Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c1
Yield: 78.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (1.00 g, 2.10 mmol) and acetic anhydride (0.24 ml, 2.54 mmol), the procedure of Inventive Example 94 was repeated to obtain 851.0 mg (78.3%) of the title compound in the form of colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](N(OC)C)=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:33])(=[O:32])[N:27]=CN(C)C)=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]1COC[CH2:36]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:15])[CH2:35][CH3:36])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:27])(=[O:32])=[O:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: C1CCOC1
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Yield: 21.08 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.531 g, 3.98 ml, 1M soln. In THF, 3.98 mmol) was added dropwise under a nitrogen atmosphere to a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N,1,4-trimethyl-1H-pyrrole-2-carboxamide (compound 49ω, 0.400 g, 0.79 mmol) in anhydrous THF (15 ml) at 25° C., and the reaction mixture was then heated to about 70 to about 75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the cooled reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so formed was extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic solution was evaporated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain the title compound (0.070 g, 21.08%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[NH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[N:8]=1
Reactant: NCCCN
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Product: NCCCNc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)-guanidino]-2-methylsulphinylpyrimidine (0.3 g.) and 1,3-diaminopropane (1 ml.) was heated to 90° for 3 hours. The mixture was evaporated to dryness and the residue taken up in 2 N aqueous acetic acid. The solution was washed with ether, basified with 17 N NaOH and the mixture extracted five times with ether. The combined ether extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylamino)pyrimidine (0.27 g.) which was characterised as the tris hydrogen maleate, m.p. 159° after recrystallisation from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(C(C)C)CC)(C)C.[Cl:22][CH2:23][C:24](Cl)=[O:25].NC1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:24](=[O:25])[CH2:23][Cl:22]
Reactant: O=C(Cl)CCl
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)CCl
Temperature: 0 °C

Procedure:
2-Methoxy-4-nitroaniline (8.40 g, 50 mmol) was dissolved in 200 mL dichloromethane and stirred at 0° C. while adding diisopropylethylamine (6.45 g, 50 mmol) then a solution of chloroacetyl chloride (5.65 g, 50 mmol) in 50 mL dichloromethane. The mixture was stirred for 17 h at 20-25° C., evaporated and 300 mL ethyl acetate added. The solution was washed with 2×100 mL 2M hydrochloric acid then brine, dried (sodium sulphate) and evaporated. The residue dissolved in 200 mL warm toluene, charcoaled then chromatographed on 300 mL flash silica in a 10 cm sinter funnel. Elution with toluene and evaporation afforded a bright yellow oil which solidified on standing. NMR showed an 11:4 mixture of product and starting aniline—product δ 9.17(s, 1H), 8.56(m,1H), 7.94(m, 1H), 7.79(m, 1H), 4.22(s, 2H), 4.03(s, 3H). Used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13].[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:11]([O:14][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[N:6][CH:5]=[CH:4][N:3]=1)[CH:12]=[CH2:13]
Reactant: CN(C)c1nccnc1Cl
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOc1nccnc1N(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
47 g of 2-chloro-3-dimethylamino-pyrazine and 35 g of allyl alcohol are dissolved in 300 ml of hexamethylphosphoric acid triamide. 14.4 g of sodium hydride are introduced into this solution at 0° C. over the course of 30 minutes. The mixture is then stirred for a further hour at 0° C. and for 15 hours at room temperature. The reaction mixture is then poured into 2 liters of ice water. After excess sodium hydride has been decomposed, the mixture is extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled under reduced pressure. 2-Allyloxy-3-dimethylamino-pyrazine, boiling point 110°-115° C./10 mm Hg, is thus obtained.
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].C([Li])CCC.[C:17](=[O:19])=[O:18].Cl>CCOCC.C1COCC1.CCCCCC>[Br:11][C:8]1[C:9]([OH:10])=[C:4]([C:17]([OH:19])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: O=C=O
Reactant: Oc1c(Br)cncc1Br
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cncc(Br)c1O
Reaction time: 0.5 h

Procedure:
A solution of methyllithium in ether (1 M, 4.8 ml) was added to a solution of 3,5-dibromopyridin-4-ol (1200 mg) in THF (10 ml) at −78° C., and the mixture was stirred for 30 minutes. A solution of n-butyllithium in hexane (1.65 M, 6.0 ml) was added at −78° C., and the mixture was stirred for one hour. Dry ice was added at −78° C. and the mixture was stirred at 0° C. for 20 minutes, followed by addition of a 4 N aqueous hydrochloric acid solution. The precipitated solid was collected by filtration and washed with water to give a mixture of the title compound and 3,5-dibromopyridin-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:40])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:21]=2[N:20]([CH3:38])[C:19]1=[O:39])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:40])[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:21]=3[N:20]([CH3:38])[C:19]2=[O:39])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-H), the title compound was prepared as a yellow solid.
Reaction SMILES: Cl[C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[N+]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.C(O)C.[Cu]>[O:24]([C:2]1([NH2:14])[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: NC1(Cl)C=C([N+](=O)[O-])C=CC1C(=O)O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])c1ccccc1
Product: NC1(Oc2ccccc2)C=C([N+](=O)[O-])C=CC1C(=O)O

Procedure:
2-Chloro-4-nitroanthranilic acid (40.2 g, 0.2 mol) is stirred in nitrobenzene (250 mL) with 3-nitrophenol (31 g, 0.22 mol), potassium carbonate (42 g, 0.3 mole), copper bronze (1 g) and cuprous iodide (1 g) at 155° C. for 6 hours. The pure product is obtained by recrystallization in ethyl alcohol to give 2-phenoxy-4-nitroanthranilic acid. (See Goldberg, Walker, J. Chem. Soc. (1953), 1348).
Reaction SMILES: [CH:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH2:9][OH:10])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[CH:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C@H:8]1[CH:9]=[O:10])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(CCCCc1ccccc1)C(=O)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C(CCCCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Reaction time: 0.17 h

Procedure:
N-(2-isopropyl-6-phenylhexanoyl)-L-prolinol was dissolved in dry DMSO (1.5 ml). Triethylamine (0.35 ml) was added to this solution. A solution of sulfur trioxide-pyridine complex (414 mg) in DMSO (1 ml) was dropped to this solution. The solution was stirred for 10 mins and poured into water. The mixture was extracted with ethyl acetate. The oily layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrocarbonate, followed by saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel to give the title compound (150 mg) having the following physical data:
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.5 %

Procedure:
In THF (15.8 ml)/methanol (15.8 ml) was dissolved methyl 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.79 g). To the solution was added 1N sodium hydroxide solution (7.9 ml) and the mixture was stirred at room temperature for 20 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed With hexane/ethyl acetate (=6/1) to give 1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.57 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][C:12]3([C:17]([C:19]3([CH3:44])[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[CH:43]=[CH:42][C:27]4[N:28]([CH3:41])[C:29]([CH2:31][NH:32][C:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=5)=[N:30][C:26]=4[CH:25]=3)=[O:18])[CH3:16])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:45][NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=1.[ClH:55].C(=O)([O-])[O-].[NH4+:60].[NH4+:61]>C(O)C>[ClH:55].[CH3:41][N:28]1[C:27]2[CH:42]=[CH:43][C:24]([CH:20]3[CH2:21][CH2:22][CH2:23][C:19]3([C:17]([C:12]3([CH3:16])[CH2:13][CH2:14][CH2:15][CH:11]3[C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:45][NH:46][C:47]5[CH:52]=[CH:51][C:50]([C:53](=[NH:60])[NH2:54])=[CH:49][CH:48]=5)=[N:4][C:5]=4[CH:10]=3)=[O:18])[CH3:44])=[CH:25][C:26]=2[N:30]=[C:29]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:61])[NH2:40])=[CH:37][CH:38]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-(1-methylcyclopent-1-yl)ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:11]=[CH:12][N:13]=1)=[O:27]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: COc1ccc(Nc2cc(N)ncn2)cn1
Product: COc1ccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)cn1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(6-methoxy-pyridin-3-yl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-(3-{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12w, and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.58-7.47 (m, 3H), 7.10 (m, 1H), 7.00 (d, 1H), 6.89 (s, 1H), 6.85 (d, 1H), 6.74 (s, 1H), 6.68 (d, 1H), 6.56 (d, 1H), 4.50 (t, 2H), 4.26 (s, 2H), 4.21 (s, 2H), 3.65 (s, 3H), 3.06 (t, 2H), 2.78 (t, 2H), 2.47 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][C:23]2[S:24][CH:25]=[N:26][N:27]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[S:24]1[CH:25]=[N:26][N:27]=[C:23]1[NH:22][C:20]([C:19]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])[C:16]([CH3:15])=[CH:29][CH:28]=1)=[O:21]
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)c(C)c2)o1

Procedure:
Example 21 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and 4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:21]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH2:20][CH3:21])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCNCCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CCO1

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-ethylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-7-[2-(2-ethylaminoethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[C:47]1([CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:57]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)[C:58]([O:60][CH2:61][CH3:62])=[O:59])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)Cc1cccc2ccccc12
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)c1cccc2ccccc12
Yield: 17.1 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (26 cc) and ethyl 2-(1-naphthyl)acetate (7.5 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume), diethyl 2-dimethylamino-5-(1-naphthyl)-2,4-hexadienedioate (2.2 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][SH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:19][CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[N:6]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCc1csc(N)n1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-amino-4-chloromethyl-1,3-thiazole (16.2 g, 0.108 mol) in dimethylformamide (80 mL) was added 2-t-butyloxycarbonylaminoethanethiol (28.9 g, 0.163 mol) followed by potassium carbonate (45 g, 0.326 mol). After 1 hour of vigorous stirring reaction mixture was partitioned between ethyl acetate and water. Organic layer was thoroughly washed with water, dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography of the oily residue (2% methanol in methylene chloride) afforded oily product (20.0 g). 1H NMR (CDCl3) δ 1.42 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H), 3.80 (s, 2H), 2.65 (m, 2H), 5.00 (s, 1H).
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([CH2:45][CH2:46]O)=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][C:39]([CH2:45][CH2:46][I:1])=[CH:40][CH:41]=2)[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCO)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCI)cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 1.21 g (4.76 mmol) iodine in 50 mL toluene is added 1.59 g (4.76 mmol) polymer bound triphenyl-phosphane. The mixture is stirred 5 min at RT and then 0.80 mL (9.92 mmol) pyridine and 1.10 g (3.97 mmol) 7-(2-hydroxy-ethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7c) is added. The reaction mixture is stirred 5 h at 90° C., is cooled to RT and is filtered. The filtrate is washed with saturated aqueous sodium thiosulfate-solution, brine and dried over MgSO4. After filtration and evaporation of the solvent, the residue is purified via chromatography (silica gel; PE/EtOAc=9:1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C#N)=[C:4](/[CH:10]=[CH:11]/[N:12]([CH3:14])C)[CH:3]=1.C(O)(=[O:17])C>Br.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:14](=[O:17])[NH:12][CH:11]=[CH:10]2
Reactant: CN(C)/C=C/c1cc(Br)ccc1C#N
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: O=c1[nH]ccc2cc(Br)ccc12

Procedure:
A solution of 4-bromo-2-[(E)-2-(dimethylamino)ethenyl]benzonitrile (Example 1a, 1.0 g) in 33% Hydrobromic acid in acetic acid (10 mL) under nitrogen was stirred at 80° C. for 4 h. The reaction mixture was diluted with water (250 mL), and the brown solid was filtered off, washed with diethyl ether and dried to afford the subtitle compound (0.70 g) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(#N)C.O>[Cl:12][C:11]1[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]([CH3:14])[C:9](=[O:13])[CH:10]=1
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Cl)cc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.2 %

Procedure:
4-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.65 g, 12.3 mmol) was dissolved in a mixture of tetrahydrofuran (16 mL), acetonitrile (16 mL) and water (8 mL). Sodium hydroxide (1.23 g, 30.8 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 24 h. The reaction mixture was diluted with water (50 mL) and was acidified to pH 2 with 1 M hydrochloric acid and was extracted many times with ethyl acetate (about 1 L). The extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an orange-tinged solid. Crystallization from methanol-ethyl acetate afforded 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.859 g, 37% yield) as an off-white solid: 1H NMR (DMSO-d6, 400 MHz) δ 13.02 (br s, 1H), 8.58 (s, 1H), 6.58 (s, 1H), 3.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[CH3:23]>[Pd].C(#N)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:23])[C:4]=1[NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC#N
Product: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1N
Reaction time: 72 h
Yield: 100.5 %

Procedure:
Ethyl 4-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]butyrate (64.3 g, 0.198 mol) was mixed with acetonitrile (2 L), and catalytic 10% palladium on carbon was added. The mixture was placed on a hydrogenator for 72 hours and filtered through a layer of CELITE filter aid. The filtrate was concentrated under reduced pressure to yield 58.2 g of ethyl 4-[(8-amino-5,6-dimethyltetrazolo[1,5-a]pyridin-7-yl)amino]butyrate.