Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1.[ClH:37]>CO.CCOCC>[ClH:1].[ClH:37].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5Cl)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 42 %

Procedure:
tert-Butyl 7-(4-(2,4-dichlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (56 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl in Et2O) provided the title compound (22 mg, 42%) as a yellow solid: mp 321-324° C.; 1H NMR (500 MHz, CD3OD) δ 7.80 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 2H), 7.13 (d, J=7.0 Hz, 1H), 6.73 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 4.54 (s, 2H), 3.80 (s, 3H), 3.72 (t, J=6.0 Hz, 2H), 3.26 (t, J=5.9 Hz, 2H); ESI MS m/z 424 [M+H]+; HPLC (Method B)>99% (AUC), tR=14.1 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:4]([CH3:28])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH2:20])=[C:4]([CH3:28])[N:3]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCN
Yield: 70.5 %

Procedure:
The product from step (viii) (76 mg) was dissolved in DCM (5 mL) and TFA (5 mL) and the mixture stirred at rt for 1 h. The solvent was evaporated and the crude material dissolved in MeOH (5 mL) and purified by SCX. The product was dissolved in THF (10 mL) then lithium hydroxide (12.2 mg) in water (5 mL) was added. The reaction mixture was heated to reflux for 1 h, the solvents were evaporated and the crude product purified by RPHPLC to afford the subtitle product 40 mg.
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][N:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)[C:19](=[O:31])[N:18]=3)[CH2:13][CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+].C(OP([C:42](Br)([F:44])[F:43])(=O)OCC)C>C(OCC)C.O>[F:43][CH:42]([F:44])[O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:20]2[CH:21]=[N:22][C:17]([N:14]3[CH2:15][CH2:16][C:11]([C:8]4[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=4)=[CH:12][CH2:13]3)=[N:18][C:19]2=[O:31])=[CH:29][CH:28]=1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(OC(F)F)cc1
Yield: 12.4 %

Procedure:
To an acetonitrile (1.0 mL)-water (1.0 mL) solution of 4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1-(4-hydroxybenzyl)-1,3,5-triazin-2(1H)-one (15.0 mg, 0.0396 mmol) synthesized in Synthesis Example 483a, potassium hydroxide (44.5 mg, 0.793 mmol) was added and while stirring the resultant reaction solution at −78° C., to the reaction solution, diethyl(bromodifluoromethyl)phosphonate (14.1 μL, 0.0794 mmol) was added, followed by stirring the resultant reaction solution at room temperature for 2 and a half hours. After the completion of the reaction, extraction with diethyl ether from the reaction solution was performed. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography to obtain the title compound (2.10 mg, yield: 11%).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>C(O)C.C(OCC)C>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2)c1
Temperature: 50 °C
Yield: 84 %

Procedure:
268 mg (6.7 mmol) of sodium hydroxide are added to a solution of 284 mg (0.67 mmol) of ethyl 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 10 mL of ethanol. The reaction mixture is heated at 50° C. for 15 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the solid obtained is taken up in ethyl ether, filtered off and dried. 222 mg (84%) of 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a white powder with a melting point of 150-152° C.
Reaction SMILES: [CH2:1]([NH2:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C.Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[N+:34]([O-:36])=[O:35]>CCO>[N+:31]([C:28]1[CH:27]=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=[CH:30][C:29]=1[NH:16][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]#[CH:15])([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C#CCOCCOCCOCCOCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCOCCOCCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
3,6,9,12-tetraoxapentadec-14-yn-1-amine 7 (1.0 g, 4.3 mmol, 1 equiv.) was dissolved in EtOH (18 mL), and triethylamine (1.68 mL, 8.6 mmol, 2 equiv.) and 1-chloro-2,4-dinitrobenzene (876 mg, 4.3 mmol, 1 equiv.) were added. The reaction flask was fitted with a reflux condenser and the reaction was heated to reflux for 2 h, cooled, and concentrated to a crude yellow oil. The crude mixture was re-dissolved in H2O (25 mL) and extracted with CH2Cl2 (5×10 mL). Organic layers were dried over Na2SO4 and concentrated to a yellow oil that was purified by flash chromatography (CombiFlash Automated Chromatographer, 25 g column, dryloaded with 25 g pre-packed dry loading column. Run using 10% EtOAc:Hexanes to 50% EtOAc:Hexanes gradient over 30 column volumes, followed by EtOAc flush) to yield 2 as a yellow solid (1.70 g, >98% yield). IR (thin film/NaCl) 3360(m), 3290 (m), 3110 (w), 2873 (m), 2114(w), 1621 (s), 1588 (m), 1336 (s), 1134 (m) cm−1; 1H-NMR (500 MHz, CDCl3) δ 9.13 (d, 1H, J=2.6 Hz), 8.80 (broad peak, 1H), 8.25 (dd, 1H, J=2.6, J=9.5 Hz), 6.94 (d, 1H, J=9.5 Hz), 4.18 (m, 2H), 3.83 (t, 2H, J=5.2 Hz), 3.67 (m, 12H), 3.60 (q, 2H), 2.41 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ 148.6, 136.2, 130.4, 124.4, 114.3, 79.8, 74.7, 70.8, 70.7, 70.5, 69.2, 68.7, 58.5, 43.4; HRMS (EI) calc'd for C17H23N3O8 (MH+) m/z 398.1558. Found 398.1557.
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:24][CH:25]=1)OCCC)#[N:13]>CO>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:24][CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCOC(=NC#N)c1ccc(N(CC)CC)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1ccc(C(=NCCO[N+](=O)[O-])NC#N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.1 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (314 mg, 2.20 mmol) in methanol (3 ml) was added sodium methoxide (115 mg, 2.13 mmol) followed by a solution of propyl N-cyano-6-diethylamino-3-pyridinecarboximidate (370 mg, 1.42 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of ethyl acetate and hexane as an eluent to give the title compound (183 mg, yield 42%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7][C:8](=[N:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:25](=[O:29])[CH2:26][C:27]#[N:28])C.C([O-])(=O)C.[NH4+]>CCO>[C:1]1([S:7][C:8]2[C:9]([CH3:10])=[C:26]([C:27]#[N:28])[C:25](=[O:29])[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(NN=C(Sc2ccccc2)C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(-n2nc(Sc3ccccc3)c(C)c(C#N)c2=O)cc1

Procedure:
The reaction of 429 mg of 1-[(phenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, 375 ul of ethylcyanoacetate and 178 mg of ammonium acetate as in Example 55, yielded 165 mg of 6-[(phenyl)thio]- 2,3-dihydro-2-(4-methoxyphenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, mp 179°-180° C. (EtOH).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([NH2:11])=[C:4]([NH2:12])[C:3]=1[O:13][CH3:14].Cl.CO[C:18](=N)[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1>CO>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]2[NH:12][C:4]3[C:3]([O:13][CH3:14])=[C:2]([CH3:1])[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]=3[N:11]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1c(C)c(C)c(OC)c(N)c1N
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Product: COc1ccc(C=Cc2nc3c(OC)c(C)c(C)c(OC)c3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A mixture of 2,3-dimethyl-5,6-diamino-1,4-dimethoxybenzene (2.57 g; 10 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.96 g; 10 mmol) in methanol (35 mL) was stirred at ambient temperature for 18 hours. The methanol solution was concentrated to 15 mL. The yellow precipitate was separated by filtration. Recrystallization from MeOH afforded 2.1 g (58% yield) of the title compound as yellow solid, m.p. 116-119° C. Anal. Calcd. for C21H24N2O4: C, 66.46, H, 6.57; N, 7.60. Found: C, 66.83; H, 6.64; N, 7.41. Mass spectrum: (EI,M+) m/z 368 1H-NMR (DMSO-d6; 400 MHz) δ12.4-12.5(broad s,1H), 7.6-7.4 (d, 1H), 7.2 (d, 1H), 7.07-7.16 (m, 2H), 7.0 (d, 1H), 3.84(s, 3H), 3.78 (s, 3H), 2.2 ppm (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.CO.C(Cl)(Cl)Cl.CO>CCOC(C)=O>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([N:15]1[CH2:19][C:18](=[CH2:20])[CH2:17][C@H:16]1[CH2:21][OH:22])=[O:14]
Reactant: C=C1C[C@@H](CO)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])C1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C1C[C@@H](CO)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
The nitro-alcohol 66 (0.637 g, 1.60 mmol), SnCl2 2H2O (1.81 g, 8.0 mmol) and methanol (36 mL) were heated at reflux and monitored by TLC (90% CHCl3/MeOH). After 1 hour the MeOH was evaporated in vacuo and the resulting residue cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give an orange glass. Flash chromatography (EtOAc) afforded the pure amine 67 as a pale yellow glass (0.37 g, 63%): [α]23D=−42.7° (c=3.7, CHCl3); 1H NMR (270 MHz, CDCl3) δ7.44-7.29 (m, 5Harom), 6.77 (s, 1Harom) 6.27 (s, 1Harom), 5.12 (s, 2H, PhCH2O), 5.06-5.00 (m, 1H, NCH2C═CH2), 4.99-4.92 (m, 1H, NCH2C═CH2), 4.63-4.53 (m, 1H, NCHCH2OH), 4.25-3.60 (m, 10H, NCHCH2OH, NCH2C═CH2, OCH3, OH and NH2), 2.77 (dd, 1H, J=8.52, 15.85 Hz, NCH2C═CH2CH2), 2.43-2.39 (m, 1H, NCH2C═CH2CH2); 13C NMR (67.8 MHz, CDCl3) δ171.4 (NC═O), 151.0 (Cquat), 143.3 (Cquat), 141.5 (Cquat), 140.6 (Cquat), 136.5 (Cquat), 128.6 and 128.0 (BnC—Harom), 127.8 (Cquat), 127.1 (BnC—Harom), 112.5 (C—Harom), 107.8 (NCH2C═CH2), 103.0 (C—Harom), 70.6 (PhCH2O), 65.9 (NCHCH2OH), 60.0 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2); MS (EI), m/z (relative intensity) 368 (M+., 100), 353 (M—CH3, 2), 340 (1), 286 (2), 273 (4), 256 (M—NCH2C═CH2CH2CHCH2OH, 59), 249 (8), 226 (4), 200 (2), 196 (2), 166 (5), 138 (17), 112 (NCH2C═CH2CH2CHCH2OH, 39), 91 (PhCH2, 70), 82 (5), 65 (5); IR (NEAT) 3600-3000 (br, NH2 and OH), 3065, 3052, 2932, 2869, 2246, 1668, 1620, 1592, 1513, 1454, 1408, 1264, 1229, 1197, 1176, 1113, 1079, 1002, 909, 733, 698, 645 cm−1; exact mass calcd for C21H24N2O4 m/e 368.1736, obsd m/e 368.1662.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:40]1[CH2:42][C@@H:41]1[CH2:43][O:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:42][C@@H:41]([OH:40])[CH2:43][O:44][C:45]3[CH:54]=[CH:53][CH:52]=[C:51]4[C:46]=3[CH:47]=[CH:48][CH:49]=[N:50]4)[CH2:28][CH2:27]2)=[O:25])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-(Piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (87) (261.8 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 25 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (190 mg) as a white solid. ESMS: MH+ 728.6
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])(=O)=O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([Cl:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cn1cc2cccc(Br)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1nc2c(Br)cccc2c1Cl
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.500 g, 2.37 mmol) in 5 mL of acetic acid was added sulfuryl chloride (0.29 mL, 3.6 mmol). The mixture was stirred for 5 h, then 30 mL of a 2 M aqueous NaOH solution were added. The mixture was extracted with three 30 mL portions of ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to a white solid. Column chromatography (0→15% EtOAc/hexanes) afforded slightly impure 7-bromo-3-chloro-2-methyl-2H-indazole (25: R=Me; 0.530 g; 90%) that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:5]([O:7]CC)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]([F:16])([F:17])[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][C:5]([OH:7])=[O:6]
Reactant: CCCCCCC(=CC(=O)OCC)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(=CC(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 112.5 %

Procedure:
13.78 g of ethyl 3-trifluoromethyl-2-nonenoate was dissolved in 138 ml of methanol, and 1.38 g of 5%-palladium/activated carbon was added thereto, followed by stirring for 4 hours at room temperature and normal pressure in a hydrogen atmosphere in a catalytic hydrogenation apparatus. After the reaction, the 5%-palladium/activated carbon was filtered out, and the remaining methanol solution was mixed with 24 ml, of water and 20 g of potassium hydroxide, followed by 2 hours of heat refluxing, distilling-off of methanol under a reduced pressure, acidification with addition of 6N-hydrochloric acid, and extraction with methylene chloride. The resultant methylene chloride solution was dried on sodium sulfate, followed by distilling-off of the solvent and purification by distillation (b.p.: 118.5°-119.7° C./20 mmHg), whereby 13.78 g of 3-trifluoromethylnonenoic acid was obtained. (Yield: 51.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH3:9][N:10]1[CH2:15][CH2:14][C:13]2([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2)[CH2:12][CH2:11]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccccc1S
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC2(CC1)Nc1ccccc1S2

Procedure:
A mixture of 125.5 g 2-amino-thiophenol, 147 g N-methyl-4-piperidone, 2 ml acetic acid and 400 ml toluene is refluxed with a water separator for 2 hours. The mixture is evaporated in vacuo. The residue is recrystallised from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 135°-140°.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].[C:20]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:21][C:22]([CH3:24])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.O>[NH2:12][C:11]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]=2[N:1]=[C:22]([CH3:24])[C:21]=1[C:20]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: N#Cc1c2c(n(Cc3ccccc3)c1N)CCCC2
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(c1N)c1c(n2Cc2ccccc2)CCCC1

Procedure:
The title compound was prepared using a modified procedure (see below) to that described by H. J. Roth et al., Arch. Pharmaz., 1976, 309, 597. 2-Amino-1-benzyl-3-cyano-4,5,6,7-tetrahydroindole (D1) (1.255 g; 5 mM) was added to a solution of ethyl acetoacetate (0.655 g; 5 mM) in toluene (60 ml) containing para-toluenesulphonic acid (30 mg), and the mixture refluxed vigorously for 1 h with water separation (Dean and Stark apparatus). To the cooled solution was then added 1M sodium ethoxide in ethanol (6 ml) and the mixture refluxed for a further 2 h. The cooled solution was poured onto water, and the pH of the stirred mixture adjusted to 7 using 5M hydrochloric acid. The toluene layer was then separated, and the aqueous phase re-extracted with toluene. The combined organic phase was washed with brine, dried and evaporated to give a brown oil (1.5 g). Crystallisation from ethanol afforded the title compound as off-white needles (0.8 g; 44%), m.p. 145.5° -147°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:22])/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C(C)=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture compound 12.2 (2.80 g, 9.45 mmol) and Pd/C (0.40 g, wt 10% on activated carbon) in EtOH (35 mL) was purged with hydrogen three times and stirred under hydrogen at ambient temperature overnight. The catalyst was removed by filtration. The filtrate was evaporated to give the crude compound 12.3 which was used in the next step without further purification. MS ESI (pos.) m/e: 209 (M+H). 1H NMR (CDCl3) δ 7.02(d, 2H), 6.75(d, 2H), 4.11(q, 2H), 2.93(dd, 1H), 2.68(m, 2H), 1.21(t, 3H), 1.16(d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][O:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([NH2:32])[S:31][C:27]=2[CH:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:32][C:30]2[S:31][C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:34]=[CH:33][C:28]=3[N:29]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: COc1ccc2nc(N)sc2c1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)/C(=N/OC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)sc2c1
Reaction time: 2 h
Yield: 55 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 6-methoxy-2-aminobenzothiazole (44 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(6-methoxy-benzothiazol-2-yl)-acetamide (67 mg, 54%) as a faintly yellow solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C22H22ClN3O5S2 [M+] 507.07, found 508 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 3.32 (s, 3 H, SO2CH3), 3.89 (d, 3 H, OCH3), 4.96 (m, 1 H, OCH), 7.07 (dd, Jo=8.9, Jm=2.5 Hz, 1 H, Ar), 7.31 (d, Jm=2.5 Hz, 1 H, Ar), 7.61 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jo=8.9 Hz, 1 H, Ar), 7.71 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 10.11 (s, 1 H, NH).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=2[O:17]C)=[CH:5][N:4]=1.C([O-])(O)=O.[Na+]>Br.O>[OH:17][C:10]1[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1
Reactant: COc1ccc(OC)c(-c2ccc(OC)nc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1ccc(-c2cc(O)ccc2O)c[nH]1
Temperature: 25 °C

Procedure:
A solution of 502 mg (2.05 mmol) of 2-methoxy-5-(2,5-dimethoxy-phenyl)pyridine in 20 mL of 48% hydrobromic acid (aqueous) is refluxed for 6 hours, cooled to ca. 25° C. and diluted with 150 mL of water. The mixture is neutralized with solid NaHCO3, cooled to 0° C. and the resulting solid product collected by filtration. The solid is washed well with water, collected by centrifugation, then further purified by recrystalization in methanol to obtain 5-(2,5-dihydroxyphenyl)-2(1H)-pyridone m.p. 303°-306° C. dec).