Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1([CH3:22])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.C.[ClH:24]>CO>[ClH:24].[NH2:4][C:5]1([CH3:22])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CO
Product: CC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.75 h

Procedure:
A suspension of 1 g of 10-acetamido-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 50 ml of 2N hydrochloric acid is boiled for 1 hour 45 minutes and the solution obtained is concentrated to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 70° C. The product obtained (1.15 g) is dissolved in 100 ml of methanol and, after addition of decolorizing charcoal, the solution is filtered. 300 ml of acetone are added and, after storing for 1 hour at 5° C., the solid formed is isolated by filtration, washed twice with 10 ml in total of chilled acetone and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.39 g of 10-amino-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one hydrochloride is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 1.97 (s, 3H: --CH3 at 10); 7.48 and 7.55 (2t, J=7.5 Hz, 1H each: --H 7 and --H 8); 7.70 and 8.75 (2 broad s, 1H each: --H of the imidazole); 7.95 and 8.08 (2d, J=7.5 Hz, 1H each: --H 6 and --H 9); 9.39 (mult., 3H: --NH3+Cl- at 10); 12.64 (mult., 1H: --NHCO--)).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([S:33][CH3:34])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([O:12]CC)=[O:11])([CH3:4])[CH3:3].O.[OH-].[Li+].O>O1CCOCC1>[OH:1][C:2]([C:5]1[N:6]=[C:7]([S:33][CH3:34])[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(SC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
500 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-methylthio-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 105(b)] and 131 mg of lithium hydroxide monohydrate were added to a mixture of 5 ml of water and 5 ml of dioxane, and the resulting mixture was stirred at room temperature for 24 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in water. 3.1 ml of 1N aqueous hydrochloric acid were then added, and the crystals which appeared were collected by filtration. These crystals were dissolved in ethyl acetate, and water was added to induce crystallization. The crystals which appeared were collected by filtration and washed with ethyl acetate and water, to give 290 mg of the title compound as crystals, melting at 169°-171° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=2)[N:3]=1.CN(C)C1C=C(C=CC=1)CO.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:17][N:16]([CH3:18])[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:3]=1
Reactant: CN(C)c1cccc(COc2cncc(Cl)n2)c1
Reactant: C1CNCCN1
Agent: CN(C)c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)c1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(3-dimethylaminobenzyl)oxy]pyrazine (3.04 g, 11.5 mmol; obtained according to the procedure of example 50, step 1, starting from 3-dimethylaminobenzyl alcohol), piperazine (3.08 g, 35.7 mmol) and K2CO3 (1.59 g, 11.5 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 2.06 g (57%) which was obtained as a beige colored oil that solidified when refrigerated. Purity 98% (HPLC). MS m/z 313 (M)+. HRMS m/z calcd for C17H23N5O (M)+ 313.1903, found 313.1910.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[F:30])=[C:11]([F:31])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O-:8])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:36](S)[CH3:37].O>C(Cl)Cl>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[F:30])=[C:11]([F:31])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:36][CH3:37])=[O:7]
Reactant: COc1cc(CNc2c(F)ccc(OCC(=O)[O-])c2F)c(F)c(-c2cccc(F)c2)c1
Reactant: CCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(O)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenoxy]acetate (150 mg, 0.32 mmol, 1.0 eq) and AlCl3 (259 mg, 1.94 mmol, 6.0 eq) in CH2Cl2 (5 mL) at 0° C. was added ethanethiol (120 mg, 1.94 mmol, 6.0 eq). The reaction mixture was stirred at 0° C. for 3 h. The resulting mixture was poured into water and extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo and the residue purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:2) to give the title as a yellow oil (120 mg, 82%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.C=CCCCC.C(O)(=[O:27])CCCC=C>>[C:5]([OH:4])(=[O:27])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCOC(C)=O
Reactant: C=CCCCC(=O)O
Solvent: C=CCCCC
Product: CCCCC=CCCCC(=O)O

Procedure:
FIG. 12 shows an alternative synthesis of 5-decenyl acetate, in which 1-hexene is cross-metathesized with 5-hexenoic acid to produce 5-decenoic acid that can be recrystallized, reduced to an alcohol, and acetylated to yield a greater than 90% E-5-decenyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[NH4+].[Cl-].O>CCO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH2:9])[C:3]=1[CH3:12]
Reactant: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1c(Br)ccc(F)c1N
Yield: 76.5 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene (3 g, 12.82 mmol, 1.0 eq) in EtOH (60 mL) was added NH4Cl (30 mL), water (30 mL) and iron powder (2.87 g, 51.28 mmol, 4.0 eq). The reaction mixture was heated at reflux for 3h, then filtered through Celite. The filtrate was evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a yellow solid (2 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23].ClC1C(CC)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:25][NH:24][C:22](=[O:23])[C:21]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:20]=2[F:19])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(F)cc1F
Agent: CCc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2F)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 95.4 %

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (1.0 g, 3.72 mmol) and 2,4-difluorobenzohydrazide (704 mg, 4.09 mmol) were reacted using the techniques described for the preparation of intermediate 11c to furnish the title compound (1.5 g, 96%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.6 (br s, 2H), 7.85-7.97 (m, 1H), 7.46 (d, J=8 Hz, 1H), 7.10-7.19 (m, 2H), 6.73 (d, J=8 Hz, 1H), 5.58 (d, J=7 Hz, 1H), 4.20-4.28 (m, 1H), 4.15-4.18 (m, 1H), 2.32 (s, 3H) and 1.38 (d, J=6 Hz, 3H).
Reaction SMILES: SC[C@H]([C@@H](CS)O)O.P([O-])(O)(O)=O.[K+].[CH2:15]([C:19]1[CH:30]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25]C)=[O:24])[CH2:16][CH2:17][CH3:18]>CO>[CH2:15]([C:19]1[CH:30]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)OC
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Product: CCCCc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1D with the product from example 100E (2.79 g, 10.0 mmol), dithiothreitol (3.08 g, 20.0 mmol), and 0.2 M potassium dihydrogenphosphate (15 ml) in 60 ml of methanol. 400 MHz 1H NMR (CDCl3) δ 7.11 (m, 2H), 6.60 (d, 1H), 4.61 (s, 2H), 3.81 (s, 3H), 3.36 (s, 1H), 2.63 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.98 (t, 3H). Step 7. Preparation of methyl 2-[2-butyl-4-({4-[4-(trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]acetate (Compound 100G)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH3:23])=[O:21])(=O)=O.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:26][C:27]([F:38])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:31][CH:30]=1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OC(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of 1-(1,1-dimethylethyl) 3-methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (2.5 g, P2), {4-[(trifluoromethyl)oxy]phenyl}boronic acid (1.52 g) and Pd(PPh3)4 (265 mg) under nitrogen, toluene (34 mL), ethanol (25 mL) and Na2CO3 (2M, 19 mL) were added in sequence. The mixture was stirred at 80° C. for 2 hours then the reaction mixture was allowed to reach room temperature. The aqueous phase was extracted with Et2O (2 times), the combined organic phases were dried on anhydrous Na2SO4 and the solvent was evaporated obtaining a crude product that was purified by flash-chromatography (eluting with ethyl acetate/cyclohexane from 1:9 to 3:7) to give the title compound (2.5 g)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:10][N:11](C)C=O.NOS(O)(=O)=O>CO>[O:3]1[C:1]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:2][CH:10]=[N:11]1
Reactant: CC(=O)c1cccnc1
Reactant: CN(C)C=O
Agent: NOS(=O)(=O)O
Solvent: CO
Product: c1cncc(-c2ccno2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of 12.1 g (0.1 mol) 3-acetyl pyridine and 15 g (0.11 mol) dimethyl formamide dimethylacetale was heated at 90° C. for 2 h. Upon concentration in vacuo the product was titrated with ethylether and filtrated. The compound was dissolved in 50 ml methanol and 11.5 g (0.1 mol) hydroxylamine-O-sulfonic acid dissolved in 50 ml MeOH was added. The reaction mixture was stirred at room temperature for 2 h, concentrated in vacuo and poured on water (150 ml). The solution was made alkaline with solid potassium carbonate and extracted with 4×40 ml methylenchloride. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography giving 1.5 g 3-(5-isoxazolyl)-pyridine, which was dissolved in 20 ml acetone. 3 ml methyliodide was added to the solution, and the reaction mixture was stirred at room temperature for 24 h. The precipitated compound was filtered and dissolved in 30 ml methanol. To this solution sodiumborohydride (600 mg) was added in small portions. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The water solution was extracted with 3×30 ml methylenchloride. The organic phase was dried over magnesiumsulfate and concentrated in vacuo. Crystallization as the oxalate salt from acetone gave the title compound in a 1.1 g yield. M.p. 164°-165° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8].N>CO>[NH2:10][C:9]1[N:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: CN(C)C=CC=C(C#N)C#N
Agent: N
Solvent: CO
Product: N#Cc1cccnc1N
Temperature: 150 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
17.3 parts of 4-dimethylamino-1,1-dicyano-1,3-butadiene and 90 parts of methanol are combined in a stirred autoclave. 16 parts of liquid ammonia are added and the mixture is stirred at 150° C. for 3 hours. The mixture is evaporated down under reduced pressure and, after the addition of ethanol, the precipitate is filtered off with suction and dried. 12.7 parts (91% of theory) of 2-aminonicotine nitrile, of melting point 130° to 132° C. (from ethanol), are obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:18](=[O:19])[C:13]=2[C:12]([CH:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)O)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCN1C2C=NNC(=O)C=2C(C(O)(C)C)=C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:28][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C(O)c3ccc(F)cc3)cn2COCc2ccccc2)c1=O
Agent: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Product: O=c1[nH]ncc2c1c(Cc1ccc(F)cc1)cn2COCc1ccccc1
Yield: 88.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 21-(e) except for using 2.73 g (5.36 mmol) of 1-benzyloxymethyl-3-[(4-fluorophenyl)hydroxymethyl]-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 38-(a) in place of 1-benzyloxymethyl-3-(1-hydroxy-1-methylethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 1.73 g of the title compound was obtained as a pale yellowish solid. (Yield: 89%)
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:34]=1)(=O)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:34]=1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.7 %

Procedure:
A mixture of N-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (2.20 g, 4.86 mmol), 4N hydrochloric acid-ethyl acetate solution (35 mL) and methanol (35 mL) was stirred at room temperature for 14 hr. The reaction mixture was neutralized by the addition of 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (1.63 g, 82%) as a yellow powder.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:8]([O:10]CCCCCCCC)=[O:9].[OH-].[K+]>C(O)C.O>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)[C:8]([OH:10])=[O:9]
Reactant: CCCCCCCCOC(=O)C(=C1SCCCS1)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=C1SCCCS1)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of n-octyl (1,3-dithian-2-ylidene)-(3-trifluoromethylphenyl)-acetate (15 g) in ethanol (375 ml), a 30% solution of potassium hydroxide in water (375 ml) is added. The mixture is refluxed for 2 hours. The solvents are removed in vacuo. Water (500 ml) and ether (500 ml) are added. The water solution is acidified to pH 4 with 5N sulphuric acid. The phases are separated and the water solution is extracted with ether (3×350 ml). The combined organic solutions are dried over magnesium sulphate and the solvent is evaporated in vacuo. The residue is triturated in petrol ether (b.p. 40°-65° ) and dried in vacuo to constant weight to give (1,3-dithian-2-ylidene)-(3-trifluoromethylphenyl)-acetic acid, m.p. 165°-166° C.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:13][C:3]1[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[N:7]2[CH3:11]
Reactant: OB(O)c1cccnc1
Reactant: COc1c(Br)ccc2c1CC(=O)N2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c(-c2cccnc2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one (105 mg, 0.410 mmol) was added 3-pyridineboronic acid (CAS#1692-25-7, 60.5 mg, 0.492 mmol), 1,2-dimethoxyethane (3 mL) and 2 M aqueous sodium carbonate (0.513 ml, 1.025 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (186 mg, 0.021 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.25 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 20 to 100%) to afford 4-methoxy-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 255.1136 (M+H)4; 1H NMR (400 MHz, CO2Cl2) δ ppm 3.20 (s, 3H), 3.66 (s, 2H), 3.72 (s, 3H), 6.68 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.38 (dd, J=7.9, 4.9 Hz, 1H), 7.79-7.96 (m, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.71 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].[N-:21]=[N+:22]=[N-].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N+:21]=[N-:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of (2-amino-benzyl)-carbamic acid tert-butyl ester [prepared from 2-aminobenzylamine and di-tert-butyl dicarbonate], (100 mg, 0.45 mmol) in acetic acid (2.46 mL), was added water (26 mL). Reaction mixture was cooled to 0° C. and a solution of sodium nitrite (62 mg, 0.9 mmol) in water (4.3 ml) was added. The reaction mixture was stirred for 30 min at the same temperature followed by addition of sodium azide (64 mg, 0.99 mmol). The reaction mixture was stirred at 0° C. for 30 min. When the reaction was complete as confirmed by TLC, reaction mixture was quenched by dropwise addition of 10 N NaOH (5.0 mL). The crude compound was extracted with ethylacetate (2×10 mL). Organic layer was separated, washed with brine, dried over Na2SO4 and the solvents were removed in vacuo to afford (2-azido-benzyl)-carbamic acid tert-butyl ester (105 mg, 96%) which was used as such without any further purification for the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([CH3:11])=[CH:9][C:10]=1[Cl:19])[CH3:18]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1ccc(C)cc1[Si](C)(C)C
Product: CCN(CC)C(=O)c1c(Cl)cc(C)cc1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 58 and 1.2 eq hexachloroethane according to General Method A. Purification by HPLC with 1:9 ethyl acetate/hexanes afforded 1.6 g of the title compound as a clear oil, a 54% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]2[N:19]=[C:20]([CH3:42])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:22]=2)=[O:11])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]2[N:19]=[C:20]([CH3:42])[NH:21][CH:22]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccsc2-c2c[nH]c(C)n2)cc1

Procedure:
2-(4-methoxyphenyl)-N-(2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide (540 mg, 948 mmol) in TFA (10 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield 2-(4-methoxyphenyl)-N-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide. Method [8] Retention time 3.52 min by HPLC (MH+ 328). 1H NMR (300 MHz, DMSO) δ 10.02 (s, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.9 Hz, 2H), 3.73 (s, 3H).
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[O:19][CH3:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1OC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(OC)c(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-azido-3-(2,3-dimethoxyphenyl)propeneoate (4.0 g, 144 mmol) was suspended in toluene (120 ml) and the mixture was refluxed for three hours and then cooled and stirred at room temperature overnight. The solids were collected by filtration in order to give the product in the form of a yellow solid.