Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>C(O)(=O)C>[CH3:15][C:11]1[CH:10]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(N)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C)c1
Yield: 96.9 %

Procedure:
To a stirred solution of 11.2 grams (g) (0.11 mole) of acetic anhydride in 100 milliliters (mL) of acetic acid, was added 10.7 g (0.1 mole) of m-toluidine. The solution exothermed to 35° C. and, ten minutes (min) after all the m-toluidine was added, the product solution was concentrated in vacuo. The residue was taken up in EtOAc and was washed with H2O. The organic layer was dried over MgSO4 and concentrated in vacuo to give 14.46 g (97%) of product as a white powder (m.p. 65°-66° C). 1H NMR (CDCl3) 8:9.2 (1H, s, NH), 7.2 (2H, d, 8 Hz, aromatic), 7.0 (1H, t, 8 Hz, aromatic), 6.7 (1H, d, 8.0 Hz, aromatic).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[OH:6].[H-].[Na+]>C1COCC1.[Ni]>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[CH2:4][CH2:3][CH2:2][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@@H](CCCCl)c1ccc(Br)cc1
Agent: [Ni]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc([C@@H]2CCCO2)cc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of [S]-1-chloro-4-(4-bromophenyl)-4-butanol (50 mmol) in THF (25 ml) was added to a cooled suspension (0° C.) of NaH (55 mmol) in THF (50 ml). After being stored for 2 h at 25° C., the reaction mixture was quenched with water, brought to pH 6 with concentrated HCl, and extracted with ether (2×50 ml). The organic phase was dried over H2SO4, filtered and all volatiles removed under reduced pressure. The residue was distilled to provide the product in 75% yield, 98% ee as determined on a chiral capillary column of Ni(HFN-IR-Cam)2.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:22][CH2:21]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:31][CH:30]=2)[CH2:22][CH2:21]1
Reactant: CS(=O)c1ncc2ccc(-c3cccnc3)n2n1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN1CCN(CCOc2ccc(Nc3ncc4ccc(-c5cccnc5)n4n3)cc2)CC1

Procedure:
Into a microwave vial, 2-Methanesulfinyl-7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazine (0.104 g, 0.000404 mol), 4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenylamine (0.209 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 12% methanol). The collected fractions afforded {4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-phenyl}-(7-pyridin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a yellow solid (28 mg, 16%). MP 107-110° C. LCMS (E/I+) 430.8 (M+H). NMR 1H (DSMO-d6)-9.42 (d, 1H, J=2.00), 9.39 (s, 1H), 9.04 (s, 1H), 8.66 (d, 1H, J=7.76 Hz), 8.61 (d, 1H, J=6.56 Hz), 7.60-7.70 (m, 3H), 7.32 (d, 1H, J=4.77 Hz), 6.98 (d, 1H, J=4.76 Hz), 6.95 (d, 2H, J=9.00 Hz), 4.16 (t, 2H, J=5.26 Hz), 2.40-3.50 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH:24](=O)[C:25]1[O:29][CH:28]=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:24]([C:25]3[O:29][CH:28]=[CH:27][CH:26]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccco1
Reactant: Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Product: Nc1cc(Br)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 281 (M++2, 100), was prepared in accordance with the (general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and furfural. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[C:12]1([SH:18])C=CC=C[CH:13]=1.[CH3:19][C:20](N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[S:18]1[CH:12]=[CH:13][CH:2]=[C:1]1[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH2:19][CH3:20])[CH:4]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: Sc1ccccc1
Solvent: c1ccccc1
Product: CCc1cc(-c2cccs2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
According to the published procedure (Gareau et al., Tet. Lett., 1994, 1837), under nitrogen atmosphere in a 50 mL round bottomed flask containing 4-vinyl-benzoic acid (1.0 g, 6.75 mmoles) in 10 mL of benzene (0.7 M) was added benzenethiol (797 μL, 7.76 mmoles) followed by VAZO™ (Aldrich Chemical Company, 495 mg, 2.02 mmoles). The mixture was stirred for 12 hours at reflux. The resulting solution was cooled at room temperature and the solvent was evaporated under vacuo. The solid was purified by trituration using hexane and dichloromethane to afford 1.94 g (85%) of white solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.Br[CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(CCN(C)C)C.[Cl-].[NH4+]>>[CH:18]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: BrC1CCCCCC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc(-c2ccccc2)cc1
Product: c1ccc(C2CCCCCC2)cc1
Reaction time: 0.17 h

Procedure:
A mixture of PhMgBr (72 mL of 0.93-M THF solution, 67 mmol) and TMEDA (7.78 g, 67 mmol) was added to a mixture of bromocycloheptane (8.85 g, 50 mmol), FeCl3 (25 mL of 0.1-M THF solution, 5 mol %) at 0° C. in such a rate as keeping the reaction mixture in its pale yellow solution (1.36 mL/min. in the case of this run), using an injection pump. After completion of the addition of PhMgBr/TMEDA, the reaction mixture was stirred for 10 minutes at this temperature. The reaction mixture was treated with saturated aqueous ammonium chloride solution in a conventional manner and then distilled to give cycloheptylbenzene as a colorless oil (8.18 g, but 0.37 g of biphenyl was contained; isolated yield: 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[NH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NN1CCCC1
Agent: Cl
Product: COc1ccc(C(=O)NN2CCCC2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 1-aminopyrrolidine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.C(N(CC)CC)C.C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[N+:41](=[C:11]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]1=[O:13])=[N-:42]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (0.63 g, 2.3 mmol) was suspended in acetonitrile (10 mL), treated with triethylamine (0.27 mL, 2.7 mmol, 1.15 equiv) and cooled to 0° C. To the mixture was added 4-acetamidobenzenesulfonyl azide (0.61 g, 2.5 mmol, 1.1 equiv) and after 30 minutes at 0° C., the mixture was warmed to ambient temperature. After stirring for 30 minutes, the mixture was poured into sodium carbonate (25 mL, aqueous saturated) and sodium hydroxide (10 mL, 1 N aqueous) and extracted with dichloromethane (2×125 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[CH2:31][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was added the product from step 1 (324 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 100 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (280 mg, 60%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.82-2.11 (m, 4H), 3.30-3.48 (m, 2H), 3.85-4.05 (m, 1H), 4.07-4.30 (m, 2H), 6.96-7.25 (m, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H):
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:6]=1[CH2:7]Cl)([O-:4])=[O:3].[OH-:19].[Na+]>>[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:6]=1[CH:7]=[CH:7][C:6]1[C:5]([N+:2]([O-:3])=[O:19])=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([O-:4])=[O:3]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(CCl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.02 h
Yield: 50 %

Procedure:
Two methods of preparing 2,2',4,4',6,6'hexanitrostilbene (HNS) are disclosed in U.S. Pat. No. 3,505,413, entitled "Hexanitrostilbene," issued to Kathryn, G. Shipp on Apr. 7, 1970. In the first 2,4,6-trinitrotoluene was reacted with 5 percent sodium hypochlorite (Clorox) at 0° C. in a tetrahydrofuran (THF)-methanol solvent mixture to produce HNS in a single step (disclosed yield 42%). In the second method, the above conditions were used except that the reaction was stopped after one minute by drowning the reaction mixture in very dilute hydrochloric acid. The reported yield of 2,4,6-trinitrobenzyl chloride was 85 percent. Next the 2,4,6-trinitrobenzyl chloride was reacted at room temperature with sodium hydroxide to give HNS (reported yield 50%). Thus, the yield of HNS using the two step method was 0.85×0.50 =0.425 or 42.5%. It would be desirable to find a method of substantially increasing this yield.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[N:31](COCC[Si](C)(C)C)[CH:32]=[CH:33][C:26]=34)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:31][CH:32]=[CH:33][C:26]=34)[CH:22]=[N:21]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:18][CH:19]=2)[CH2:7]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{3-(Cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide was dissolved in dichloromethylene (5 mL). To the solution was added trifluoroacetic acid (TFA) (2.5 mL). The mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. The residue was dissolved in methanol (10 mL). To the solution was added ethylenediamine (1 mL). The mixture was stirred at room temperature for 4 hours, and was purified by RP-HPLC (pH=10) to afford the desired product (0.415 g). LCMS (M+H)+: m/z=440.1. The high purity (99.6%) of the product was obtained by re-crystallization from acetone-ether. 1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.31 (d, J=4.9 Hz, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.70 (m, 2H), 7.39 (d, J=3.4 Hz, 1H), 7.18 (d, J=4.9 Hz, 1H), 6.70 (d, J=3.4 Hz, 1H), 6.55 (m, 2H), 5.79 (d, J=7.8 Hz, 1H), 4.47 (d, J=8.3 Hz, 2H), 4.38 (d, J=8.3 Hz, 2H), 4.27 (m, 1H), 3.45 (s, 2H), 1.25 (d, J=6.7 Hz, 6H).
Reaction SMILES: [IH:1].[CH3:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15](SC)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(O)(C)C>[IH:1].[CH3:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: CSC(=N)NC(c1ccccc1)c1ccc(C)cc1
Agent: I
Solvent: CC(C)(C)O
Product: Cc1ccc(C(NC(=N)N2CCCC2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 13.3 g (0.0334 mole) of methyl N-(4-methylbenzhydryl)carbamimidothioate hydroiodide and 5.0 g (0.07 mole) of pyrrolidine in 40 mls of t-BuOH is heated under reflux for 24 hrs. The crude product crystallizes out of the reaction mixture while refluxing. The mixture is allowed to cool over night at room temperature and filtered to yield crude product; mp 227°-30° C. Recrystallization from MeOH/t-BuOH yields the pure N-(4-methylbenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp 229°-230° C, as a white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CCOC(C)=O.CCCCCC>[O:31]=[C:4]1[C:3](=[CH:2][NH:49][C:46]2[CH:45]=[CH:44][C:43]([CH2:42][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:48][CH:47]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:27]=[C:26]([CH2:28][CH3:29])[N:25]([CH3:30])[N:24]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)nn1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)nn1C
Temperature: 65 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A small screw cap test tube was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 345, 70 mg, 0.1681 mmol) and THF (2.0 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (30.1 mg, 0.171 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. iPrOH (˜10 mL) affording the title compound in 18% yield (0.018 g, 0.031 mmol).
Reaction SMILES: C([OH:3])C.[OH-].[K+].[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23](N)=[O:24])=[CH:21][C:8]1=2>O>[O:6]=[C:7]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][C:9]2[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:24])=[O:3])=[CH:21][C:8]1=2
Reactant: CCO
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Reaction time: 5 h
Yield: 77 %

Procedure:
To a mixture of 2 ml of water, 2 ml of ethanol and 0.4 g of potassium hydroxide was added 100 mg of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetamide, and the resulting mixture was refluxed with stirring for 5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow crystals, which were chromatographed over 9 g of silica gel and eluted with chloroform/methanol (50/1), thereby obtaining 77 mg (yield: 77%) of (10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-acetic acid. This acid was recrystallized from acetone/n-hexane to give colorless crystals having a melting point of 155.7°-157° C.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]2=O)=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:19]=[C:18]([F:20])[C:17]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=[C:22]2[Cl:35])=[CH:16][C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
23.3 g of pyridine are added at room temperature while stirring and cooling to a suspension of 38.8 g of isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate in 45.2 g of phosphorus oxychloride and 40 ml of toluene. A solution forms rapidly. The temperature is maintained between 30° to 35° C. and, after 15 minutes, a colourless precipitate begins to separate. The reaction mixture is stirred at 30°-35° C. for 45 minutes and is then poured onto 300 g of ice. The mixture is subsequently extracted with 200 ml of ethyl acetate and the organic phase is washed three times with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from n-hexane. There is obtained isopropyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate, m.p. 72°-75° C.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O=C(C1C=CC=CN=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:4]([O:3][C:1]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccn1
Product: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1

Procedure:
Ethyl 5-benzyloxycarbonylamino-3-oxo-pentanoate was prepared from N-Cbz-β-alanine in the same manner as ethyl 3-oxo-3-pyridin-2-yl-propionate (Example 94).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[NH2:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22]>O1CCCC1.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[NH:17][CH:18]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Reactant: CCN=C=O
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 46.7 %

Procedure:
0.074 cm3 (0.891 mmol) of ethyl isocyanate and 0.005 mg (0.040 mmol) of dimethylaminopyridine are added, at a temperature close to 25° C., to a solution of 0.2 g (0.81 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature close to 60° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 100 cm3 of water and then extracted with three times 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.120 g of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is obtained in the form of a yellow powder. ES+: m/z=318 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][CH:13]([Cl:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCC(Cl)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(Cl)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16](B2OC(C)(C)C(C)(C)O2)[C:15]([CH3:28])=[N:14]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:11])=[CH:4][CH:3]=2)[C:15]([CH3:28])=[N:14]1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
6-Bromo-indan-1-one (0.94 mmol) was dissolved in DME/H2O 1/1 (10 mL) under argon atmosphere. 1,3,5-Trimethyl-1H-pyrazole-4-boronic acid pinacol ester (1.42 mmol), K2CO3 (2.82 mmol), and tetrakis-(triphenylphosphine)palladium (5 mol %, 0.047 mmol) were added and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was evaporated to dryness, then dissolved in CHCl3 and filtered through Celite® to give the crude product 6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-one. The crude was purified by flash column chromatography (AcOEt-Cyclohexane as eluents) by using a CombiFlash Companion™ system to yield the title compound (84%). MS [MH]+=240