Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[N+:39]([O-])([OH:41])=[O:40].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([N+:39]([O-:41])=[O:40])[CH:25]=[CH:24][C:23]=1[NH:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)CN(CC(=O)OC)c1ccc(C)cc1OCCOc1ccccc1NC(C(=O)OC)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)CN(CC(=O)OC)c1ccc(C)cc1OCCOc1cc([N+](=O)[O-])ccc1NC(C(=O)OC)C(=O)OC
Temperature: 30 °C

Procedure:
50 g ((2-(2-(2-(Bis-methoxycarbonylmethyl-amino)-phenoxy)-ethoxy)-4-methyl-phenyl)-methoxycabonylmethyl-amino)-acetic acid methyl ester were dissolved in 600 ml glacial acetic acid. Under vigorous stirring 91.5 ml 1 molar nitric acid in glacial acetic acid was added and in a second step 28 ml of concentrated sulfuric acid was added. The temperature increased up to 30° C. The reaction mixture was directly poured in a 10 l ice/water mixture. The residue was filtered off, washed several times with water and dried under vacuum. The crude product was further purified by column chromatography on silica gel first with hexane/acetic acid ethyl ester (1:1) as eluent and a second time with toluene/acetonitrile (1:1) as eluent. The product was finally crystallized from propan-2-ol. Yield: 20 g.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:14]=2)=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O.O1CCCC1>[CH3:28][C@H:23]1[O:24][C@@H:25]([CH3:27])[CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[S:11][C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=4)=[N:14][N:13]=3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(c2ccc(-c3nnc(-c4ccc(C(=O)O)cc4)s3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
A mixture of 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester (527 mg) and 1.0 mol/l sodium hydroxide solution (2.6 ml) in a mixed solvent of methanol (10 ml) and tetrahydrofuran (25 ml) was refluxed for 6 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water and the mixture was adjusted with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and dried to give 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid (429.1 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12](C(O)=O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[CH:12][O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Solvent: c1ccc2ncccc2c1
Product: O=c1ccocc1OCc1ccccc1
Temperature: 25 °C

Procedure:
5-(Benzyloxy)-4-oxo-4H˜pyran-2-carboxylic acid (68.9 g, 280 mmol) was added to 300 mL of quinoline at 235° C. and the mixture was heated at reflux for 30 min. The mixture was cooled to room temperature and concentrated to give a residue which was purified by silica gel chromatography to give 3-(benzyloxy)-4H-pyran-4-one. 1H-NMR (CDCl3, 400 MHz) δ 7.64 (dd, J=5.6, 0.8 Hz, 1H), 7.53 (d, J−0.4 Hz, 1H), 7.39-7.28 (m, 5H), 6.40 (d, J=5.6 Hz, 1H)S 5.06 (s, 2H). MS (M+H)+ 203.0.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:34]3[CH:33]=[N:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)=[CH:36][CH:35]=3)=[CH:14][C:6]1=2
Reactant: FC(F)(F)c1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(C(F)(F)F)ccc3Cl)CCN4)cn2)CC1
Yield: 13 %

Procedure:
1-(2-Chloro-5-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow film (13% yield). M.p. (film), LCMS: m/z=502.98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.51 (t, J=5.3 Hz, 4H), 3.28 (t, J=5.3 Hz, 2H), 3.54 (t, J=5.0 Hz, 4H), 3.66-3.72 (m, 2H), 4.53 (s, 2H), 4.89 (bs, 1H), 6.53 (s, 1H), 6.64 (d, J=8.8 Hz, 1H), 7.46-7.54 (m, 4H), 7.63 (d, J=1.8 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Nc1cccc(Br)c1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cc1C
Temperature: 25 °C
Yield: 75 %

Procedure:
4-methoxy-3-methylphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.074 g in 75% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:13][OH:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[OH2:26].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]([CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:22])=[O:26])[O:12][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCC(O)CO)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(COC(=O)c2ccccc2)OS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of 35.5 g (181 mmol) of (-)-1-benzoyl glycerol (G) in 250 ml of dry pyridine at 0° C. is added 83 g (433 mmol) of p-toluenesulfonyl chloride. The mixture is stirred at 0° C. for 15 minutes and then stored in a refrigerator for 144 hours. After cooling the reaction mixture to 0° C., 10 ml of water are added, the mixture is stirred for 10 minutes, and then poured into excess water. The aqueous solution is separated from the gummy product, and extracted with chloroform. The gummy residue is dissolved in chloroform and the combined chloroform solution is washed sequentially with 3 N hydrochloric acid, water, 5% sodium bicarbonate solution, and water. The chloroform solution is dried over Na2SO4 and concentrated under reduced pressure to obtain a solid which, upon recrystallization from absolute ethanol, gives 65.5 g (130 mmol, 72%) of (-)-1-benzoyl-2,3-di-p-toluenesulfonyl glycerol (see Formula (H) in Scheme 2), m.p. 105°-106° C. [α]D2° -22.7 (c, 5.92, CHCl3). 1H NMR (CDCl3) δ8-7 (m, 13H); 4.9 (m, 1H); 4.45 (d, 2H, J=6 Hz); 4.35 (d, 2H, J=5 Hz); 2.42 (s, 3H); 2.38 (s, 3H). 13C NMR (CDCl3) 165.162, 145.136, 133.108, 132.466, 131.649, 129.430, 128.671, 128.087, 127.678, 75.306, 66.899, 61.994, 21.591 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.Cl.[O:15]1[CH2:18][CH:17]([NH2:19])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:19]([CH:17]3[CH2:18][O:15][CH2:16]3)[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: NC1COC1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Cl)nc2CN1C1COC1

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (Example 1, Step 4) (0.15 g, 0.68 mmol), oxetan-3-amine hydrochloride (0.15 g, 1.36 mmol) and potassium carbonate (0.38 g, 2.7 mmol) were stirred in DMF (10 mL) at room temperature overnight. Water and ethyl acetate were added and the biphasic mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (6-50% EtOAc/hexanes) gave the title compound as a white solid.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])C)C=[CH:6][CH:7]=1.NC1C=C(C([O:31]C)=S)SC=1C.C(OC1C=C(C=CC=1)C=O)(=O)C>>[OH:31][C:3]1[CH:4]=[C:8]([CH2:9][NH:11][C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: COC(=S)c1cc(NC(C)Cc2cccc(O)c2)c(C)s1
Agent: CC(=O)Oc1cccc(C=O)c1
Product: COC(=S)c1cc(NCc2cccc(O)c2)c(C)s1

Procedure:
Methyl 4-{[(3-hydroxyphenyl)methylethyl]amino}-5-methylthiothiophene-2-carboxylate: Using the procedure described in Example 220, step (a), 61.6 mg (0.30 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg (0.30 mmol) of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C14H16NO3S2, 352.07 (M+H), found, 350.2 (imine), 352.1.
Reaction SMILES: [Cl:1][C:2]12[C:10]([O:13][CH3:14])([O:11][CH3:12])[C:5]([Cl:15])([C:6]([Cl:9])=[C:7]1[Cl:8])[CH:4](O)[CH:3]2O.I([O-])(=O)(=O)=O.[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[Cl:15][C:5]12[C:10]([O:11][CH3:12])([O:13][CH3:14])[C:2]([Cl:1])([C:7]([Cl:8])=[C:6]1[Cl:9])[CH2:3][N:31]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[CH2:4]2
Reactant: COc1ccc(CN)cc1
Reactant: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(O)C2O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(CN2CC3(Cl)C(Cl)=C(Cl)C(Cl)(C2)C3(OC)OC)cc1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
1,4,5,6-Tetrachloro-7,7-dimethoxy-bicyclo[2.2.1]hept-5-ene-2,3-diol (1.23 g, 3.80 mmol) and sodium periodate (1.19 g, 3.80 mmol) were stirred vigorously for 1.5 h in DCE (10 mL) and water (10 mL). The di-aldehyde was extracted with DCE (2×15 mL), washed with water (5×10 mL, or until no reaction to starch iodide is observed in the aqueous wash), then filtered through a cotton plug under N2 into a slurry of p-methoxybenzylamine (0.52 mL, 3.99 mmol) and NaBH(OAc)3 (2.58 g, 12.16 mmol) in DCE (10 mL). After 3 h at room temperature the reaction was judged complete by TLC. The solvent was removed in vacuo, and the residue was quenched with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×30 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4, filtered through a silica pad (2×3 in), eluted with 100% EtOAc and concentrated to yield the title compound as a white solid (1.32 g, 82%). (TLC 30% EtOAc/hexanes Rf 0.65); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 3.77 (s, 3H), 3.61 (s, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.76 (d, J=11.4 Hz, 2H), 2.71 (d, J=11.1 Hz, 2H); GCMS m/z 427 (M)+.
Reaction SMILES: [N:1]1([C:10]2([C:15]#N)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O[Li].[OH2:19].C(OCC)(=[O:22])C.Cl>O.CCCCCC>[N:1]1([C:10]2([C:15]([OH:22])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: N#CC1(n2ccc3cccnc32)CCCC1
Reactant: CCOC(C)=O
Reactant: O
Agent: Cl
Agent: [Li]O
Solvent: CCCCCC
Product: O=C(O)C1(n2ccc3cccnc32)CCCC1
Temperature: 0 °C
Yield: 86 %

Procedure:
To a stirred suspension of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonitrile (393) (6.2 g, 29.35 mmol) in water (90 mL) was added LiOH.H2O (14 g, 334.56 mmol). The reaction mixture was refluxed for 24 h (TLC, 30% ethyl acetate in hexane, Rf=0.3). It was thereafter cooled to 0° C. and the aqueous part was acidified with HCl (6N) to pH 3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated to get 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarboxylic acid (394) (5.8 g, 86%) as an off-white solid.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].C(N(CC)CC)C.Cl.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.O>[O:3]=[C:2]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)NN
Reactant: NCCCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)NNC(=O)NCCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To 4-nitrophenyl chloroformate (1.008 g, 5.00 mmol) in THF (25.000 mL) at 0° C. was added ethyl carbazate (0.521 g, 5 mmol) and triethylamine (2.218 mL, 16.00 mmol). The mixture was stirred at 0° C. for 1 hour. Benzyl 4-aminobutylcarbamate hydrochloride (1.552 g, 6.00 mmol) was then added. The mixture was stirred at room temperature for 1 hour, water was then added, extracted twice with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% ethyl acetate/heptane) giving ethyl 4,11-dioxo-13-phenyl-12-oxa-2,3,5,10-tetraazatridecan-1-oate (I-9a: 965 mg, 55%) as a white solid. LC-MS (M+1) 353.2, t=0.94 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.Cl.[NH2:21][NH:22][C:23]([NH:25][OH:26])=[NH:24].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:21][NH:22][C:23](=[NH:24])[NH:25][OH:26])[CH2:9]1
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(NN)NO
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 155.8 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (101 mg) and 1-amino-3-hydroxyguanidine hydrochloride (48 mg) were added ethanol (2 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol and dried to give 7-(2-chlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 156) (110 mg) as gray white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Mg].BrCCBr.[C:17]1([C:27]#N)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][N:18]=1.Cl.[OH-:30].[Na+]>CO.O1CCCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:30])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: [OH-]
Reactant: CCCCc1ccc(Br)cc1
Reactant: N#Cc1nccc2ccccc12
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: BrCCBr
Product: CCCCc1ccc(C(=O)c2nccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 1-bromo-4-butylbenzene (2.29 ml, 13.0 mmol) was added to a mixed solution of magnesium (338 mg, 13.9 mmol) and tetrahydrofuran (6.5 ml), and as an initiator, catalytic amount of 1,2-dibromoethane was added, and this was stirred under reflux for 10 minutes. The solution was cooled to 0° C., a tetrahydrofuran solution of 1-isoquinolinecarbonitrile (1.0 g, 6.49 mmol) was added, and was stirred for another 1 hour at room temperature, and at 70° C. for 3 hours. Subsequently, the solution was cooled again to 0° C., concentrated hydrochloric acid (2.56 ml) and methanol (11 ml) were added, and then refluxed for 2 hours. The concentrated residue was dissolved in 5 N sodium hydroxide and toluene, and was filtered through celite. The toluene layer of the filtrate was divided, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1.72 g of the title compound.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[O:38])=[CH:33][C:32]=1[F:46]>C(Cl)Cl>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)[OH:38])=[CH:33][C:32]=1[F:46]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Br)c(F)c1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1ccc(Cl)cc1)(c1ccc(Br)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
4-Iodo-1-trityl-1H-imidazole (1.39 g, 3.18 mmol) was dissolved in anhydrous CH2Cl2 (10 mL). To this solution was added a 3.0M solution of ethylmagnesium bromide (1.11 mL, 3.34 mmol) and stirred under Ar. After 3 hr, a solution of (4-bromo-3-fluoro-phenyl)-(4-chloro-phenyl)-methanone (1.00 g, 3.18 mmol) dissolved in CH2Cl2 (5 mL) was added dropwise and the resulting solution was stirred overnight. The reaction was quenched with satd. NH4Cl solution, diluted with satd. NaHCO3 solution to pH=8.5, and extracted with CH2C2 (3×). The combined organic layers were dried (MgSO4), concentrated and purified using SiO2 chromatography (10-20% EtOAc/Hexane) to yield the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.N12CCC(CC1)CN2>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: C1CN2CCC1CN2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOCC3)c(F)cc2c1=O
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A mixture of 2.83 g (0.01 mol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.9 g (0.01 mol) of morpholine and 2.3 g of diazabicyclo[2.2.2]octane (0.02 mol) in 35 ml of dimethyl sulphoxide is heated to 140° C. for 5 hours. The solvent is distilled off in vacuo, 50 ml of water are added to the residue, the mixture is acidified with semiconcentrated hydrochloric acid, and, when the mixture is cold, the product is filtered off under suction, washed with water, dried in vacuo and recrystallised from glycol monomethyl ether. 2.4 g of 1-cyclopropyl-6,8-difluoro-7-(morpholin4-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 257°-260° C. are obtained.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])=[O:2].[C:10]1([C:16]2[C:18](=[O:19])[C:17]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:4]1([CH3:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:19])[O:2]1
Reactant: Cc1ccccc1N=O
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1N1OC(=O)C(c2ccccc2)C1c1ccccc1

Procedure:
2.4 Parts of o-nitrosotoluene and 4.1 parts of diphenylcyclopropenone in 50 parts of tetrahydrofuran is heated at the reflux temperature for 48 hours. Solvent then is removed under reduced pressure and the residue is crystallized from cyclohexane. Recrystallization from ethanol gives, as red granules, 2-(o-tolyl)-3,4-diphenylisoxazolin-5-one, melting at about 142°-143° C. That compound is represented structurally by the following formula. ##STR6##
Reaction SMILES: [CH2:1]([N:6]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:7](=[O:19])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:1]([N:6]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=2[CH:21]=1)[C:7](=[O:19])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Nc1ccc(C(=O)OC)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Nc1ccc(C(=O)O)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A solution of methyl 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-nicotinate (55) (37 mg) in 5 mL THF, 2 mL methanol and 2 mL water was treated with lithium hydroxide hydrate (50 mg), stirred at room temperature for two hours. The reaction mixture was diluted with 5 mL water, the pH adjusted to 2 with concentrated HCl and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to give a pale yellow solid. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane) followed by trituration in hexanes, yielding 17 mg 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ureido]-nicotinic acid (49) as a white solid. M.P. 175-179.5° C.
Reaction SMILES: [Na].[CH3:2][SH:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8](F)=[C:9]([CH:12]=1)[C:10]#[N:11].O>CS(C)=O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:3][CH3:2])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: CS
Reactant: N#Cc1cc(Cl)ccc1F
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) A 3 M aqueous solution of methyl mercaptan sodium salt (15 ml) was added to a solution of 5-chloro-2-fluorobenzonitrile (5.0 g) in DMSO (100 ml). The resulting mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (200 ml) and the resulting mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water, and dried to give 5-chloro-2-(methylsulfanyl)benzonitrile (4.6 g) as a white solid.