Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[N:42]1([C@H:47]2[CH2:51][CH2:50][NH:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:49]2[CH2:50][CH2:51][C@H:47]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:48]2)=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: C1CCN([C@H]2CCNC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cc2nc3ccccc3[nH]2)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate (400 mg, 1.5 mmol) in methanol was treated with aqueous sodium hydroxide (2.5 M, 3.75 mmol), heated at reflux temperature for 3 h and concentrated in vacuo. The resultant residue was dispersed in water and acidified with excess formic acid. The resultant precipitate was removed by filtration, washed with water and dried under vacuum overnight to provide 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (92%) as a white solid, [M+H] 253.2. A solution of 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (200 mg, 0.79 mmol) in DMF was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (183 mg, 0.952 mmol) and 1-hydroxybenzotriazole (134 mg, 0.873 mmol), stirred at room temperature for 3 h, treated with a solution of (3′S)-1,3′-bipyrrolidine (166.6 mg, 1.19 mmol) in DMF, stirred at room temperature for 6 h and concenrated in vacuo. This residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purification of the concentrate by flash column chromatography (silica, dichloromethane:methanol 20:1 to 10:1) afforded the title compound (73%), identified by mass spectral analysis. [M+H] 253.2.
Reaction SMILES: [CH:1](/[P:4](=[O:15])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:2]/[CH3:3].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:1](/[P:4](=[O:15])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:2]\[CH3:3]
Reactant: C/C=C\P(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C
Reaction time: 6 h
Yield: 80 %

Procedure:
(1)-1 Di-tert.-butyl cis-1-propenylphosphonate (15.0 g.) was added to a solution of potassium tert.-butoxide in tert.-butyl alcohol (K: 250 mg., tert.-C4H9OH: 150 ml.) and then the mixture was stirred for 6 hours at 55°-60° C. The resultant mixture was concentrated under reduced pressure and the residue was shaken with a mixture of ethyl acetate (400 ml.) and ice-water (100 ml.). The ethyl acetate layer was separated, washed with water (50 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily residue (13.34 g.), which was distilled under reduced pressure to give oily di-tert.-butyl trans-1-propenylphosphonate (12 g.), b.p. 78°-80° C./2 mmHg.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[CH3:44][N:45]1[CH:49]=[N:48][N:47]=[C:46]1[SH:50].C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:50][C:46]5[N:45]([CH3:44])[CH:49]=[N:48][N:47]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: Cn1cnnc1S
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnnc1SCC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reaction time: 12 h

Procedure:
To a solution of 230.0 mg (0.34 mmol) (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate in 5 ml N,N-dimethylformamide was added 40.0 mg (0.37 mmol) 4-methyl-4H-[1,2,4]triazole-3-thiol. After 1 h 47.0 μl (0.34 mmol) triethyl amine was added and stirring was continued for 12 h. The solution was poured on diethyl ether and the resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[N:12]([CH2:21][CH2:22][NH:23][CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[N:12]([CH2:21][CH2:22][N:23]([C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH3:24])[C:13]3[C:18]([C:19]=2[OH:20])=[N:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1
Reactant: CNCCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)N(C)CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21

Procedure:
The compound was prepared in a manner similar to that described for Example 22, using N-[4-fluoro-2-(methylsulfonyl)benzyl]-4-hydroxy-1-[2-(methylamino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and N,N-dimethylcarbamoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH2:13][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:9][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=2)=[N:7]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 55 %

Procedure:
Following the procedure of Example 1(10), 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as slightly-yellow neeldes (yield: 55.0%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[CH3:19][CH:20]([CH3:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24]C(O)=O.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:19][CH:20]([CH3:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: CC(C)CC(=O)CCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Add benzyl chloroformate (0.712 g, 4.17 mmol), triethylamine (0.464 g, 4.59 mmol), and 4-dimethylaminopyridine (0.051 g, 0.42 mmol) to a solution of 6-methyl-4-oxo-heptanoic acid (0.66 g, 4.17 mmol) in dichloromethane (13 mL) at 0° C. Stir at 0° C. for 1 hour. Add saturated aqueous ammonium chloride (30 mL). Extract with dichloromethane (1×50 mL). Dry organic phase over magnesium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with 0-50% ethyl acetate in hexane to provide 0.87 g (84.1%) of the desired compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][CH:15](O)[O:16][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:25][CH:15]1[CH2:14][CH2:13][C:12]2[CH:18]=[CH:19][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][C:11]=2[O:16]1)[CH3:24]
Reactant: OC1CCc2ccc(OCc3ccccc3)cc2O1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)CC1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 92.8 %

Procedure:
A 2.2 g sample of racemic-3,4-dihydro-7-(phenylmethoxy)-2h-1-benzopyran-2-ol was condensed with (carbethoxymethylene)triphenylphosphorane (3.2 g) using the procedure of Example 30. There was obtained 2.6 g (92.8%) of racemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid ethyl ester as a yellow oil, after column chromatographic purification. This material was hydrogenolyzed over 0.2 g of 10% palladium on carbon as described in Example 30. There was obtained 1.9 g of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)N>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCO)c34)cc2C)cn1
Yield: 81.9 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (1.50 g, 6.72 mmol) and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (1.44 g, 6.72 mmol) to give the title compound as a white solid (2.16 g, 82%); NMR Spectrum: 2.20 (s, 3H), 2.44 (s, 3H), 3.81 (br t, 2H), 4.32 (t, 2H), 5.14 (br s, 1H), 6.96 (d, 1H), 7.19 (dd, 1H), 7.24 (d, 1H), 7.58 (dd, 1H), 7.62 (s, 1H), 8.17 (d, 1H) 8.28 (s, 1H), 8.44 (br s, 1H); Mass Spectrum: 393 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:4]2[CH:3]=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=[N:6][CH:5]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1ccc(C(=O)Nc2cncc(Br)c2)cc1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2cncc(B(O)O)c2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.4 %

Procedure:
N-(5-Bromopyridin-3-yl)-4-methoxybenzamide (2.18 g, 7.06 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.6 g, 22 mmol), potassium acetate (2.7 g, 27.55 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (680 mg, 0.83 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (460 mg, 0.83 mmol) were suspended in dioxane (50 ml) and stirred at 90° C. overnight. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 2.12 g (100% yield) of the title compound. Purity (UPLC 92%, estimated 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cscn1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cscn1

Procedure:
90 mg (about 0.298 mmol) of 2-amino-6-sulfanyl-4-(1,3-thiazol-4-yl)pyridine-3,5-dicarbonitrile, together with 93 mg (0.382 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 88 mg (1.041 mmol) of sodium bicarbonate, were stirred in 20 ml of DMF at room temperature for 2 h. The reaction mixture was purified twice by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 36 mg (22% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:9]2[O:10][CH2:13][CH2:14][CH2:15][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cc(Cl)c2c(c1)OCCCO2
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-4,5-dihydroxy benzaldehyde (4.15 g), of 1,3-dibromopropane (4.71 g, 0.92 eq.) and potassium carbonate (8.28 g, 2.5 eq.) in acetonitrile (160 ml) was heated to 60° C. overnight. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica (20% ethyl acetate in hexanes) to give the product as a white crystal. MS (m+1)=212.1
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH3:28])=[C:23]([CH3:30])[CH:22]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24](/[C:27](=[N:3]/[NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])/[CH3:28])=[C:23]([CH3:30])[CH:22]=1
Reactant: CCOC(=O)NN
Reactant: CC(=O)c1ccc(Cl)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N/N=C(\C)c1ccc(Cl)cc1C

Procedure:
Ethyl carbazate (2.970 g, 28.53 mmol) and p-toluenesulfonic acid monohydrate (4.456 g, 28.53 mmol) were added to a stirred solution of 1-(4-chloro-2-methylphenyl)ethanone (4.81 g, 28.53 mmol) in toluene (50 mL). The mixture was heated to relux in a Dean-Stark apparatus. After 2 h the solution was evaporated and the viscous red-orange oil was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 5–40% EtOAc). Ethyl (2E)-2-[1-(4-chloro-2-methylphenyl)ethylidene]hydrazine carboxylate was obtained as white crystals. MS m/z=255.6; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, J=6.8 Hz, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 4.31 (q, J=6.8 Hz, 2H), 7.19 (m, 3H), 7.72 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO.O>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 72 %

Procedure:
To 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid methyl ester (0.853 g, 3.69 mmol) in methanol (12 mL) was added 2N NaOH (8 mL) the reaction solution was stirred at ambient temperature for 60 hr. The solution was dilute with water and extracted twice with ethyl acetate. The combined extract was washed with brine and dried over MgSO4 and concentrated. Recrystallization (hexanes/ethyl acetate) afforded a white solid (0.540 g, 72% yield).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[OH:15])[CH:10]=[O:11].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](=[O:35])[NH:31][N:30]=1>N1C=CC=CC=1>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[O:15][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[C:22]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](=[O:35])[NH:31][N:30]=2)[CH:23]=1)[CH:10]=[O:11]
Reactant: COc1ccc(O)cc1Cc1ccc(=O)[nH]n1
Reactant: O=Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Oc2c(Br)cc(C=O)cc2[N+](=O)[O-])cc1Cc1ccc(=O)[nH]n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Methane sulphonyl chloride (3.6 g) was added to a solution of 3-bromo-4-hydroxy-5-nitrobenzaldehyde (7.7 g) in dry pyridine (100 ml), and the mixture heated at reflux for 10 min. A solution of 4-methoxy-3-(6-oxo-3(1H)-pyridazinylmethyl)phenol (prepared as in Example 44(a)) (6.6 g) in dry pyridine (50 ml) was then added and the resultant dark mixture heated at reflux for 1.5 hours, then allowed to cool to room temperature. The solvent was then evaporated and the residue dissolved in dichloromethane (150 ml), washed with aqueous 2N hydrochloride acid (100 ml), water (100 ml), aqueous saturated sodium bicarbonate solution (2×100 ml) and water (4×100 ml), then dried and evaporated to dryness. The orange residue was dissolved in IMS, treated with charcoal and filtered. On addition of water (200 ml) and cooling a precipitate was formed which was filtered off and dried. This solid was recrystallised from ethyl acetate/petroleum spirit to give 3-bromo-5 -nitro-4-(4-methoxy-3-(6-oxo-3(1H)-pyridazinylmethyl)phenoxy)benzaldehyde (5.2 g, 40%) as a yellow solid, m.p. 188°-190°.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[N:22]1.C(Cl)CCl>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH:23]=[N:22][NH:21]4)=[CH:25][CH:26]=3)=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3cn[nH]c3c2)cc1
Reaction time: 12 h
Yield: 26 %

Procedure:
To a stirring solution of N2-(4-t-butylbenzoyl)-1,2-benzenediamine (830 mg, 3.1 mmol) and 6-indazolecarboxylic acid (European Pat. Appln. Pub. No. 242 167 A2, p 43) (500 mg, 3.1 mmol) in DMF (5 mL) was added EDC (1.19 g, 6.2 mmol). After 12 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with water and twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo, then chromatographed over silica gel, eluting with a solvent gradient of dichloromethane through 5% methanol/dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 330 mg (26%) of an off-white solid.
Reaction SMILES: C(Cl)Cl.[CH:4](OC=C)=[CH2:5].[F:9][C:10]([N+:16]([O-:18])=[O:17])([N+:13]([O-:15])=[O:14])[CH2:11][OH:12].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl.O>[CH:4]([O:12][CH2:11][C:10]([F:9])([N+:16]([O-:18])=[O:17])[N+:13]([O-:15])=[O:14])=[CH2:5]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: C=COC=C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: C=COCC(F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 73.1 %

Procedure:
A 50 ml single necked, round bottom flask was charged with 20 ml of methylene chloride, 0.5 g (7.14 mmoles) divinyl ether (I), 1.1 g (7.14 mmoles) 2-fluoro-2,2-dinitroethanol, and 0.1 g red mercuric oxide. The solution was stirred with a Teflon coated magnetic bar while 100 μl trifluoroacetic acid was used. The reaction flask was then fitted with a water cooled reflux condenser and drying tube filled with Drierite desiccant. The reaction mixture was then stirred under reflux (~37° C.) for 22.5 hours. At the end of this period, the methylene chloride solvent was removed in vacuo, leaving a slightly yellow, clear oil. The oil was taken up in carbon tetrachloride and eluted with 35 ml carbon tetrachloride through 2.5 g neutral alumina (pH 7.3) packed in a 15 ml "course" glass sintered funnel. The carbon tetrachloride was removed in vacuo, leaving 0.94 g of colorless crude 2-fluoro-2,2-dinitroethyl vinyl ether (VII) which was shown by nuclear magnetic resonance spectrometry to be 84 percent pure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2
Solvent: c1ccncc1
Product: CC(=O)OCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 2-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (261 mg) in anhydrous pyridine (7 ml), acetic anhydride (233 mg) was added. The mixture was stirred at room temperature for 1 hour, and further stirred at 50° C. for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in chloroform, and washed with water. After drying, the solvent was distilled off to obtain 305 mg of a crude product. The crude product was purified by silica gel column chromatography (eluent=chloroform:methanol=70:1) to obtain 247 mg of a target product (80.0%). The product was recrystallized from chloroform-n-hexane, and as a result, colorless powdery crystals were obtained (mp. 197°-200° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.Br[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([NH:27][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:10]=2)=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cnccc1Br
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4C(F)(F)F)n3)c3ccccc32)cc1

Procedure:
1 g of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 2.77 mmol, 1. eq.), 938 mg of 4-bromo-3-(trifluoromethyl)pyridine (4.15 mmol, 1.5 eq.), 127 mg of Tris(dibenzylideneacetone)dipalladium (0) (0.138 mmol, 0.05 eq.), 345 mg of 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.553 mmol, 0.2 eq), 1.06 g of sodium 2-methylpropan-2-olate (97%) (11.1 mmol, 4 eq.) and 15 ml of N,N-dimethylformamide were stirred under nitrogen atmosphere for 24 hours at 100° C. bath temperature in a pressure pipe. The reaction mixture was washed with half-saturated aqueous ammonium chloride solution. The organic layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated in vacuo. The residue was purified twice by flash chromatography (hexane/ethyl acetate/methanol) and preparative TLC. A crystallisation gave 56.9 mg (0.1 mmol, 3.73%) of the analytically pure target compound.