Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:26]COC)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=2[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]1[CH3:33])=[O:4].[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[NH:45][C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:43]3([CH3:50])[NH:47][C:46](=[O:48])[N:45]([CH2:2][C:3]([N:5]4[CH2:10][CH2:9][N:8]([C:11]5[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:18]([F:19])([F:21])[F:20])[C:22]([F:24])([F:25])[F:23])=[CH:13][C:12]=5[CH2:30][CH2:31][CH3:32])[CH2:7][C@H:6]4[CH3:33])=[O:4])[C:44]3=[O:49])=[CH:42][C:37]=2[CH2:36][CH2:35]1
Reactant: CC1(c2ccc3c(c2)CCO3)NC(=O)NC1=O
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)[C@H](C)C1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)CCO4)C2=O)[C@H](C)C1

Procedure:
(R)-2-bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-2-methylpiperazin-1-yl)ethanone and 5-(2,3-dihydrobenzofuran-5-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:11](Br)[C:12]#[CH:13]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:12]#[CH:11]
Reactant: C#CCBr
Reactant: Oc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1cccnc1
Yield: 33.8 %

Procedure:
To a mixture of 9.5 g (0.1 mole) 3-hydroxypyridine, 5.2 g (0.1 mole) sodium methylate and 150 ml N,N-dimethylformamide, there was added 12.0 g (0.1 mole) propargyl bromide at room temperature over a two hour period. Most of the solvent was removed under reduced pressure. The residue was taken up with 200 ml methylene chloride and 100 ml water, the layers were separated and the methylene chloride evaporated to give 4.5 g 3-(2-propynyloxy)pyridine, yield 34%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.B(Br)(Br)Br.CCOC(C)=O>C(Cl)(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
To a solution of 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (3.5 g, 15.83 mmol) in 20 ml of CHCl3 was added a solution of 1M boron tribromide (23.74 ml, 23.74 mmol) and the reaction was stirred at RT for 3 days resulting in conversion to product by TLC (20% EtOAc:Hexanes). The reaction was partitioned between CH2Cl2/1N NaOH and extracted. The aqueous phase was acidified with 1N HCl and again extracted with CH2Cl2. The organics were dried over sodium sulfate and stripped down in vacuo giving 3-Nitro-5-trifluoromethyl-phenol (1.4 g, 6.76 mmol) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:64][C:65]1[CH:66]=[CH:67][C:68]2[N:69]([CH2:78][CH3:79])[C:70]3[C:75]([C:76]=2[CH:77]=1)=[CH:74][CH:73]=[CH:72][CH:71]=3>C1(C)C=CC=CC=1>[CH2:78]([N:69]1[C:68]2[CH:67]=[CH:66][C:65]([NH:64][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:77][C:76]=2[C:75]2[C:70]1=[CH:71][CH:72]=[CH:73][CH:74]=2)[CH3:79]
Reactant: COC(=S)c1cc(Br)c(C)s1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(Nc3cc(C(=S)OC)sc3C)ccc21
Yield: 46.8 %

Procedure:
The same procedure as in Example 254, step (a) was followed using 120 mg (0.449 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a), 41 mg (10 mol %) of tris-(dibenzylidineacetone)dipalladium, 42 mg (15 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 205 mg (0.629 mmol) of cesium carbonate and 118 mg (0.56 mmol) of 3-amino-9-ethylcarbazole in 900 μL of toluene, and chromatographed as before using 40% CH2Cl2-hexane to afford 80 mg (47%) of the title compound as a yellow resin. 1H-NMR (CDCl3, 400 MHz) δ1.46 (t, 3H, J=7.2 Hz), 2.44 (s, 3H), 3.85 (s, 3H), 4.39 (q, 2H, J=7.2 Hz), 6.25 (s, 1H), 7.24 (m, 1H), 7.28 (s, 1H), 7.40 (m, 2H), 7.49 (m, 1H), 7.61 (s, 1H), 7.83 (d, 1H, J=2.1 Hz), 8.06 (d, 1H), J=7.8 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.Cl.[NH2:15][CH:16](C)[C:17](OC)=O>N1C=CC=CC=1>[CH3:17][CH:16]1[NH:15][C:7](=[O:12])[C:6]2[CH:13]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9]1=[O:11]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COC(=O)C(C)N
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(=O)NC(C)C(=O)N2
Temperature: -10 °C
Yield: 50.5 %

Procedure:
A mixture of 17.7 parts of 6-methyl-4H-3,1-benzoxazine-2,4(1H)-dione, 15.0 parts of methyl 2-aminopropanate monohydrochloride and 62.7 parts of pyridine was refluxed for 6 hours under argon. The reaction mixture was cooled at -10° C. for 1 hour. The precipitate was filtered off, rinsed with water, triturated in ethanol and rinsed with ethanol and 1,1'-oxybisethane, yielding 10.32 parts (50.5%) of 3,4-dihydro-3,7-dimethyl-1H-1,4-benzodiazepine-2,5-dione (interm. 43).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][O:19][C:20](=[O:29])[C@:21]([CH3:28])([CH2:23][S:24]C(=O)C)[NH2:22]>>[CH3:18][O:19][C:20](=[O:29])[C@:21]([CH3:28])([CH2:23][SH:24])[NH2:22]
Reactant: COC(=O)[C@@](C)(N)CSC(C)=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@@](C)(N)CS

Procedure:
Methyl t-butyl 2-methylidenyl-1,3-dipropionate is reacted with thioacetic acid to form methyl t-butyl 2-acetylthiomethyl-1,3-dipropionate. Methyl t-butyl 2-acetylthiomethyl-1,3-dipropionate is alkylated with potassium carbonate and methyl iodide in the presence of a phase transfer catalyst to form methyl t-butyl 2-acetylthiomethyl-2-methyl-1,3-dipropionate. The t-butyl group is hydrolyzed by acidifying the reaction mixture. The free carboxylic acid group produced by hydrolyzing the t-butyl group is converted to an amino group through a reaction with diphenylphosphoryl azide, thereby forming S-acetyl-2-methylcysteine methyl ester. The acetyl group is removed to form 2-methylcysteine methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[C:5](=O)[CH2:6][CH3:7].Cl.[NH2:20]O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH2:6][CH3:7])=[N:20][O:17][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:18]
Reactant: NO
Reactant: CCC(=O)C(C(=O)OC)C(=O)c1ccc(Br)cc1
Agent: Cl
Product: CCc1noc(-c2ccc(Br)cc2)c1C(=O)OC

Procedure:
Prepared according to the procedure described in Example 1, Step 3 using 2-(4-bromo-benzoyl)-3-oxo-pentanoic acid methyl ester and hydroxylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1)and 3,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:30][C:31]1[C:32]([F:39])=[C:33]([OH:38])[CH:34]=[CH:35][C:36]=1[F:37]>C(Cl)Cl.C1COCC1.O>[F:39][C:32]1[C:33]([OH:38])=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[NH:30][C:4](=[O:6])[C:3]1[C:7]([F:18])=[CH:8][CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:2]=1[F:1]
Reactant: O=C(O)c1c(F)ccc(-c2cccc(F)c2)c1F
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1c(F)ccc(O)c1F)c1c(F)ccc(-c2cccc(F)c2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 2,6-difluoro-3-(3-fluorophenyl)benzoic acid (765 mg, 3.03 mmol, 1.1 eq) and oxalyl chloride (1.05 g, 8.5 mmol, 3.0 eq) in DCM (20 mL) was added DMF (0.1 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated in vacuo. The residue obtained was dissolved in THF (5 mL) and added dropwise to a solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (400 mg, 2.76 mmol, 1.0 eq) in THF (25 mL) at 0° C. over 10 min. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as a yellow solid (600 mg, 61%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[O:9]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10]1>CN(C=O)C.C1(C)C=CC=CC=1>[O:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:16])=[CH:10]1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccoc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccoc1
Reaction time: 3 h
Yield: 1.4 %

Procedure:
To a stirred mixture of 18.3 g (162 mM) of creatinine in 120 ml of anhydrous DMF was added a solution of 17.2 g (162 mM) of 3-furanyl isocyanate in 80 ml of toluene. After stirring the mixture for 3 hrs. at 65° C., the mixture was partially concentrated under vacuum and the residue poured into 1200 ml of water. The resulting precipitate was collected, washed with water and recrystallized from ethyl acetate. The solid was then chromatographed over silica gel using ethyl acetate as the eluant and the fractions containing the product were concentrated and the residue recrystallized from toluene to give 0.5 g of the above urea as a tan solid, m.p. 179°-181° C. (dec.).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[N:7]=4)[N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCCC5)n4)c3n2)cn1
Temperature: 160 °C
Yield: 33 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (45 mg, 0.138 mmol) was dissolved in dioxane/pyrrolidine (0.6 mL, 1:1) in a microwave tube under nitrogen. This was sealed and heated at 160° C. for 1 h. The mixture was concentrated in vacuo and re-dissolved in MeOH (2 mL). A solid precipitated over 16 h and was collected by filtration, and triturated with more MeOH to give N-(1-methyl-1H-pyrazol-4-yl)-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine as a white solid (17 mg, 33% yield). 1H NMR (d6-Acetone) δ 8.86 (s and br s, 2H), 8.05 (s, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.35 (t, 1H), 6.28 (d, 1H), 6.18 (d, 1H), 5.47 (s, 2H), 3.82 (s, 3H), 3.38 (m, 4H), 1.95 (m, 4H); LC-MS method B, (ES+) 376.2, RT=4.95 min.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]#[N:14])=[CH:7][N:6]=1.C(N(CC)CC)C>C(O)C>[C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[N:6][CH:7]=1)[NH:3][N:2]=[C:11]2[NH2:12])#[N:14]
Reactant: N#Cc1cnc(Cl)c(C#N)c1
Reactant: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cnc2[nH]nc(N)c2c1
Temperature: 60 °C

Procedure:
Hydrazine hydrate (55%, 125 μL, 2.20 mmol) was added to a stirred suspension of 2-chloro-3,5-dicyanopyridine (240 mg, 1.47 mmol) and triethylamine (205 μL, 1.47 mmol) in ethanol (3 mL) and the resulting red mixture was heated to 60° C. After 16 h the mixture was cooled and filtered to give the title compound:
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([C:13](OC)=[O:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:31]([O:34][CH2:35][CH3:36])(=[O:33])[CH3:32]>C1(C)C=CC=CC=1>[O:14]=[C:13]([C:11]1[N:10]=[CH:9][N:8]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]=1)[CH2:32][C:31]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
202.65 g (0.55 mol) methyl (1-triphenylmethyl-1H-imidazol-4-yl)carboxylate are dissolved in 0.8 l dry toluene at 85° C. 44 g (1.1 mol) sodium hydride (60% dispersion in mineral oil) are added. To the stirred mixture 96.92 g (1.1 mol) ethyl acetate are dropped over 2 hours. The mixture is allowed to react 16 hours at 70° C. Subsequently the toluene is removed under reduced pressure. The resulting mixture is introduced into the following step without purification. For analytical purposes a small amount of the brown oily residue is dissolved in methylene chloride, washing with aqueous ammonium chloride solution and water, drying by means of sodium sulphate and evaporation lead to an oil. Crystallization with diethyl ether and recrystallization from ethanol/diethyl ether afford the title compound as white crystals, melting point 136°-139° C.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]([F:24])([F:23])[CH:7]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH:8]([OH:13])[C:9](OC)=[O:10].Br.[CH3:26][NH:27][C:28](NC)=[NH:29].C(O)(=O)C>C(O)C>[NH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH:7]([CH:8]2[O:13][C:28]([NH:27][CH3:26])=[N:29][C:9]2=[O:10])[C:6]([F:24])([F:23])[F:5])=[CH:15]1
Reactant: COC(=O)C(O)C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: CNC(=N)NC
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNC1=NC(=O)C(C(c2c[nH]c3ccccc23)C(F)(F)F)O1
Temperature: 0 °C
Yield: 20.5 %

Procedure:
Sodium ethoxide (580 mg) was added to a solution of methyl 4,4,4-trifluoro-2-hydroxy-3-(indol-3-yl)butyrate (980 mg) and N,N′-dimethyl guanidine hydrogen bromide (630 mg) in ethanol (2.5 ml). The mixture was refluxed for 1.5 hours and then cooled. To the cooled reaction mixture was added ice water (20 ml). After the pH of the mixture was adjusted to 7 using acetic acid, the whole was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. Concentration of the solution under the reduced pressure gave residue, which was subjected to silica gel chromatography. Eluent with ethyl acetate-hexane was collected and concentrated to provide the titled compound (218 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C([Li])CCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C(OCC)(=O)C.C1COCC1.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([B:19]([OH:22])[OH:20])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(B(O)O)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
The compound (22) (84.6 g) and THF (500 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyllithium (1.65 M in a n-hexane solution; 303.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, the mixture was added dropwise to a THF (200 ml) solution of trimethyl borate (56.7 g) in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. Subsequently, the reaction mixture was poured into a vessel containing 1N—HCl (100 ml) and ice-water (500 ml), and mixed. Ethyl acetate (300 ml) was added thereto and the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, giving 4-butoxy-2,3-difluorophenylboronic acid (23) (6.4 g). The yield based on the compound (22) was 69.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Yield: 95 %

Procedure:
N-(4-Bromophenyl)acetamide obtained in step I above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-(4-bromo-2-nitrophenyl)acetamide. (Yield=95%)
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[S:13][C:14]([C:21](Cl)=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:12]1[S:13][C:14]([C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=1
Reactant: OCCOc1ccccc1
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCCOc1ccccc1)c1sc(Cl)nc1C(F)(F)F

Procedure:
6.3 g (0.045 mol) of 2-phenoxyethanol are added slowly while stirring to a solution of 11 g (0.44 mol) of 2-chloro-5-chlorcarbonyl-4-trifluoromethyl-thiazole in 100 ml of absolute toluene. The solution is then cooled to 0°-5° and 3.6 g (0.045 mol) of triethylamine are added dropwise while stirring. Triethylamine-hydrochloride precipitates from the reaction mixture. After everything is added, the suspension is stirred for 20 hours at room temperature and then poured onto ice-water. The organic phase is separated, dried over sodium sulfate and concentrated in a rotatory evaporator. The residue cristallizes. In order to purify it, the crystals are suspended in petrol-ether, filtered and dried. In this manner 8.7 g (57% of the theoreticl yield) of the title compound are obtained, m.p. 70°-72°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.C(N(CC)CC)C.Cl.[C:23]1([C:29]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:37]3[C@@H:33]([CH2:34][NH:35][CH2:36]3)[C@@:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])([OH:38])[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:47]1([C:29]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:37]3[C@@H:33]([CH2:34][N:35]([C:11](=[O:12])[C:10](=[O:14])[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:36]3)[C@@:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])([OH:38])[CH2:31][CH2:30]2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)C(=O)c3c[nH]c4ccccc34)C[C@H]21
Yield: 97.3 %

Procedure:
A solution of 0.43 g of 2-(3-indolyl)-2-oxoacetyl chloride in 20 cm3 of dry methylene chloride and then a solution of 0.6 cm3 of triethylamine in 5 cm3 of dry methylene chloride are added successively to a suspension of 0.96 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3Of dry methylene chloride at room temperature, while stirring. The reaction mixture is stirred at this temperature for 24 hours and then diluted with 200 cm3 of methylene chloride, washed with 100 cm3 of an aqueous 1N sodium hydroxide solution and with 50 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 31 cm) by eluting under a pressure of 0.4 bar of nitrogen with a mixture of 1,2-dichloroethane and methanol (70/30 by volume) and collecting fractions of 15 cm3. Fractions 2 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of (3aS,4S,7aS)-7,7-diphenyl-2-[2-oxo-2-(3-indolyl)acetyl]-4-(2-methoxyphenyl)-perhydroisoindol-4-ol are obtained in the form of an orange foam.
Reaction SMILES: S1C=CC=C1.CC(N(O)C(N)=[O:12])C#C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2S[C:26]([C:28]#[C:29][CH:30]([N:32]([OH:36])[C:33]([NH2:35])=[O:34])[CH3:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[O:12][C:26](/[CH:28]=[CH:29]\[CH:30]([N:32]([OH:36])[C:33]([NH2:35])=[O:34])[CH3:31])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: C#CC(C)N(O)C(N)=O
Reactant: CC(C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Solvent: c1ccsc1
Product: CC(/C=C\c1ccc(Cc2ccc(F)cc2)o1)N(O)C(N)=O

Procedure:
The desired compound is prepared according to the method of Example 1, except substituting furan for thiophene, and substituting N-(3-butyn-2-yl)N-hydroxyurea, prepared as in Example 3, step 2, for (R) N-(3-butyn-2-yl)N-hydroxyurea.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[C:21]([O-])(O)=O.[Na+]>CO>[OH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([O:5][CH3:21])=[O:4]
Reactant: O=C([O-])O
Reactant: O=C(O)C(O)c1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 2-hydroxy-2-(naphthalen-2-yl)acetic acid (0.75 g, 1 eq) in dry MeOH was added sulfuric acid (0.1 mL) dropwise and heated to reflux. Stirring was then continued for 2 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (0.63 g, 78%) that was not further purified.