Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][C:24]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:27][C:28]([CH3:30])=[CH2:29])[O:23][C:22]2=[O:35])[CH3:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][C:24]([CH2:31][CH:32]3[CH2:34][CH2:33]3)([CH2:27][C:28]3([CH3:30])[CH2:29][O:9]3)[O:23][C:22]2=[O:35])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CC1(CC2CC2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
m-Chloroperbenzoic acid (455 mg) was added to a solution of 3-[(S)-1-(4-bromophenyl)-ethyl]-6-(cyclopropylmethyl)-6-(2-methylallyl)-1,3-oxazinan-2-one (516 mg) in CH2Cl2 (15 mL) at 0° C. The mixture was stirred at room temperature overnight. The mixture was then washed with 3% aqueous Na2SO2O3 solution and saturated aqueous NaHCO3 solution. The aqueous washing phase was extracted with ethyl acetate (3×30 mL) and the combined organic layer was washed with brine, dried (Na2SO4), and concentrated to afford the crude title compound which was used without further purification. Yield: 490 mg (91% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 160 °C
Reaction time: 41 h
Yield: 19.5 %

Procedure:
2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrolidone (65 ml), and 2-fluoro-4-nitrophenol (19.55 g) and N,N-diisopropylethylamine (43.36 ml) were added thereto, followed by stirring at 160° C. for 41 hr. The reaction mixture was allowed to cool down to room temperature, and was partitioned between ethyl acetate-tetrahydrofuran (1:1) and a 2N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine in this order. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated, and crystals were precipitated by addition of ethyl acetate to the residue. The crystals were collected by filtration and dried under aeration to provide the titled compound as opalescent crystals (3.02 g, 20%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C@@H:10]2[CH2:18][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][C@@H:12]3[CH2:11]2)[N:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1>CS(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:16]2[CH2:15][CH2:14][N:13]3[CH2:18][C@@H:10]([NH:9][C:5]4[N:4]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:8]=[CH:7][N:6]=4)[CH2:11][C@H:12]3[CH2:17]2)=[N:29][CH:30]=1
Reactant: FC(F)(F)c1ccnc(N[C@H]2C[C@H]3CNCCN3C2)n1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccnc(N[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)n1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of Example 33 (115 mg, 0.4 mmol) and sodium carbonate (72 mg, 0.68 mmol) in dimethyl sulfoxide (0.5 mL) was added 2,5-dichloropyridine (95 mg, 0.64 mmol). The mixture was stirred at 100° C. for 2 days. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=15:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (m, 1H), 2.00-2.15 (m, 2H), 2.30-2.40 (m, 2H), 2.60 (m, 1H), 2.88-3.00 (m, 3H), 4.20-4.40 (m, 3H), 6.89 (d, 1H, J=7 Hz), 6.98 (m, 1H), 7.58 (d, 1H, J=7 Hz), 8.04 (m, 1H), 8.06 (s, 1H), 8.60 (m, 1H); MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[Cl:24])=[C:7]([F:15])[C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:9]3[C:10]([CH3:13])=[N:11][O:12][C:8]=3[C:7]=2[F:15])=[C:18]([Cl:24])[CH:19]=1
Reactant: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid methyl ester (8a) (200 mg, 0.48 mmol) in THF-water (3 mL/1.5 mL) was added aqueous LiOH (1 M, 1.00 mL) at room temperature. After 15 hours, the reaction mixture was acidified to pH 1 with aqueous HCl (1 M), diluted with water, and extracted with EtOAc/THF. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 191.5 mg (99%) of the crude acid (9a) which was used without further purification. MS APCI (−) m/z 397, 399 (M+, Br, Cl pattern) detected: 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.37 (s, 1H), 7.75 (s, 1H), 7.42 (d, 1H), 6.97 (t, 1H), 2.60 (s, 3H): 19F NMR (376 MHz, DMSO-d6) −140.15 (s, 1F).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])[CH:29]=4)[CH:25]=3)[CH:16]=[CH:15][C:13]=2[N:14]=1>N1C=CC=CC=1>[C:37]([C:34]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[C:27]([NH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:40])[O:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:7])[S:11][C:12]=2[CH:18]=1)=[O:39])([CH3:36])[CH3:35])#[N:38]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)c1cocn1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (4.0 mL) at 0° C., N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vi) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in methanol (4.0 mL). 1N Aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 1N hydrochloric acid (10 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (70 mg, 29%) as a colorless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]=[C:24]([C:23]([O:30][CH3:31])=[O:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 4-[2-(2-naphthoxy)ethoxy]benzaldehyde (1.24 g, 4.26 mmol) and dimethyl malonate (1.69 g, 12.78 mmol) in toluene (30 ml) is added a catalytic quantity of piperidinium acetate. Then the mixture is refluxed in a Dean-Stark trap for 8 hours. After cooled to room temperature, the solution was concentrated under a vacuum to give title compound (1.45 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[CH2:9][CH2:10][CH2:11][OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:12][CH2:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][N:5]=[CH:6][C:7]=2[O:13][CH3:14])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Reactant: COc1cncc(OC)c1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cncc(OC)c1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3,5-Dimethoxypyridin-4-yl)-1-propanol (0.60 g, 3.0 mmol) obtained in Example 1 and triphenylphosphine (1.18 g, 4.5 mmol) are dissolved in THF (30 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (0.78 g, 3.9 mmol) and 2-(3-bromophenoxy)-3-pyridinol (1.04 g, 3.9 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and the reaction; solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 m), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine, which is further treated with fumaric acid to give the title compound (1.26 g), m.p. 106-154° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[Cl-].[NH4+:14].CCOC(C)=O.O>N>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:14])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 214.4 %

Procedure:
To a stirred mixture of methyl 4-chloro-2-pyridinecarboxylate hydrochloride (1.0 g, 4.81 mmol) dissolved in conc. aqueous ammonia (32 mL) was added ammonium chloride (96.2 mg, 1.8 mmol, 0.37 equiv.), and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into EtOAc (500 mL) and water (300 mL). The organic layer was washed with water (2×300 mL) and a saturated NaCl solution (1×300 mL), dried (MgSO4), concentrated in vacuo to give 4-chloro-2-pyridinecarboxamide as a beige solid (604.3 mg, 80.3%): TLC (50% EtOAc/hexane) Rf 0.20; 1H-NMR (DMSO-d6) δ 8.61 (d, J=5.4 Hz, 1H), 8.20 (broad s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.81 (broad s, 1H), 7.76 to 7.73 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=O>>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)cc3Cl)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 8 %

Procedure:
4-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (24 mg, 8%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,4′-dichloroacetophenone (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.57-7.78 (m, 4H), 7.43 (t, J=8.3 Hz, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:44]([C:42]3[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:32]4[C:31]([F:30])=[CH:36][CH:35]=[CH:34][C:33]=4[F:37])[N:43]=3)=[O:45])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.030 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036 mmol), HATU (28.2 mg, 0.074 mmol) in DMF (0.07 mL) and DIPEA (11.5 mg, 0.089 mmol) was stirred at room temperature for 2 h. The reaction mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to afford the sub-title compound (11 mg, 58%). LCMS calc. for C33H37F3N5O5 (M+H)+: m/z=640.3. Found: 640.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](OC=C)(=O)[CH3:9]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[CH2:9]
Reactant: C=COC(C)=O
Reactant: O=C(O)CCCBr
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C=COC(=O)CCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromobutyric acid (1.0 g, 6.0 mmol) in vinyl acetate (54 mL) add with stirring palladium(II) acetate (188 mg, 0.84 mmol) and continue stirring overnight at ambient temperature. Filter and concentrate in vacuo to provide the crude desired intermediate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([O-:20])=[O:19]
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To a solution of the 1H-indazol-5-ol (300 mg, 2.24 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (6 ml) were added 2-bromonitrobenzene (497 mg, 2.46 mmol) and potassium carbonate (402 mg, 2.91 mmol), and the resulting mixture was heated to 120° C. After 6 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(2-nitrophenoxy)-1H-indazole (57 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](O)(=O)[CH3:16]>C(O)C>[NH2:13][C:3]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:7]([C:15]2[CH:16]=[CH:8][CH:6]=[CH:5][CH:4]=2)[CH:2]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (0.245 g) in ethanol (2 ml) was added to benzoylacetonotrile (0. 145 g) in ethanol (8 ml) and the solution heated at 80° C. for 6 hours. Glacial acetic acid (1 ml) was added and the mixture heated at 80° C. for 4 hours and then 90° C. for 2 hours. The reaction mixture was evaporated and the residue purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of appropriate fractions followed by further purification of their residue by reverse phase high performance liquid chromatography on C18 silica eluted with methanol: acetonitrile: water (1:5:4). Combination and evaporation of appropriate fractions gave the title compound as a white solid m.p. 141.5-142.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Pd]>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:14]=[N:13]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 120 °C

Procedure:
8.1 A suspension of 1.00 g (5.0 mmol) of 5-bromo-7-azaindole, 2.00 g (9.1 mmol) of 1-methylpyrazole-4-boronic acid pinacol ester, 300 mg (0.26 mmol) of Pd[(PPh3]4 and 9 ml of Na2CO3 (addition as 2 M solution) in 12 ml of DMF is heated at 120° C. under microwave conditions for 30 min. The reaction mixture is filtered, and the filtrate is evaporated. The residue is purified on a silica-gel column with dichloromethane/methanol as eluent, giving 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine as yellow solid, ESI 199
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]([F:68])([F:67])[C:57]1[CH:62]=[CH:61][C:60]([C:63]2([NH2:66])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:66][C:63]3([C:60]4[CH:61]=[CH:62][C:57]([C:56]([F:55])([F:67])[F:68])=[CH:58][CH:59]=4)[CH2:65][CH2:64]3)=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: NC1(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 20 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.290 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.193 g, 0.590 mmol) and 1-[4-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-13, 0.073 g, 0.350 mmol) to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.35 (s, 4H), 7.36 (d, J=7.8 Hz, 2H), 7.46-7.70 (m, 5H), 8.01 (s, 4H), 9.30 (s, 1H), 12-13 (br s, 1H); MS (m/z): 515.23 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[C:25]([O:44][CH2:45][CH2:46][CH2:47]O)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[CH3:1][C:2]1([CH3:24])[S:6][CH:5]2[N:4]([C:8](=[O:9])[CH:7]2[NH:10][C:11](=[O:12])[CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]1[C:21]([O:23][CH2:47][CH2:46][CH2:45][O:44][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:22]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)C2SC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of penicillin V (1 g, 2.9 mmol), 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4-(N,N-dimethylamino)pyridine (catalytic amount) in dichloromethane (30 ml) was stirred overnight at room temperature. The reaction mixture was diluted with hexane (50 ml), filtered and concentrated to dryness. The residue was washed with hexane (3×50 ml) to remove unreacted 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane. The semisolid residue was disolved in diethyl ether (150 ml), washed with water (100 ml) and dried. The ether solution was diluted with hexane (125 ml) and the solution filtered through a bed of silica (4 cm×4 cm). The filtrate was concentrated, yielding 1-(3,3-dimethyl-7-oxo-6([phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptan-2-oyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane as a viscous colourless oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)C.[O:8]1[CH2:30][CH:9]1[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]>O>[OH:8][CH:9]([CH2:30][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]
Reactant: NCCO
Reactant: CCCCOC(=O)CCCCCCCCCCCOCC1CO1
Solvent: O
Solvent: CCO
Product: CCCCOC(=O)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was charged with 23.7 g (250 mmol) of ethanolamine and 23.7 g of ethanol. While stirring the mixture at 80° C., an ethanol solution of 8.20 g (25 mmol) of butyl 12-(2,3-epoxypropoxy)-dodecanate was added dropwise over 1 hour. After completion of the reaction, water was added to the reaction mixture, followed by extraction with chloroform. The resultant chloroform solution was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 5.40 g (yield: 55.4%) of the title compound (Ia-15).