Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.[NH2:11][C:12]1[C:13]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:14][CH:15]=[C:16]([CH3:18])[N:17]=1.[Br:27]Br>>[NH2:11][C:12]1[C:13]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:14][C:15]([Br:27])=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1cnc(C(=O)c2ccccc2)c(N)n1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1nc(N)c(C(=O)c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium carbonate (0.23 g, 1.64 mmol) is dissolved in glacial acetic acid (5 ml, 1.64 mmol) and (3-amino-5-methyl-pyrazin-2-yl)-phenyl-methanone (0.17 g, 0.82 mmol) and bromine (0.055 ml, 1.07 mmol) are added. The resulting yellow solution is stirred at room temperature for 1.5 hours. The solvent is removed in vacuo, and the residue is suspended in DCM, filtered and washed with DCM. The filtrated is concentrated and dried in vacuo to yield the title compound as a yellow solid. [M+H]+ 292.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([OH:21])[C:12]([N:16]4[N:20]=[CH:19][CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:3][CH2:2]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:12]([N:16]4[N:17]=[CH:18][CH:19]=[N:20]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:2][CH2:3]1
Reactant: C[C@H]1CCc2c(ccc(-n3nccn3)c2O)N1C(=O)C1CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CCc2c(ccc(-n3nccn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A 50-mL round-bottom flask equipped with balloon of air was charged with (S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.150 g, 0.50 mmol), phenylboronic acid (0.185 g, 1.52 mmol), copper (II) acetate (0.228 g, 1.26 mmol), pyridine (0.12 mL, 1.49 mmol), triethyl amine (0.10 mL, 0.75 mmol), and dichloromethane (4 mL), and the resulting mixture stirred for 18 h at 40° C. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5% dichloromethane/methanol). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (55% to 75% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(2-methyl-5-phenoxy-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.025 g, 14%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.76-0.84 (m, 1H), 0.91-1.06 (m, 2H), 1.15-1.23 (m, 4H), 1.43-1.52 (m, 1H), 1.94-2.04 (m, 1H), 2.21-2.49 (m, 2H), 2.75-2.88 (m, 1H), 4.75-4.83 (m, 1H), 6.65-6.74 (m, 2H), 6.92 (d, J=7.20 Hz, 1H), 7.17 (t, J=7.50 Hz, 2H), 7.52 (d, J=8.70 Hz, 1H), 7.62 (d, J=8.70 Hz, 1H), 7.75 (s, 2H). MS (ESI, pos. ion) m/z 375 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][OH:11].[CH3:12][C:13]([C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])[CH3:14].C(OCC)(=O)C>C(Cl)Cl>[CH3:24][C:23]([C:18]1[CH:19]=[C:20]([S:22][CH2:9][CH2:10][OH:11])[CH:21]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:17]=1[OH:27])([CH3:26])[CH3:25]
Reactant: OCCBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O

Procedure:
Triethylamine (0.42 g, 0.0042 mole), 2-bromoethanol (0.52 g, 0.0044 mole) and the title compound of Example 2 (1.0 g, 0.0042 mole) were stirred in methylene chloride (50 ml) for 20 hours. The reaction was condensed and ethyl acetate (25 ml) added to the residue. After filtering the white solid the filtrate was concentrated and the product purified by chromatography on silica, m.p. ca. 66° C.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][O:19][C@H:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[N+:33](=[CH2:35])=[N-:34].Cl>O1CCCC1.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][C@@H:15]1[CH2:16][CH2:17][C@@H:18]([C:21](=[O:23])[CH:35]=[N+:33]=[N-:34])[O:19][CH2:20]1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)OC1
Reactant: C=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)C=[N+]=[N-])OC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Ethyl chloroformate (605 μL, 6.36 mmol, 1.2 eq) is added dropwise at 0° C. to a stirred solution of (2S,5R)-5-tert-butoxycarbonylamino-tetrahydro-pyran-2-carboxylic acid (1.3 g, 5.30 mmol, 1.0 eq) and diisopropylethylamine (1.38 mL, 7.95 mmol, 1.5 eq) in tetrahydrofuran (50 mL). After 30 minutes stirring at room temperature the reaction mixture is cooled down to −20° C. before the addition of diazomethane (2.0 M solution in diethyl ether, 26.5 mL, 53.0 mmol, 10.0 eq). After 15 hours stirring at −20° C., the reaction mixture is carefully acidified to pH 6 with 1.0 N hydrochloric acid aqueous solution and then extracted with ethyl acetate (3×30 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 3:1, v/v) to afford (3R,6S)-[6-(2-diazo-acetyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white solid (1.14 g, 80% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[NH3:28]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([NH2:28])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Reactant: N
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(N)=O
Yield: 80 %

Procedure:
The title compound (0.2 g, 80%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2ethoxypropanoic acid (0.25 g, 0.67 mmol) obtained in example 26 and aqueous ammonia (4 mL) by an analogous procedure to that described in example 31. mp: 107-109° C.
Reaction SMILES: [C:1]([C:4]1([CH3:26])[C:9]([NH2:10])=[CH:8][C:7]([C:11](N2C3C(=CC=CC=3)C(C)CC2(C)C)=[O:12])=[CH:6][CH2:5]1)(=[O:3])[CH3:2].[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](Cl)=[O:34])=[CH:29][CH:28]=1.[CH:42]([N:45](CC)[CH:46]([CH3:48])[CH3:47])([CH3:44])[CH3:43]>O1CCCC1>[C:1]([C:4]1([CH3:26])[C:9]([NH:10][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][CH:29]=2)=[CH:8][CH:7]([C:11]([C:5]2[C:42]([CH3:43])([CH3:44])[NH:45][C:46]3[C:47]([C:6]=2[CH3:7])=[CH:4][CH:1]=[CH:2][CH:48]=3)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)C1(C)CC=C(C(=O)N2c3ccccc3C(C)CC2(C)C)C=C1N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)C1(C)CCC(C(=O)C2=C(C)c3ccccc3NC2(C)C)C=C1NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Acylation of 1-acetyl-6-amino-4-toloyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-biphenylcarbonyl chloride (14 mg) and N,N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:31][C:32]1([CH3:43])[O:36][CH2:35][CH:34]([CH2:37][NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[O:33]1>C(O)C>[CH3:31][C:32]1([CH3:43])[O:36][CH2:35][CH:34]([CH2:37][N:38]([S:39]([CH3:42])(=[O:40])=[O:41])[CH2:31][CH:32]([OH:33])[CH2:43][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]2)[O:33]1
Reactant: CC1(C)OCC(CNS(C)(=O)=O)O1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CC2COC(C)(C)O2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.31 g (20 mmol) of N-[(3,3-dimethyl-2,4-dioxa-cyclopentyl)-methyl]-methanesulfonic acid amide is added (Example 21), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.[BH4-].[Na+].C(OCC)(=O)C>CC(O)(C)C>[NH2:14][C:13]1[C:8]([NH:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1NCc1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Nc1cccnc1NCc1ccc(Cl)cc1

Procedure:
A procedure similar to that described in Preparation 42 was repeated, except that 5.00 g of 2-(4-chlorobenzyl)amino-3-nitropyridine (prepared as described in Preparation 52), 21.4 g of tin(II) chloride dihydrate, 0.36 g of sodium borohydride and 150 ml of a 9:1 by volume mixture of ethyl acetate and 2-methyl-2-propanol were used, to give the title compound as a crude product. This crude product was crystallized by trituration with a mixture of ethyl acetate and hexane, to give 3.55 g of the title compound, melting at 123°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1>C(O)C.[Pd]>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[OH:8]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(F)cc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
To 5-fluoro-2-nitrophenol (26.63 g, 170 mmol) in Ethanol (250 ml) under N2 atmosphere was added palladium on carbon (10 wt %, 250 mg, 0.235 mmol). The mixture was flushed with H2 and stirred at RT under H2 (balloon) until complete conversion according to thin layer chromatography (TLC) analysis. Pd/C was removed by filtration and the filtrate was concentrated to yield 21.6 g of the title compound.
Reaction SMILES: [CH2:1]([NH:19][C:20](=[O:45])[CH2:21][CH2:22][CH:23]([CH:25]1[C:41]2([CH3:42])[CH:28]([CH:29]3[CH:38]([CH2:39][CH2:40]2)[C:37]2([CH3:43])[CH:32]([CH2:33][CH:34]([OH:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:46](=O)([O:55]N1C(=O)CCC1=O)[O:47][N:48]1[C:52](=[O:53])[CH2:51][CH2:50][C:49]1=[O:54].C(N(CC)CC)C.C(#N)C>ClCCl>[O:54]=[C:49]1[CH2:50][CH2:51][C:52](=[O:53])[N:48]1[O:47][C:46](=[O:55])[O:44][CH:34]1[CH2:33][CH:32]2[C:37]([CH3:43])([CH:38]3[CH:29]([CH2:30][CH2:31]2)[CH:28]2[C:41]([CH3:42])([CH:25]([CH:23]([CH3:24])[CH2:22][CH2:21][C:20](=[O:45])[NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:26][CH2:27]2)[CH2:40][CH2:39]3)[CH2:36][CH2:35]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
Referring to scheme 22, amide 88 (14.5 g, 23 mmol) was dissolved in anhydrous dichloromethane (150 mL). To the solution were added disuccinimidyl carbonate (8.87 g, 34 mmol), triethylamine (15 mL) and acetonitrile (50 mL). The reaction mixture was stirred at room temperature under argon for 6 h and then evaporated dryness. The residue was dissolved in dichloromethane (300 mL). It was washed with saturated NaHCO3 aqueous solution (3×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Compound 89 (14.3 g, 81%) was obtained as colorless powder after drying in high vacuum, which was directly used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[C:5]([N+:20]([O-])=O)[CH:4]=[N:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH:8]=1
Reactant: Cn1ncc([N+](=O)[O-])c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1ncc(N)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
To a solution of tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.15 g, 0.48 mmol) in ethanol (10 mL) and water (1 mL) was added ammonium chloride (0.131 g, 2.44 mmol) and iron powder (0.109 g, 1.95 mmol). The mixture was heated at 100° C. for 1 hr. The mixture was cooled and filtered through celite and washed with EtOAc. The organic layer was washed with water, separated and dried over MgSO4. The solvent was removed under reduced pressure to yield tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a brown oil (86 mg, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1)=[O:17]
Reactant: C#Cc1ccccc1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#Cc2ccccc2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of 25 with ethynyl-benzene yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(2-phenylethynyl)phenyl)propyl)acetamide as yellow oil. Yield (0.78 g, 73%).
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccc(C)cc3)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccc(C)cc3)C=C1C(C)=O)C2=O

Procedure:
The title compound 154 is prepared according to the procedure reported in Example 39.1 with compound 130 (75 mg, 0.154 mmol) and BNAH (33 mg, 1 equiv) as reactants. Yellow solid. (Yield 32.9 mg, 51%).
Reaction SMILES: Cl.Cl.Cl.C(NN=C([NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH:55][C:56]1[CH:61]=[CH:60][C:59]([C:62](=[O:64])[CH3:63])=[CH:58][CH:57]=1)=[O:54])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=NNC(=N)N)[NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1)NC1C=CC(C(=NNC(=N)N)C)=CC=1)(=N)N.[C:65]([C:68]1[CH:73]=[CH:72][C:71]([N:74]=[C:75]=[O:76])=[CH:70][CH:69]=1)(=[O:67])[CH3:66].NCCCN(CCCN)CCCN.C([OH:92])C>O1CCCC1>[C:65]([C:68]1[CH:73]=[CH:72][C:71]([NH:74][C:75]([NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41](=[O:43])[CH3:42])=[CH:39][CH:40]=2)=[O:92])[CH2:49][CH2:50][CH2:51][NH:52][C:53]([NH:55][C:56]2[CH:61]=[CH:60][C:59]([C:62](=[O:64])[CH3:63])=[CH:58][CH:57]=2)=[O:54])=[O:76])=[CH:70][CH:69]=1)(=[O:67])[CH3:66]
Reactant: CCO
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: CC(=O)c1ccc(NC(=O)NCCCN(CCCNC(=NNC(=N)N)Nc2ccc(C(C)=O)cc2)CCCNC(=NNC(=N)N)Nc2ccc(C(C)=NNC(=N)N)cc2)cc1
Agent: Cl
Agent: NCCCN(CCCN)CCCN
Solvent: C1CCOC1
Product: CC(=O)c1ccc(NC(=O)NCCCN(CCCNC(=O)Nc2ccc(C(C)=O)cc2)CCCNC(=O)Nc2ccc(C(C)=O)cc2)cc1
Reaction time: 8 h

Procedure:
Compound 35, FIG. 7H.35: 4-acetylphenyl isocyanate (3 g) and tris(3-aminopropyl)amine (1.06 g) in tetrahydrofuran (50 mL) were stirred for 30 min. Ethanol (100 mL) was added and the mixture was left at r.t. for overnight. Filtration gave 2.8 g of tris(3-[([(4-acetylphenyl)amino]carbonyl)amino]propyl)amine, mp 184°-5° C. This diketone (0.4 g) and aminoguanidine dihydrochloride (0.29 g) were heated in methanol (3 mL) for 4 hours. Addition of ethanol (3 mL) and filtration gave 0.5 g of tris (3-[([(4-acetylphenyl)amino]carbonyl)amino]propyl)amine tris(amidinohydrazone) trihydrochloride (Compound 35) as the dihydrate ethanolate, mp 209°-10° C. dec.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pd]>[CH2:5]([NH:3][CH2:2][CH2:1][NH2:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: O=Cc1ccccc1
Agent: [Pd]
Product: NCCNCc1ccccc1

Procedure:
Benzylethylenediamine (Bz-EDA) was prepared by placing 250 g of ethylenediamine (4.16 moles) and 2.5 g of 5% Pd/C catalysts were placed in a stainless steel reactor under hydrogen pressure (800 psig) at 120° C. Benzaldehyde (441.7 g, 4.16 moles) were pumped inside the reactor over a period of an hour. The reaction was allowed to proceed for an extra hour. The reactor was then cooled down, the catalyst was removed by filtration to give the corresponding product.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=O)[CH3:2].[C:11]([NH:19][NH2:20])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)C>O>[CH3:9][C:7]1[S:8][C:4]([C:1](=[N:20][NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2])=[C:5]([CH3:10])[N:6]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1sc(C)nc1C
Solvent: CCO
Solvent: O
Product: CC(=NNC(=O)c1ccccc1)c1sc(C)nc1C
Yield: 54 %

Procedure:
A mixture of 5.0 gm (0.322 mole) of 5-acetyl-2,4-dimethylthiazole, 4.38 gm (0 0322 mole) of benzhydrazide, 10 drops of glacial acid and 100 ml of ethanol is refluxed 48 hrs. The reaction mixture is diluted with water to the cloud point then chilled. The product is collected and dried to give 4.75 gm (54%) of the title compound having a melting point of 138.4° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6](F)[CH:5]=[CH:4][N:3]=1.BrC1C=NC=C(Cl)C=1[CH2:24][O:25]C1CCCCO1.C([O-])([O-])=O.[Cs+].[Cs+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:6]([O:25][CH3:24])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cncc(Br)c1COC1CCCCO1
Reactant: Fc1ccnc(Cl)c1COC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1ccnc(Cl)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.20 g. 0.81 mmol) which was prepared according to the synthesis of 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine in anhydrous MeOH (4 mL) was added Cs2CO3 (0.54 g. 1.6 mmol). After vigorous stirring for 20 h at room temperature acedic acid (92 μL. 1.6 mmol) was added the solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and water (4 mL). The organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 257.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.5 %

Procedure:
A solution of the ester from step 1 (1.0 g, 2.6 mmol) was dissolved in THF (5 mL) and methanol (5 mL) was treated with a 2.5 N NaOH solution (4.0 mL, 10.4 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue taken up in ethyl acetate and acidified with 3 N HCl. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo yielding a yellow solid. Recrystallization from ethyl acetate-hexanes afforded the title compound as a pale yellow solid (0.42 g, 46%): mp 196.3–197.7° C. 1H NMR (CDCl3/300 MHz) d 7.65 (s, 1H), 7.40–7.23 (m, 6H), 7.15 (s, 1H), 5.63 (q, 1H, J=6.5 Hz), 3.35 (broad s, 1H). 19F NMR (CDCl3/282 MHz)d −78.71 (d, J=5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M−H, Calc'd 353.0192).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[N:1]/[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11]
Reactant: O=Cc1ccccn1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=C1OCc2c(/N=C/c3ccccn3)cccc21
Yield: 49.9 %

Procedure:
4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), picolinaldehyde (856 mg, 8 mmol) and 1 g of MgSO4 were added into 40 mL of dichloromethane and the mixture was stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 476 mg of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one was obtained. A mixture of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), sodium methanolate (432 mg, 8 mmol) and ethyl propionate (40 mL) was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to give 30 mg of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate; yield 5%. LC-MS (ESI) m/z: 459 (M+1)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH2:13]([C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[S:21])[CH3:14]>>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:21][C:16]1[C:15]([CH2:13][CH3:14])([CH3:22])[NH:19][C:18](=[O:20])[N:17]=1
Reactant: CCC1(C)NC(=O)NC1=S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Product: CCC1(C)NC(=O)N=C1SCc1ccccc1N(C)C

Procedure:
In the present Example, 2.3 g of 2-dimethylaminobenzylchloride hydrochloride and 1.5 g of 5-ethyl-5-methyl-4-thiohydantoin were reacted following the procedure used in Example 36. Crystallization from diethyl ether-n-hexane gave the desired compound in the form of a needle-like crystal. The yield of this compound was 1.9 g with a yield ratio of 68.6%, and the melting point was 111°-113° C.