature for 3 days and the solvent was evaporated in vacuo. The residue was dissolved in chloroform and the organic solution was washed successively with 1N hydrochloric acid, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-acetoxymethylphenyl)benzamide (105 mg) as a white powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3cccc(F)c3)ccc21
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 97% of theory, C26H25FN6O3 (488.5); Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=489; (M+Na)+=511; (M+2Na)++=267.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]CC2C=CC(OC)=CC=2)[N:3]=1.FC(F)(F)C(O)=O>>[CH:7]1[C:2]([NH2:1])=[N:3][C:4](=[S:9])[NH:5][C:6]=1[Cl:8]
Reactant: COc1ccc(CSc2nc(N)cc(Cl)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)[nH]c(=S)n1

Procedure:
4-amino-6-chloro-2-(4-methoxyphenylmethylthio)-pyrimidine (11.0 g, 39.15 mmol: Cpd #93) and trifluoroacetic acid (84 ml) are heated to reflux for 20 hours, then the excess solvent is removed in vacuo. The sample is triturated with chloroform then stirred with ether and filtered. The solid is washed with ether then air dried, mp >320° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CCOCC.CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 5.24 g of 2,4,5-trifluorobenzoic acid in 50 ml of ether containing two drops of N,N-dimethylformamide was added, under argon, oxalyl chloride dropwise over 30 minutes. Stirring was continued for an additional 30 minutes when gas evolution ceased. The ether was removed in vacuo and the residue vacuum distilled to give 5.07 g of the desired compound, bp 26°-27° C./0.75 mm.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5=[CH:30][C:31]([Cl:32])=[C:21]([Cl:20])[CH:22]=[C:23]5[C:28]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: ClCCl
Product: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.83 gm, 10.7 mmol) and 4,5-dichlorophthalic anhydride (2.56 gm, 11.93 mmol, 1.1 eq) in methylene chloride (100 ml, DCM) was stirred for 2 h, white solids precipitated and the TLC showed disappearance of the starting material. The solvent was removed, and the crude solid was loaded onto a flash chromatography column (28 gm, SiO2, sorbsil C-30, eluted with 1% MeOH in DCM; 0.5% of NH4OH was added towards the end of elution). The material thus purified weighed 2.26 gm as white crystals. Recrystallization twice from a large volume of hot ethanol (400 ml) yielded 1.57 gm of white shining crystals, m.p.=132°-134° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1)/[CH:12]=[C:13]1/[C:14](=[O:33])[N:15]2[C@@H:20]([CH2:21][CH2:22]/1)[CH2:19][CH2:18][CH2:17][C@H:16]2[C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[OH:28][CH2:27][C:26]1[CH:31]=[CH:32][C:23]([C@@H:16]2[CH2:17][CH2:18][CH2:19][C@H:20]3[N:15]2[C:14](=[O:33])/[C:13](=[CH:12]/[C:11]2[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:9]([O:8][CH3:7])[CH:10]=2)/[CH2:22][CH2:21]3)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc([C@@H]2CCC[C@@H]3CC/C(=C\c4ccc(-n5cnc(C)c5)c(OC)c4)C(=O)N32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(CO)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Lithium aluminum hydride (4 mg) was added to a solution of methyl (E)-4-{(4S*,9aR*)-7-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-6-oxooctahydroquinolizin-4-yl}benzoate (50 mg) in THF (1 mL) at 0° C., and the reaction solution was stirred at 0° C. for two hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 24 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH:11][C:12](=[NH:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5])C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([N:16]1[C:4](=[O:5])[C:6]2=[CH:10][CH:9]=[CH:8][N:7]2[N:11]=[C:12]1[CH2:13][CH2:14][CH3:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCC(=N)Nn1cccc1C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCc1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 1-butyrimidoylamino-1H-pyrrole-2-carboxylic acid ethyl ester (7.6 g, 34 mmol) in dioxane (70 mL) at room temperature was added cesium carbonate (21.7 g, 66.7 mmol). The mixture was heated at 85° C. for 45 min and then benzyl bromide (4.2 mL, 35 mmol) was added. The reaction was stirred at 85° C. for 1 h. After cooling to room temperature, the reaction was filtered through a plug of silica gel and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:4) gave the title compound as a white solid (8.9 g, 99%): 1H NMR (CDCl3) δ 7.22 (m, 6H), 6.96 (m, 1H), 6.43 (m, 1H), 5.17 (s, 2H), 2.47 (q, 2H, J=7.44 Hz), 1.63 (m, 2H), 0.88 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3) δ 155.7, 149.7, 136.9, 129.3, 128.0, 126.8, 121.0, 118.4, 110.9, 108.8, 45.2, 34.6, 20.5, 14.1; MS (ESI+) 268.12 (M++H).