Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][N:69]([CH3:71])[CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]=[N:68][N:69]([CH3:71])[CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1cc(SCC2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(=O)OC(C)(C)C)n4)[C@H]3SC2)nn1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cn1cc(SCC2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)nn1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (708 mg: 0.683 mMol.) in a mixture of anisole (2 ml) and nitromethane (8 ml) is added dropwise a solution of aluminum chloride (727 mg: 5.47 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -30°--40° C. The reaction mixture is diluted with 1N-hydrochloric acid (5.5 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4carboxylic acid as pale yellow powder (96.3 mg). Yield: 27%.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:18]C(=O)C)[CH2:12][C:11]1([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl>>[NH2:18][CH:13]1[CH2:14][C:15]([CH3:16])([CH3:17])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:22])([CH3:23])[CH2:12]1
Reactant: CCCCCCCCON1C(C)(C)CC(NC(C)=O)CC1(C)C
Agent: Cl
Product: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Yield: 82.6 %

Procedure:
A mixture of 40.0 grams (0.123 mol) of N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)acetamide and 6N hydrochloric acid is heated at reflux for three hours. The reaction mixture is cooled and extracted with 2×150 ml). The aqueous layer is made basic and extracted with 3:1 ether:dichloromethane (3×150 ml). The three organic extracts are combined, dried over anhydrous magnesium sulfate and then concentrated to an oil. Purification by Kugelrohr distillation at 110°-120° C./0.5 mm affords 28.9 grams (83% yield) of the title compound as a pale yellow oil.
Reaction SMILES: [Li]CCCC.[Br-].[CH:7]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH3:41])=[C:36]([CH:39]=1)[CH:37]=O>C1COCC1>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH3:41])=[C:36]([CH:39]=1)[CH:37]=[C:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Reactant: COc1ccc(Br)cc1C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C=C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
n-BuLi (1.6M solution in hexane) (72.5 ml, 116 mmol) was added dropwise at 0° C. to a solution of cyclopentyltriphenylphosphonium bromide (45.8 g, 111 mmol) in THF (300 ml). The red solution was stirred at 0° C. for 0.5 h then treated with a solution of 5-bromo-2-methoxybenzaldehyde (23.5 g, 109 mmol) in THF (150 ml). The reaction mixture was stirred at RT overnight, concentrated in vacuo, then partitioned between CH2Cl2 (250 ml) and water (150 ml). The organic phase was separated and combined with further CH2Cl2 extracts (2×50 ml). The organic phase was washed (brine; 50 ml), dried (Na2SO4), and concentrated in vacuo. The residue was subjected to chromatography (SiO2; CH2Cl2) to afford the title compound (24.6 g), as a colourless oil δH (80 MHz; CDCl3) 1.6-1.9 (4H, br m, CH2(CH2)2), 2.3-2.6 (4H, br m, CH2(CH2)2CH2), 3.76 (3H, s, OMe), 6.4-6.5 (1H, br m, CH═C), 6.65 (1H, d, J 8.5 Hz, ArH ortho to OMe), 7.18 (1H, dd, J 8.5, 2.4 Hz, ArH para to olefin), and 7.39 (1H, d, J 2.4 Hz, ArH ortho to olefin).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[C:7]([I:11])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: O
Product: Nc1ncc([N+](=O)[O-])cc1I
Temperature: 100 °C
Yield: 134.8 %

Procedure:
A mixture of 2-amino-5-nitropyridine (86.3 g, 0.625 mol) and potassium iodate (53.5 g, 0.25 mol) in 2 M sulfuric acid was heated at 100° C. and a solution of potassium iodide (100 g, 0.603 mol) in water (250 mL) was added dropwise over 1 h. The resulting brown mixture was refluxed for 12 h. After being cooled to room temperature, the mixture was adjusted to pH 7 by careful addition of solid sodium bicarbonate. The mixture was extracted with dichloromethane, washed with a saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solvent removed in vacuo to afford 2-amino-3-iodo-5-nitropyridine (89.3 g, 60%) as a yellow solid: LC/MS m/e calcd for C5H4IN3O2 [M+H]+ 266.01, observed 266.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=3)=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][C:41](Cl)([Cl:43])[Cl:42])=[O:38].O>ClCCl>[Cl:42][CH:41]([Cl:43])[CH2:40][O:39][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=3)=[CH:11][C:10]=2[N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(NC(=O)OCC(Cl)Cl)cc3)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 239c (2.8 g, 6.8 mmol) in dichloromethane (40 mL) was added pyridine (1.1 g, 13.7 mmol) and 2,2,2-trichloroethyl chloroformate (1.7 g, 2.8 mmol). The mixture was stirred at room temperature for 72 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate/methanol (80:15:5) to give the desired product (2.0 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[CH3:14]
Reactant: COC(=O)C(=O)C(F)(F)F
Reactant: Cc1cc(=O)n(-c2ccc(F)cc2)[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(F)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-fluorophenyl)-3-methyl-5-pyrazolone (96 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (174 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C@@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (305 mg, 0.685 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(+)-1-amino-2-propanol (110 μmL, 1.40 mmol), WSCI.HCl (200 mg, 1.04 mmol) and 4-dimethylaminopyridine (170 mg, 1.39 mmol) were added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (285 mg, yield 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C(OCCO)C>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1O
Yield: 89.2 %

Procedure:
Using an analogous procedure to that described in Example 367, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 167.0 mg (1.2 mmol) of 5-amino-2-methoxyphenol to give 313.3 mg (89.3%) of the product as a gray solid, m.p. 254-256° C., mass (electrospray, m/e): M+H351.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:18][C:19]3[N:20]=[CH:21][S:22][C:23]=3[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[CH2:36](Br)[C:37]#[CH:38]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([N:18]([CH2:38][C:37]#[CH:36])[C:19]3[N:20]=[CH:21][S:22][C:23]=3[C:24]([O:26][CH3:27])=[O:25])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1scnc1NC(=O)Cc1cc(-c2ccc(Cl)cc2)ccc1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: C#CCN(C(=O)Cc1cc(-c2ccc(Cl)cc2)ccc1C)c1ncsc1C(=O)OC
Temperature: 25 °C

Procedure:
600 mg (1.5 mmol) of methyl 4-{[(4′-chloro-4-methylbiphenyl-3-yl)acetyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 20 ml of acetonitrile, and 1.2 g (3.7 mmol) of cesium carbonate, 449 mg (3 mmol) of sodium iodide and 0.33 ml (3 mmol, 80% pure) of propargyl bromide were added. The mixture was then stirred at RT for 12. The resulting suspension was filtered. The mother liquor was concentrated by evaporation. The residue was taken up in water and the solution was extracted with dichloromethane. The organic phase was dried and concentrated by evaporation. The residue was taken up in acetonitrile and chromatographed (acetonitrile/water (0.05% trifluoroacetic acid 20/80 to 100/0)). This gave 415 mg of methyl 4-{[(4′-chloro-4-methylbiphenyl-3-yl)acetyl](prop-2-yn-1-yl)amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:13])[CH2:10][CH2:9][S:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCSc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCSc2cc(Br)ccc21
Reaction time: 96 h
Yield: 31.9 %

Procedure:
A mixture of 3[(3-bromophenyl)thio]propanoic acid (390 mg) and concentrated sulfuric acid (1.6 ml) was allowed to stand at 20° C. for 4 days. Water was added and the mixture was extracted with ethyl acetate. The organic solution was washed with sodium bicarbonate solution, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on a silica SPE cartridge (10 g) eluting with cyclohexane, dichloromethane-cyclohexane (1:2, 1:1) and dichloromethane to give the title compound (116 mg) 13C NMR δ (CDCl3) 193.5, 144.4, 131.0, 130.3, 130.0, 128.9, 128.8, 39.6, 27.1.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:54])[C@@H:14]([NH:16][C:17](=[O:53])[C@@H:18]([O:22][C:23]([C:25]2(/[CH:31]=[CH:32]/[C:33]3[CH:42]=[C:41]4[C:36]([CH:37]=[CH:38][C:39]([C@H:43]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH3:44])=[N:40]4)=[CH:35][CH:34]=3)[CH2:30][O:29][CH2:28][CH2:27][O:26]2)=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].[OH-].[Na+].Cl>O1CCCC1>[C:49]([O:48][C:46]([NH:45][C@@H:43]([C:39]1[CH:38]=[CH:37][C:36]2[C:41](=[CH:42][C:33](/[CH:32]=[CH:31]/[C:25]3([C:23]([O:22][C@@H:18]([CH:19]([CH3:21])[CH3:20])[C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]4)=[O:54])=[O:53])=[O:24])[CH2:30][O:29][CH2:28][CH2:27][O:26]3)=[CH:34][CH:35]=2)[N:40]=1)[CH3:44])=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (69 mg, 0.081 mmol) in tetrahydrofuran (4 mL) was stirred at 0° C. under nitrogen. An ice-cold aqueous solution of sodium hydroxide (0.1 M, 0.82 mL, 0.082 mmol) was added and the reaction mixture was stirred at 0° C. for 20 minutes. Cold 1 M hydrochloric acid was added to acidify the mixture to pH 2 and the solvent was evaporated. The residue was co-evaporated with tetrahydrofuran/toluene (1:1, 3×) and the residue was triturated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (0.081 mmol) as a yellow solid and as a 1:1 mixture of diastereoisomers which was used crude in the next reaction. LCMS (m/z) 712.3 [M+H], Tr=2.46 min.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: COc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.O.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:20])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 130 °C

Procedure:
A suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (10 g; ex. Maybridge) in phosphorus oxychloride (10 ml) was heated at 130° C. to give a red solution. The solution was heated at 130° C. for 2.5. The reaction mixture was poured onto iced water and then neutralised by the portionwise addition of solid sodium bicarbonate. The aqueous was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and evaporated to give the title compound as a yellow solid (10.28 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C1C=CC=CC=1>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)N=C(Nc1ccc(C(=O)c2ccccc2)cc1N)SC
Solvent: c1ccccc1
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc([N+](=O)[O-])cc2)C1=N)SC
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-4-(3-carbomethoxy-S-methylisothioureido)benzophenone (3.43 g.; 0.01 mol) in benzene (100 ml.) there is added 4-nitrobenzaldehyde (1.5 g.; 0.01 mol). The mixture is refluxed and stirred for 3 hours. Water of the reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is vacuum filtered. The filter cake is dried to afford 3-imino-(4-nitrophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=3)=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25]1[CH:30]=[C:29]([CH2:31][NH:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[N:28]1[CH:27]=[CH:26][CH:25]=[CH:30][C:29]=1[CH2:31][N:32]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=1)[C:22](=[O:23])[CH2:21][N:18]1[CH:19]=[CH:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[CH:15][CH:14]=2)=[N:17]1
Reactant: O=C(O)Cn1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)n1
Reactant: c1ccc(CNCc2ccccn2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cn1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)n1)N(Cc1ccccn1)Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
2-[3-(4-Imidazo[1,2-a]pyridin-2-ylphenyl)-1H-1-pyrazolyl]acetic acid (51 mg), 2,2′-dipicolylamine (32 mg), and 1-hydroxybenzotriazole (27 mg) were dissolved in N,N-dimethylformamide (1 mL), and triethylamine (56 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg) were added to the solution, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with chloroform and then drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to flash column chromatography. Fractions eluted by dichloromethane-methanol (20:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of diethyl ether, to thereby yield the title compound (58 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Nc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Nc2ccc(C(C)(C)C(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 175.8 %

Procedure:
To a solution of methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoate (0.100 g, 0.24 mmol) in dioxane (9 mL) and water (6 mL) was added LiOH.H2O (0.031 g, 0.73 mmol) and the reaction mixture stirred under a nitrogen atmosphere at 50° C. for 16 h. After this time, the reaction mixture was cooled and treated with 1M HCl to pH 3.0 and concentrated to afford the title compound (0.167 g, 100%) as a yellow oil. MW=395.88. 1H NMR (CDCl3, 300 MHz) δ 9.79 (s, 1H), 8.86 (s, 1H), 8.44-8.39 (m, 1H), 8.33-8.26 (m, 1H), 7.43-7.40 (m, 1H), 7.40-7.35 (m, 4H), 6.77 (s, 1H), 6.52 (s, 1H), 2.89 (q, J=7.6 Hz, 2H), 2.42-2.38 (m, 3H), 2.08-2.00 (m, 3H), 1.65-1.57 (m, 3H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH:10]([C:16]([OH:18])=[O:17])[CH2:9][CH2:8][CH2:7][C:6]2=1>[C].[Pd].C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]([C:16]([OH:18])=[O:17])=[CH:9][CH:8]=[CH:7][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCCC3C(=O)O
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: COc1ccc2[nH]c3c(C(=O)O)cccc3c2c1

Procedure:
2.05 g. of the ethyl ester of 6-methoxy-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid is dissolved in 20 ml. of xylene, mixed with 2 g. of 10% palladium-carbon catalyst, and refluxed for 4 hours. After the reaction mixture has cooled, the catalyst is filtered off, the solution is concentrated under vacuum, the residue is recrystallized from benzene, and 1.5 g. of the ethyl ester of 6-methoxycarbazole-1-carboxylic acid is thus produced, m.p. 107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc(=O)oc2c1
Product: O=c1ccc2ccc(CBr)cc2o1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
To a solution of 7-methylcoumarin (50 g) in acetonitorile (1.2 L) were added N-bromosuccinimide (56 g) α,α′-azobisisobutyronitrile (510 mg) and the mixture was stirred at 78° C. for 30 minutes. The reaction solution was concentrated and then added water (1 L). The appeared crystal was filtrated to give the title compound (76 g) having the following physical data.