Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[CH2:4]([C@@H:6]1[O:8][CH2:7]1)[Cl:5].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC)(C)(C)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:5][CH2:4][C@H:6]([OH:8])[CH2:7][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClC[C@H]1CO1
Reactant: Oc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O[C@@H](CCl)COc1ccccc1
Reaction time: 1 h
Yield: 109.6 %

Procedure:
To a mixture of N′,N′-disalicylidene ethylenediaminatocobalt(II) (173 mg, 0.532 mmol) and dichloromethane (13 ml) was added (±) camphorsulfonic acid (148 mg, 0.638 mmol) and the reaction system was stirred for 1 hour while being filled with air. The reaction solution was evaporated to dryness under reduced pressure to give a crude blackish (dark) brown cobalt (III) complex. Thereto was added tert-butylmethyl ether (5 ml) to disperse the crude cobalt (III) complex and then thereto were added (R)-epichlorohydrin (2.50 ml, 31.9 mmol, optical purity 99% e.e.) and phenol (2.50 g, 26.6 mmol) in order. The mixture was stirred for 24 hours under nitrogen atmosphere at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (20 ml), the solution was washed with a 6% aqueous sodium hydroxide solution (10 ml) and a saturated sodium chloride solution (10 ml) in order, and the organic layer was condensed under reduced pressure to give crude (R)-1-chloro-3-phenoxy-2-propanol (5.44 g). This crude compound (5.44 g) was dissolved in isopropanol (10 ml) and thereto was added a 24% aqueous sodium hydroxide solution (6.64 g, 39.8 mmol) under ice-cooling. The mixture was stirred for 1 hour at room temperature. After the reaction, the reaction mixture was diluted with tert-butylmethyl ether (50 ml) and the solution was washed with water (2.0 ml), a saturated aqueous ammonium solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml) in order. The organic layer was condensed under reduced pressure to give crude (S)-glycidylphenyl ether (3.80 g). Quantitative analysis by gas chromatography and optical purity measurement by HLPC were conducted on the compound. As a result the subject compound, (S)-glycidylphenyl ether (3.71 g, 93.0%) was produced with optical purity at 99% e.e.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH:29]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccccc1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCCC2)cc1
Product: O=C1NC(=O)c2ccc(Nc3ccccc3)cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1

Procedure:
Using the procedure described for the preparation of example 118, the title compound is obtained as yellow solid (70% yield) from 6-bromo-4-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione and aniline.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccccc1-c1cccc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: COc1ccccc1-c1cccc2c1OC(CN)C2
Yield: 12 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-methoxyphenylboronic acid (2.57 g, 16.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.677 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.76 g, 11.69 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.072 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.453 g (12%) of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.72; H, 6.15; N, 4.86.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-])=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.C(N(C(C)C)C([S:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:35]=1[NH2:36])=S)(C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:13]=[C:8]([CH:7]=[C:6]([C:14]2[S:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:35]=3[N:36]=2)[CH:5]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2]
Reactant: CC(C)N(C(=S)Sc1cnccc1N)C(C)C
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2nc3ccncc3s2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
Mono-methyl 5-nitro-isophthlate (1.25 g, 5.58 mmol) was suspended in 25 mL of CH2Cl2 and oxalyl chloride (0.49 mL, 5.58 mmol) was added. After 3 drops of DMF was added, the reaction mixture was stirred at room temperature until all gas evolution had ceased and all the solids had dissolved. This freshly prepared solution of the acid chloride was then added dropwise to a solution of 4-aminopyridin-3-yl diisopropylcarbamodithioate (1.5 g, 5.58 mmol) and triethylamine (0.77 mL, 5.58 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 1 hour. It was then quenched with 25 mL of brine and the two layers were separated. The organic layer was dried (Na2SO4) and concentrated. The resulting residue was suspended in 25 mL of 2 N HCl and stirred under reflux for 30 min. It was then cooled to room temperature and the solids were collected by filtration and dried to afford 1.0 g of methyl 3-nitro-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate. This material was then mixed with 20 mL of methanol and 3 mL of water along with 1 g of sodium hydrosulfide hydrate and stirred under reflux for 2 hours. The resulting reaction mixture was cooled and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 150 mg of methyl 3-amino-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate (MS, M++H=286).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][N:13]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:12]1=O.[BH4-].[Na+].[BH3-]C#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=2)[C:15](=[O:29])[CH2:14][N:13]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12]1
Reactant: COc1cccc(OC)c1C1C(=O)N(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(OC)c1C1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of tert-butyl 3-(2,6-dimethoxyphenyl)-2,5-dioxo-4-(4-(trifluoromethoxy)benzyl)piperazine-1-carboxylate (718 mg; 1.36 mmol) in anh. MeOH (15 ml) was treated with NaBH4 (221 mg; 5.47 mmol), and stirring at 0° C., under nitrogen, was continued for 30 min. After concentration to dryness under reduced pressure, the residue was dissolved in AcOEt, and washed successively with 1 M aq. HCl and brine. The separated aq. layer was further extracted with AcOEt (3×10 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Acetic acid (20 ml) was added, and the cooled (0° C.) mixture was then treated portionwise with NaBH3CN (516 mg; 8.21 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. DCM and aq. sat. Na2CO3 were then added, and the separated aq. layer was further extracted with DCM. The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded tert-butyl 3-(2,6-dimethoxyphenyl)-5-oxo-4-(4-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as an orange oil. LC-MS (conditions D): tR=1.12 min.; [M+H]+: 511.01 g/mol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[CH:8][N:7]=1)=O)C.[BH4-].[Na+].CC(C)=O>C(O)(C)(C)C>[OH:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]([CH2:4][OH:3])[CH:11]=1
Reactant: CCOC(=O)c1cc(O)ncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: OCc1cc(O)ncn1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a suspension of 1.7 g (10.1 mMol) 6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester in 30 ml of tert-butanol, 1.2 g (31 mMol) of NaBH4 are added. The mixture is stirred at 60° C. for 20 h and cooled to rt. Then 45 ml of acetone are added. After stirring for 15 min, the mixture is concentrated in vacuo. The residue is diluted with toluene and again concentrated, yielding (6-hydroxy-pyrimidin-4-yl)-methanol (MS: [M−1]=125).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)[CH3:2].Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([S:16][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:13][C:12]=12)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (4.00 g, 12.4 mmol) in N,N-dimethylformamide (30 mL) were serially added bromodiphenylmethane (3.38 g, 13.7 mmol) and potassium carbonate (1.90 g, 13.7 mmol) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer pas washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl[(2-diphenylmethylthio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (2.70 g). This compound (1.40 g, 2.87 mmol) was dissolved in dichloromethane (30 mL) followed by addition of m-chloroperbenzoic acid (55%, 2.00 g, 6.32 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. This reaction mixture was washed with saturated sodium hydrogen carbonate solution and water, dried over MgSO4, filtered, and concentrated under reduced pressure to provide ethyl[(2-diphenylmethylsulfonyl-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.10 g). To a solution of this compound (1.10 g, 2.12 mmol) in tetrahydrofuran (10 mL)-methanol (5 mL) was added 1N-aqueous sodium hydroxide (3.0 mL) dropwise and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture was added 1N-hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 550 mg of the title compound. Yield 39%.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH:17]=[C:16]2[C:11]([N:12]=[C:13]3[S:21][CH2:20][CH2:19][N:14]3[C:15]2=[O:18])=[N:10]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][N:9]1[CH:17]=[C:16]2[C:11]([N:12]=[C:13]3[S:21][CH2:20][CH2:19][N:14]3[C:15]2=[O:18])=[N:10]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cn1cc2c(=O)n3c(nc2n1)SCC3
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc2c(=O)n3c(nc2n1)SCC3
Yield: 69.5 %

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 0.95 g (3.08 mmol) of Compound 35 prepared in Example 26, followed by heating under reflux for one hour. After evaporation of the solvent, water was added to the residue. The precipitated crystals were collected by filtration, followed by washing with water to give 0.54 g (70%) of Compound 37. The compound was recrystallized from dimethylformamide/water for purification.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[F:11][C:12]([F:37])([F:36])[C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:35])[C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([NH2:30])=[N:23][C:22]=2[O:31][CH2:32][CH2:33][OH:34])[CH2:15][CH2:14]1>CC#N.[Cu]I>[F:37][C:12]([F:36])([F:11])[C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:35])[C:21]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([NH2:30])=[N:23][C:22]=2[O:31][CH2:32][CH2:33][O:34][CH:2]([F:10])[F:1])[CH2:17][CH2:18]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Nc1nc(OCCO)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Cu]I
Solvent: CC#N
Product: Nc1nc(OCCOC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
2,2-Difluoro-2-fluorosulfonylacetic acid (205 μl, 1.98 mmol) in MeCN (20 ml) is added via a syringe pump to a mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-(2-hydroxy-ethoxy)-6-amino-5-nitro-nicotinamide (390 mg, 0.994 mmol) and CuI (94 mg, 0.49 mmol) in MeCN (40 ml) over 2.5 h at 55° C. It is stirred for additional 20 min, then the mixture is concentrated and purified via extensive chromatography.
Reaction SMILES: [Cl-].[Cl:2]C1N(C)CC[NH+]1C.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([Cl:2])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CN1CC[NH+](C)C1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Cl)cc1
Yield: 93.2 %

Procedure:
To 9.72 g (0.0575 mole) of 2-chloro-1,3-dimethylimidazolinium chloride, 83 g of toluene was added and successively 8.61 g (0.05 mole) of p-toluenesulfonic acid was added. The mixture was reacted at 110° C. for 4 hours. The reaction mass was analyzed by gas chromatography. p-Toluenesulfonyl chloride was obtained in the yield of 93.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](Br)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].O>O1CCOCC1.[Cu]I>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])[CH:13]=1
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccccc1NCc1ccnc(N2CCCC2=O)c1
Yield: 77.4 %

Procedure:
870 mg (2.78 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester, 53 mg (0.28 mmol) of copper (I) iodide, 1.126 g (5.5 mmol) of potassium phosphate and 0.26 ml (3.6 mmol) of pyrrolidin-2-one are refluxed in 15 ml of dioxane for 8 hours. After water is added, the dioxane is distilled off in a vacuum, made alkaline with about 12% ammonia solution and shaken out several times with ethyl acetate. The collected ethyl acetate phase is washed, dried, filtered and concentrated by evaporation. As a residue, 700 mg (77% of theory) of 2-{[2-(2-oxo-pyrrolidin-1-yl)-pyridin-4-ylmethyl]-amino}-benzoic acid methyl ester is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:17])=O.Cl>C1(C)C(C)=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1cccc(C(=O)Cl)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
In a flask, 60.0 g of 3-acetoxy-2-methylbenzoic acid are suspended under nitrogen in 140.0 g of xylene. The suspension is heated to 70° C. and 42.9 g of thionyl chloride are added dropwise. The mixture is heated further. At approx. 75° C., vigorous gas evolution (SO2, HCl) commences. The liquid phase temperature rises continuously and reaches 108° C. after approx. 4 h. The solution is cooled to approx. 50° C. under nitrogen and the reflux condenser is replaced by Vigreux column. At atmospheric pressure and later under reduced pressure, first xylene and thionyl chloride residues and then the product are distilled over. The product distills over at 15 mbar and 147.0-148.0° C. 59.6 g of 3-acetoxy-2-methylbenzoyl chloride (97.3%) are obtained. This corresponds to 91.0% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.N1CCCC1>CO>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15](/[C:16](=[CH:4]/[C:3]3[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=3[Cl:1])/[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1Cl
Yield: 107.8 %

Procedure:
In a manner similar to the method described in Example 227b, 2,5-dichloro-benzaldehyde (5 g, 28.57 mmol) was reacted with 6-chlorooxindole (4.77 g, 28.57 mmol) and pyrrolidine (2.43 g, 34.3 mmol) in methanol to give title compound as yellow solid (10 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=C([O:62][C:63]([F:66])([F:65])[F:64])C=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:62][C:63]([F:66])([F:65])[F:64])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cccc(OC(F)(F)F)c1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 37 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3-(trifluoromethoxy)benzene in 37% yield.
Reaction SMILES: [C:1]([C:3]1([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH2:6][O:5][CH2:4]1)#[N:2].C([NH:17][C@H](C(O)=O)CS)(=O)C.N>CO>[CH3:11][C:10]([CH3:13])([S:8]([NH:7][C:3]1([C:1](=[NH:17])[NH2:2])[CH2:4][O:5][CH2:6]1)=[O:9])[CH3:12]
Reactant: CC(C)(C)S(=O)NC1(C#N)COC1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: N
Solvent: CO
Product: CC(C)(C)S(=O)NC1(C(=N)N)COC1

Procedure:
To a mixture of N-(3-cyanooxetan-3-yl)-2-methylpropane-2-sulfinamide (0.1 g, 0.494 mmol) in methanol (2 ml) in a 50 ml sealed tube was added N-acetyl-L-(+)-cysteine (0.081 g, 0.494 mmol), and the reaction mixture stirred for few minutes. A solution of ammonia in methanol (0.5 ml, 3.50 mmol, 7 N) was added, and the reaction mixture stirred at 60° C. for overnight. The reaction mixture was then concentrated under vacuum, and the crude was used for the next step without further purification.
Reaction SMILES: O[C:2]1[C:3]([CH3:27])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[C:3]([CH3:27])=[C:4]3[C:9]([NH:10][C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:15][CH:16]=4)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]3[CH:26]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cn3ncc(C#N)c(Nc4ccc(Oc5ccccc5)cc4)c3c2C)cc1
Temperature: 90 °C
Yield: 91.4 %

Procedure:
A mixture of Example 397 (24 mg, 0.049 mmol), 4-methoxybenzeneboronic acid (11 mg, 0.072 mmol), Pd(OAc)2 (1.0 mg, 0.0045 mmol), 2-(dicyclohexylphosphino) biphenyl (5.0 mg, 0.014 mmol) and K3PO4 (20 mg, 0.10 mmol) in toluene (0.5 ml) was degassed with argon. The mixture was heated at 90° C. for 20 min, then directly purified by silica gel flash column chromatography to give title compound (20 mg, 92%) (10% EtOAc—hexanes). LCMS Found: (M+H)+=447.2
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[NH:7].C(N(CC)C(C)C)(C)C.Cl[C:45](OC1C=CC=CC=1)=[O:46].O>O1CCCC1>[F:34][CH:2]([F:1])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH2:16][CH3:17])[CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:45](=[O:46])[O:9][N:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCC(Oc1ccc(C(=N)NO)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC(Oc1ccc(-c2noc(=O)[nH]2)c(OC(F)F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 315 mg of 2-difluoromethoxy-N-hydroxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-benzamidine in 6.5 mL of tetrahydrofuran at 0° C. was added 1.5 mL of N,N-diisopropylethylamine followed by 0.08 mL of phenyl chloroformate. The resulting mixture was stirred for 5 minutes at 0° C. then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved 6.5 mL of tetrahydrofuran and 0.3 mL of N,N-diisopropylethylamine. The resulting solution was heated in a sealed tube to 150° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (diisopropyl ether 100 followed by a gradient from dichloromethane 100 to dichloromethane 90/methanol 10) to give 31 mg of 3-(2-difluoromethoxy-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-phenyl)-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][C:8]([NH2:20])([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:9]([F:12])([F:11])[F:10])C>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:19][C:15]1[CH:14]=[C:13]([C:8]2([C:9]([F:12])([F:11])[F:10])[NH:20][C:4](=[O:3])[CH2:5][O:6][CH2:7]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COCC(N)(c1cccc(Br)c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1COCC(c2cccc(Br)c2)(C(F)(F)F)N1

Procedure:
A solution of 598 mg (1.616 mmol) [2-Amino-2-(3-bromo-phenyl)-3,3,3-trifluoro-propoxy]-acetic acid ethyl ester in 5.4 ml toluene and 2.7 ml TFA was heated at reflux temperature for 5 h. The cooled down mixture was evaporated, taken up in EtOAc, washed with 5% aqueous NaHCO3, dried with Na2SO4 and evaporated to give the essentially pure title compound as a colorless solid.