Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]12[CH2:25][O:24][C@@H](C=O)[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:17]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:4][CH:1]=[C:2]1[O:24][CH2:25][C@:16]2([C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[F:8])[N:17]=[C:18]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:19][CH2:20][C@@H:21]2[CH2:22]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC=C1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (1.5 mL, 16 mmol) was added to a slurry of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P3) (661 mg, 1.59 mmol) and potassium carbonate (1.34 g, 9.70 mmol) in acetonitrile (16 mL). After the flask had been flushed with nitrogen, the reaction mixture was heated at reflux for 2.5 hours, then allowed to cool to room temperature and stir for 18 hours. The slurry was diluted with ethyl acetate and filtered; the solids were washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid, which was assigned as a roughly 4:1 mixture of geometric isomers from the 1H NMR. Yield: 437 mg, 0.953 mmol, 60%. LCMS m/z 459.1 [M+H+]. 1H NMR (400 MHz, CDCl3), major isomer only: δ 8.09-8.32 (br s, 2H), 7.50-7.56 (m, 1H), 7.39-7.45 (m, 3H), 6.85-6.99 (m, 2H), 6.75 (d, J=1.9 Hz, 1H), 4.31 (dd, J=11.7, 1.2 Hz, 1H), 4.02 (d, J=11.8 Hz, 1H), 3.13-3.26 (m, 1H), 2.97-3.07 (m, 1H), 2.70-2.87 (m, 2H), 2.19 (s, 3H), 2.17-2.25 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([O:20][NH2:21])[CH3:19].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:21][O:20][CH2:18][CH3:19])[CH2:10][CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCON=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution was made containing (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (5.0 g, 22 mmol) and O-ethylhydroxylamine hydrochloride (6.4 g, 65.5 mmol) in a 1:1 mixture of pyridine and ethanol (100 ml). The reaction was heated to reflux for 2.5 h before cooling and removal of solvent. The residue was dissolved in ethyl acetate and washed rapidly with 1.3N HCl (40 ml). The acidic layer was then extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine before drying over magnesiom sulfate, filtering and removal of solvent in vacuo. The desired product (5.5 g, 93%) was isolated as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: Oc1ccccc1F
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3F)cn2)CC1
Temperature: 0 °C
Yield: 6.7 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol), 2-fluorophenol (1.1 g, 10.0 mmol), copper (650 mg, 10.0 mmol) and cesium carbonate (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0° C. in a sealed tube overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and then filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 20:1) to give tert-butyl 4-(5-(2-fluorophenoxyl)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 6%) as a yellow solid. MS (ES+) C19H23FN4O3 requires: 374, found: 397 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: ClC(Cl)=C(Cl)c1cc(Br)cc(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Yield: 55.5 %

Procedure:
A solution of crude 3-bromo-5-(trichlorovinyl)benzyl bromide (2.2 g) and sodium azide (760 mg) in 30 ml of ethanol was heated at reflux for 1 hour. The reaction solution was concentrated under reduced pressure and the residue triturated with 100 ml of hexane. The mixture was filtered and the filtrate chromatographed on silica (hexane) to give 1.1 g of pure azide
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(F)cccc23)CC1
Yield: 65.3 %

Procedure:
A stirred solution of 7-fluoroindole (400 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue subjected to chromatography on silica gel with 20% ethyl acetate/hexanes to afford a yellow solid (620 mg, 66%).
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH:37]([Si:40]([CH:58]([CH3:60])[CH3:59])([CH:55]([CH3:57])[CH3:56])[O:41][C:42]1[CH:51]=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[C:49]2[C:52](O)=[O:53])=[CH:44][CH:43]=1)([CH3:39])[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH:1]([Si:4]([O:11][C:12](=[O:36])[N:13]([CH2:19][CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([F:35])[CH:28]=2)[CH:24]=[N:23][CH:22]=1)[C@H:14]1[CH2:18][CH2:17][N:16]([C:52]([C:49]2[C:50]3[C:45](=[CH:44][CH:43]=[C:42]([O:41][Si:40]([CH:55]([CH3:57])[CH3:56])([CH:58]([CH3:60])[CH3:59])[CH:37]([CH3:38])[CH3:39])[CH:51]=3)[CH:46]=[CH:47][CH:48]=2)=[O:53])[CH2:15]1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCNC1)(C(C)C)C(C)C
Reactant: CC(C)[Si](Oc1ccc2cccc(C(=O)O)c2c1)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)c2cccc3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-{2-[1-(4-Cyano-3-fluorobenzyl)-1H-imidazol-5-yl]ethyl}-N-(pyrrolidin-3-yl)carbamic acid triisopropylsilyl ester, as described above in Step H, (242 mg, 0.471 mmol), 7-(triisopropylsilyloxy)-1-naphthlenecarboxylic acid, as described in Example 54, Step C, (162 mg, 0.471 mmol), PYBOP (245 mg, 0.471 mmol), and triethylamine (0.085 mL, 0.612 mmol) were combined in CH2Cl2 (4 mL). The reaction mixture was stirred at ambient temperature for 4 hours, then poured into 10% aqueous citric acid and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[CH2:15]/[C:16](/[C:19]3[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)=[N:17]\[OH:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C(OCC)(=O)C>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:15]/[C:16](=[N:17]\[OH:18])/[C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[C:28]([CH3:34])[CH:29]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NC(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of (E)-5-(3-(4′-aminobiphenyl-4-yl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (0.05 g, 110 μmol, example 259) in N,N-dimethylformamide was added at room temperature succinic anhydride (12.1 mg, 121 μmol) and the resulting solution was stirred at room temperature for 26 hours. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate and the organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown foam (0.043 g, 70%). MS (ESI+): m/z=556.2 ([M+H]+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[CH2:13]1)=O)C.O>C1COCC1>[O:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH2:13]1
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.11 g, 2.78 mmol) in dry THF (1 ml) was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (0.17 g, 0.55 mmol) in dry THF (10 ml). The reaction mixture was refluxed for 2 h. Water was slowly added under cooling and the reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=O)[CH:3]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[N:13][OH:14])[CH:3]=1
Reactant: O=Cc1cc(Br)sc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1sc(Br)cc1C=NO

Procedure:
5-Bromo-2-nitrothiophene-3-carbaldehyde (22.5 g, 95 mmol), hydroxylamine hydrochloride (6.96 g, 100 mmol) and sodium acetate (8.21 g, 100 mmol) were stirred in ethanol (225 mL) at room temperature overnight. The solvent was removed in vacuo, saturated NaHCO3 was added and the mixture extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as an orange solid.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[S:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[S:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:14]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccsc1

Procedure:
2-(thiophen-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and thiophen-3-ylboronic acid (60 mg, 101.8 mg theoretical, 58.9%). LC-MS m/z 190.2 (M+1).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6])=[N+]=[N-].[BH4-].[Na+].C(O)(C)C>CO>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropanol (100 ml) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. LCMS [M+H]+ 172.4. 1H NMR (300 MHz, DMSO) δ 7.24-7.39 (m, 4H), 4.46 (dd, J=4.3, 7.5 Hz, 1H), 2.68 (dd, J=4.3, 12.8 Hz, 1H), 2.57 (dd, J=7.5, 13.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[C:13]([CH2:30][CH2:31][CH3:32])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:19][O:18][CH2:17][CH2:16][CH2:15][N:14]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:45])[C:7]=2[N:12]=[C:13]1[CH2:30][CH2:31][CH3:32]
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCON
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (1.00 g, 2.03 mmol) in chloroform (20 mL) at room temperature and under an atmosphere of nitrogen was added mCPBA (1.00 g, 4.06 mmol). The reaction was stirred for 2 hours, then was cooled to 0° C. Concentrated ammonium hydroxide (1 mL) was added followed by p-toluenesulfonyl chloride (111 mg, 0.58 mmol) in portions. The mixture was stirred for 1.5 hours at 0° C. and then filtered to remove a solid, which was washed with chloroform. The filtrate was washed with brine (2×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% CMA in chloroform) to afford 300 mg of 1-[3-(aminooxy)propyl]-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C1COCC1.[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
To a mixture of methyl 4-allyloxybenzoate (10.0 g), THF (50 mL) and methanol (50 mL) was added 2N aqueous NaOH solution (50 mL), and the mixture was stirred at 50° C. for 40 minutes. The reaction solution was concentrated to about 50 g, washed with hexane, and acidified with conc. hydrochloric acid. The precipitated crystals were collected by filtration, dissolved in ethyl acetate, dried over magnesium sulfate, and the solvent was evaproated under reduced prssure to give crude crystals of 4-allyloxybenzoic acid (4.68 g, 50%). To the crystals were added dichloroethane (50 mL) and DMF (2 drops), and the mixture was heated to 80° C., and thereto was added dropwise thionyl chloride (4.61 g) over a period of 10 minutes. The mixture was stirred for 30 minutes, and the reaction solution was concentrated to give an oily acid chloride (5.3 g). The compound (3.81 g) of Example 6-1 and the above acid chloride (5.07 g) were dissolved in methylene chloride (50 mL), and thereto was added boron trifluoride diethyl ether complex (4.39 g), and the mixture was allowed to stand at room temperature for 5 days. The reaction solution was washed successively with aqueous hydrochloric acid, water, and aqueous sodium hydroxide solution, dried, filtered, and concentrated. The residue was purified by silica gel chromatography to give a mixture of (1-p-toluenesulfonyl-1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone and 4-allyloxybenzoic acid. This mixture was dissolved in 1N aqueous NaOH solution, and extracted three time with ethyl acetate. The combined oil layer was dried and concentrated to give crude crystals of (1-p-toluenesulfonyl-1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone (5.79 g), which was dissolved in methanol (70 mL), and thereto was added 5N aqueous NaOH solution (70 mL), and the mixture was heated for 1.5 hour. The methanol was evaporated under reduced pressure, and extracted with ethyl acetate, dried, and concentrated. The residue was purified by silica gel column chromatography to give (1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone (2.51 g, 43%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.O.NN>CCO.[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: COCOc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Yield: 99 %

Procedure:
The nitro group in 11 (250.8 mg, 0.73 mmol) was reduced in the presence of 10% Pd/C (46.8 mg, 5% mole ratio) and hydrazine monohydrate (365.4 mg, 7.3 mmol) in EtOH (10 mL) at reflux. Once the starting material was fully consumed (about 3.5 h), the reaction mixture was filtered through a Celite pad and concentrated to afford 12 as white amorphous solid (226.5 mg, 99%), which was used directly for the next step without any purification: 1H NMR (400 MHz, CDCl3, δH) 7.07-6.81 (m, 6H), 6.72-6.63 (m, 2H), 5.13 (s, 2H), 3.49 (d, J=1.3 Hz, 3H), 3.46-3.34 (m, 2H), 3.22 (qd, J=7.1, 3.1 Hz, 8H); 13C NMR (100 MHz, CDCl3, δC) 151.53, 146.97, 144.63, 140.64, 119.05, 118.30, 117.51, 116.43, 95.36, 56.10, 51.45, 50.93. MALDI-MS: 314.2 (M+H+), 336.2 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[CH:17]=[CH:18][N:19]=[C:20]2[C:25]=1[N:24]=[CH:23][C:22]([O:26][CH3:27])=[CH:21]2>CN(C=O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=[N:19]2)=[N:24][CH:23]=1
Reactant: Nc1ccc(O)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Alternatively, the title compound may be prepared by the following method: In a nitrogen purged sealed pressure vessel, dissolved 4-aminophenol (0.617 g, 5.65 mmol) in DMF (0.030 L). Cesium carbonate (3.68 g, 11.3 mmol) was added and the mixture was stirred at RT for 5 min. Added 8-chloro-3-methoxy-1,5-naphthyridine (1.00 g, 5.14 mmol), heated to 90° C., stirred for 17 h. The mixture was allowed to cool to RT and was concentrated. The crude material was triturated with methanol, filtered, washed with methanol followed by water, and air dried to yield 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine as brown solid. MS [M+H]=268.1; Calc'd 267.3 for C15H13N3O2.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[Br:12][C:13]1[C:18]([CH2:19]Cl)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:12][C:13]1[C:18]([CH2:19][O:1][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(OCc2cccnc2Br)cn1
Temperature: 50 °C
Yield: 85 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (306 mg, 2 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine (crude above, 2 mmol), and K2CO3 (828 mg, 6 mmol, 3 eq.) in DMF (1.0 mL) was heated at 50° C. for 2 h. The mixture was cooled and added to water (50 mL) dropwise. The precipitate was filtered, washed with water, dried under high vacuo to give 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (350 mg, 85%) as an yellow solid. 1H NMR (400 MHz; CDCl3) δ=10.51 (s, 1H), 8.42 (dd, 1H), 8.09 (s, 1H) 7.91 (d, 1H), 7.40 (dd, 1H), 7.15 (s, 1H), 5.27 (s, 2H), 3.95 (s, 3H). LRMS (M+H+) m/z 323.0.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cc(-n2ccnc2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) in NMP (2 mL) was added with imidazole (5 mmol). The resulting mixture was subjected to microwave irradiation at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The product, 4-amino-2-imidazol-1-yl-N-(1H-indazol-6-yl)-5-nitro-benzamide, obtained as a yellow solid was used without any purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[N:12]2[N:13]=[C:14](Cl)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1>>[N:1]1([C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([NH2:7])=[N:9][N:10]=3)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: C1CCNCC1
Product: Nc1nnc2ccc(N3CCCCC3)nn12

Procedure:
A mixture of piperidine and 3-amino-6-chloro-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-piperidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:29][CH3:30])[C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])[CH2:10]O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:3][CH2:10][C:9]1[CH:8]=[C:7]([O:6][CH3:5])[C:14]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[C:13]([O:29][CH3:30])[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (3.62 g) was added dropwise to a stirred suspension of 3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (9.00 g) in tetrahydrofuran (50 ml)-toluene (150 ml) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole as crystals. Recrystallization from acetone-hexane gave colorless needles (7.00 g, yield 74%). m.p. 118-119° C.