Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([O:21][CH2:22][CH2:23]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].C(=O)(O)[O-].[Na+]>CCOCC.CN(C=O)C.C(N(CC)CC)C>[ClH:25].[ClH:25].[O:21]([CH2:22][CH2:23][N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:10][CH2:11]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOc1ccccc1
Reactant: C1CCN(CCC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(OCCN2CCC(CCN3CCCCC3)CC2)cc1

Procedure:
A mixture of 4-(2-piperidinoethyl)piperidine (3.27 g), 2-bromoethyl phenyl ether (3.35 g), triethylamine (2.3 ml) and DMF (50 ml) was heated on a steam bath for 16 hours. The mixture was worked up as described in Example 16. The crude solid hydrochloride was treated with sodium bicarbonate solution and the mixture extracted with dichloromethane to give the free base which was purified by flash chromatography on silica using methanol/triethylamine, 99:1 as the mobile phase. The oil obtained was dissolved in ether and acidified with ethereal hydrogen chloride to give 1-(2-phenoxyethyl)-4-(2-piperidinoethyl)piperidine dihydrochloride, m.p. 285° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[CH:10]=1.Cl.[CH3:22]O>>[CH3:22][O:19][C:18]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)=[O:20]
Reactant: CO
Reactant: COc1ccccc1-c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: Cl
Product: COC(=O)c1cc(-c2ccccc2OC)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2′-Methoxy-5-nitro-biphenyl-3-carboxylic acid (8.62 g, 31.5 mmol) was added to a mixture of MeOH (89 mL) and conc. aqueous HCl (4.9 mL). The reaction mixture was stirred at 80° C. for 24 hours, and then stirred for 18 hours at room temperature. The reaction mixture was filtered, and the resulting solid was washed with MeOH and dried to give 8.2 g of 2′-methoxy-5-nitro-biphenyl-3-carboxylic acid methyl ester, MS (M+H)=288.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].C(O)(=O)C.[OH:14][C:15]1[N:20]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:19]2[N:18]=[CH:17][N:16]=1>O>[OH:14][C:15]1[N:20]2[N:21]=[CH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([N+:6]([O-:9])=[O:7])=[CH:26][CH:25]=3)=[C:19]2[N:18]=[CH:17][N:16]=1
Reactant: Oc1ncnc2c(-c3ccccc3)cnn12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 1 h

Procedure:
To a mixture of conc. sulfuric acid (0.5 ml), conc. nitric acid (0.5 ml) and acetic acid (2 ml) is addded 4-hydroxy-8-phenylpyrazolo[1,5-a]-1,3,5-triazine (310 mg), and the mixture is stirred at 50°-60° C. After reacting for one hour, to the reaction mixture is added water. The insoluble material is separated by filtration, washed with water and hot methanol and dried to give the title compound (210 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[C:24]1([CH2:29][OH:30])[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][CH2:28][C:24]([CH2:29][OH:30])([C:23]([F:31])([F:32])[F:22])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: OCC1(C(F)(F)F)CCNC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(CO)(C(F)(F)F)C1
Yield: 35.9 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with (3-(trifluoromethyl)pyrrolidin-3-yl)methanol hydrochloride (CAN 1260812-78-9, 17.4 mg, 84.4 μmol) to obtain the title compound (11 mg, 36%) as colorless liquid, MS (EI): m/e=436.4 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.C(N(CC)CC)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63]>ClCCl>[CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([S:62]([CH3:61])(=[O:64])=[O:63])[CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(S(C)(=O)=O)CC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (3 mL), triethylamine (42 mg, 0.42 mmol, 3.00 equiv), and methanesulfonyl chloride (17 mg, 0.15 mmol, 1.05 equiv). The resulting solution was stirred for 40 min at 25° C. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 1×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (90 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 55.8 mg (50%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.97 (d, J=5.1 Hz, 1H), 8.764 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 8.16˜8.10 (m, 3H), 7.89˜7.87 (m, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.72˜7.67 (m, 4H), 7.62˜7.53 (m, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.68˜3.55 (m, 14H), 3.11 (s, 3H), 2.96 (s, 3H), 2.04 (d, J=4.8 Hz, 1H), 1.83 (d, J=5.1 Hz, 1H). MS (ES, m/z): 806 [M+H]+.
Reaction SMILES: COC1C=C2C(CC(C3C=CC=CC=3N)C(C)(C)O2)=CC=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N1(CCOC2C=C[C:55]([CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[CH2:73][C:72]4[C:67](=[CH:68][C:69]([O:74][CH3:75])=[CH:70][CH:71]=4)[O:66][C:65]3([CH3:77])[CH3:76])=CC=2)CCCCCC1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][N:57]([CH2:56][CH3:55])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[CH:64]3[CH2:73][C:72]4[C:67](=[CH:68][C:69]([O:74][CH3:75])=[CH:70][CH:71]=4)[O:66][C:65]3([CH3:76])[CH3:77])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1Cc2ccc(OC)cc2OC1(C)C

Procedure:
Synthesized from 2-(7-methoxy-2,2-dimethylchroman-3-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (473 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (472 mg). This compound (470 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (200 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:27]([F:30])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: [O-]B([O-])Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.00 g), 4-trifluoromethylphenyl borate (0.63 g) and potassium carbonate (0.84 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.174 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(4-trifluoromethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (704.7 mg).
Reaction SMILES: [CH:1]1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)[CH:2]=1.[CH2:27]([C@H:42]([NH2:46])[C:43]([OH:45])=[O:44])[CH2:28][C:29]([NH:31][C@H:32]([C:35]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])[CH2:33][SH:34])=[O:30].[CH2:47](N(CC(O)=O)CC(O)=O)[CH2:48]N(CC(O)=O)CC(O)=O>C(O)(=O)C>[CH3:1][CH2:2][O:40][C:39]([CH2:38][NH:37][C:35]([C@@H:32]([NH:31][C:29]([CH2:28][CH2:27][C@H:42]([NH2:46])[C:43]([O:45][CH2:47][CH3:48])=[O:44])=[O:30])[CH2:33][SH:34])=[O:36])=[O:41]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)CNC(=O)[C@H](CS)NC(=O)CC[C@H](N)C(=O)OCC

Procedure:
Analysis of Erythrocyte Thiol by DTNB. Cell supernatant (40 μl) was added to 1 ml of 6 mM DTNB (in 143 mM phosphate buffer, pH 7.5, containing 6.3 mM EDTA). The change in absorbance at 412 nm after 1 min was converted to a value for total thiol using a GSH standard curve. The GSH standard were prepared in a 1:2:2 mixture of PBS: 0.435M acetic acid: 10% SSA (containing 2 mM EDTA) ("RBC Mix").
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH2:30]([O:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO.O>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:42][NH:1][C:2]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][C:3]=2[CH:4]([OH:20])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=2)=[CH:44][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)COc1ccc(N)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)COc1ccc(NCc2ccc(OCc3ccccc3)cc2)c(C(O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
NMR(CDCl3) δ: 1.02(6H,d,J=6.6 Hz), 1.449(9H,s), 2.05(1H,m), 3.64(2H,d,J=6.6 Hz), 4.31(2H,d,J=5.6 Hz), 4.85(1H,m), 6.797(1H,s), 6.6-7.5(7H,m) (5) In methanol (12 ml) were dissolved 2-amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-isobutyloxybenzyl alcohol (0.36 g), 4-benzyloxy-benzaldehyde (0.2 g) and acetic acid (0.05 g). To the solution was added cyano sodium borohydride (0.065 g). The mixture was stirred for 20 minutes at 60° C. To the reaction mixture was added water (6 ml), which was subjected to extraction with ethyl acetate (60 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-(4-benzyloxybenzylamino)-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-isobutyloxybenzyl alcohol as a yellow oily product (0.45 g).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=3[F:43])[C:30]([C:32]([O-])=[O:33])=[CH:31][C:24]=12.[Na+].[CH3:45][C:46]1([CH3:54])[O:50][C@@H:49]([CH2:51][O:52][NH2:53])[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH3:45][C:46]1([CH3:54])[O:50][C@@H:49]([CH2:51][O:52][NH:53][C:32]([C:30]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=3[F:43])[C:25]3=[CH:26][N:27]=[CH:28][C:23]([Br:22])=[C:24]3[CH:31]=2)=[O:33])[CH2:48][O:47]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C([O-])c1cc2c(Br)cncc2n1Cc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CONC(=O)c2cc3c(Br)cncc3n2Cc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 70 h
Yield: 68.6 %

Procedure:
EDCI (99 mg, 0.52 mmol) and HOBt (78 mg, 0.58 mmol) were added to a suspension of sodium 4-bromo-1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.23 g, 0.41 mmol) in THF (4 ml). The suspension was warmed gently for 1 minute before the addition of a solution of O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (85 mg, 0.58 mmol) in THF (1 ml), followed by DIPEA (73 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 70 hours, poured into ethyl acetate (40 ml) then washed sequentially with 0.1M HCl (10 ml), saturated NaHCO3 solution (10 ml) and brine (10 ml). The organic layer was isolated then dried over magnesium sulphate and concentrated in vacuo to provide a solid residue. Purification of the residue by flash chromatography (Si-SPE, dichloromethane:ethyl acetate 100:0 to 70:30 to 40:60 to 0:100) afforded the title compound as a waxy white solid (0.17 g, 68%). LCMS (method B): RT=3.51 min, M+H+=604, 606.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[CH3:19][N:20]=[C:21]=[O:22].[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27](C(O)=O)=[C:26]([O:34][CH3:35])[CH:25]=1>>[NH2:23][C:24]1[C:32]([Cl:33])=[CH:31][C:27]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:21]([NH:20][CH3:19])=[O:22])[CH2:11]2)=[O:7])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN=C=O
Product: CNC(=O)NCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.12 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isocyanate (0.38 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.96 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(3-methylureido)propyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=O>CC1CCCO1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:31]([C:27]3[O:26][CH:30]=[CH:29][CH:28]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccco1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Product: Clc1ccc(-c2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
The 4-chlorobenzamidoxime (1.24 g, 7.25 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) and 50% aqueous solution of sodium hydroxide (736 mg, 9.20 mmol) were added. The mixture was stirred and a precipitate formed. Furoyl chloride (1.24 g, 7.25 mmol) was added dropwise and an exotherm was noted. The mixture was stirred at 70° C. for 1 hour and cooled to room temperature. The solution was poured into water (25 mL) and the 2-methyltetrahydrofuran removed at reduced pressure. The resulting solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-furanyl)-1,2,4-oxadiazole (1.22 g, 4.94 mmol) was obtained as a white solid. (68% yield).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[F:35][C:34]([F:36])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([CH:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:7][C:6]([OH:38])=[O:5])=[CH:15][CH:16]=3)[CH:23]=2)=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Ester 50.4 (48 mg, 0.09 mmol) was dissolved in dichloromethane/TFA solution (3:1, 2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent removed under reduced pressure, and the product was purified on reserve phase HPLC to yield acid 50 (30 mg). MS ESI (pos.) m/e: 472 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.59-7.28 (3H, m); 7.2 (2H, d, J=8.6 Hz); 7.0 (2H, d, J=8.6 Hz); 5.13 (2H, s); 4.24-4.21 (1H, m); 3.20-3.13 (1H, m); 3.0 (3H, s); 2.95 (3H, s); 2.76-2.71 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=408.05.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (40 ml), and thereto are added ethyl 5-bromopentanoate (11.4 g) and potassium carbonate (6.38 g), and the mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into water, and the mixture is extracted three times with ethyl acetate. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, solvent; hexane/ethyl acetate=5:1 to 5:2). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (9.86 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.N1CCCCC1.[CH2:23]([C:26]#[N:27])[C:24]#[N:25].[Cl-].[Al+3].[Cl-].[Cl-].C([OH:34])C>C1C=CC=CC=1>[C:24]([C:23]1[C:26]([NH2:27])=[C:11]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6](=[O:34])[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]=3[CH:15]=1)#[N:25]
Reactant: CCO
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: N#CCC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: N#Cc1cc2c3c(cccc3c1N)C(=O)c1ccccc1-2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
927 parts of anthracene-9-aldehyde are suspended in 4.2 liters of ethanol. The suspension is treated with 10 parts by volume of piperidine and at about 45° C. over the course of one hour with 310 parts of malonic acid dinitrile in 400 parts by volume of ethanol. The orange suspension is stirred for 2 hours at 70° C. and subsequently cooled to 5°-10° C. The suspension is filtered with suction and the residue is washed with 500 parts by volume of ethanol and dried in vacuo at 90°-100° C. to yield 1077 parts of the intermediate of the formula ##STR22## 254 parts of the resulting intermediate are finely suspended in 1.75 liters of dry benzene. At room temperature, 320 parts of anhydrous aluminium chloride are added thereto over the course of about 2 hours. The green suspension is heated to 80° C. over the course of 45 minutes, stirred for 15 minutes at this temperature and then allowed to cool to 10° C. The benzene is decanted off from the viscous mass and the residue is poured onto 7 kg of ice. The aqueous suspension is stirred for 8 hours at room temperature. The suspension is filtered off and the residue is washed neutral with about 2 liters of water and dried in vacuo at 105° C. to yield 254 parts of 2-cyano-3-aminobenzanthrone. The compounds of the formula ##STR23## wherein R4 represents a halogen atom, a lower alkyl group or hydrogen, are ordinarily accessible by reaction of the vinylidene compounds of the formula ##STR24## with Friedel-Crafts reagents, wherein treatment is effected in inert solvents such as benzene, nitrobenzene or carbon disulphide at -20° C. to 150° C., preferably at 0° C. to 100° C., with ferric trichloride, boron trifluoride, boron trifluoride etherate or preferably aluminium chloride, and processing is carried out in the conventional manner.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:18]([O:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[CH:26]=[CH:25][C:22]=1[CH2:23]O)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>>[CH2:18]([O:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[CH:26]=[CH:25][C:22]=1[CH2:23][N:12]1[C:11](=[O:16])[CH:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[S:14][C:13]1=[O:15])[CH3:19]
Reactant: CCOc1ccc(CO)c(OCC)c1
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(CN2C(=O)SC(S(=O)(=O)c3ccc(C)cc3)C2=O)c(OCC)c1

Procedure:
5-(Toluene-4-sulfonyl)thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.] was reacted with 2,4-diethoxybenzyl alcohol in the presence of triphenylphosphine and diethyl diazodicarboxylate to give the title compound as colorless crystals, mp 121-123° C.