Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1.C[OH:17]>O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([C:11]1[N:15]=[CH:14][NH:13][N:12]=1)=[O:17]
Reactant: Cc1cc(C)c(Sc2nc[nH]n2)c(C)c1
Reactant: CO
Solvent: O
Product: Cc1cc(C)c(S(=O)c2nc[nH]n2)c(C)c1
Temperature: 25 °C

Procedure:
To a mixture of OXONE monopersulfate compound (3.02 g) and water (30 ml) was added dropwise a mixture of 3-(2,4,6-trimethylphenyl)thio-1H-1,2,4-triazole (Example 32-a) (1.08 g) and methanol (30 ml) with stirring it at room temperature. After the addition was completed, the reaction mixture was stirred for 3 hours, and water (20 ml) was added. Precipitated crystals were collected by filtration, and washed with water, ethyl acetate, and hexane in this order to yield the title compound (820 mg).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:52]1[CH2:55][CH:54](O)[CH2:53]1.CN1CCOCC1.CC#N.Cl.O1CCOCC1>C(Cl)Cl>[O:52]1[CH2:55][CH:54]([O:13][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:2][CH:3]=2)[CH2:53]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: OC1COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OC1COC1
Reaction time: 0.25 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol), HOBt (98 mg, 720 μmol), and EDCI (130 μL, 720 μmol) were dissolved in DCM and stirred for 15 minutes. Oxetan-3-ol (140 mg, 1.9 mmol) and 4-methylmorpholine (110 μL, 970 μmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the DCM layer was separated and concentrated. The product was then purified (Interchim reverse phase chromatography column) and dried under vacuum. The purified material was combined with MeCN (1 mL, 20 mmol) and 4 M HCl in dioxane (240 μL, 970 μmol) and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid oxetan-3-yl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2].[OH-].[K+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2]
Reactant: CCCOc1cc2sc(C(=O)OC)cc2cc1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1cc2sc(C(=O)O)cc2cc1OCC
Yield: 36 %

Procedure:
A solution of 0.45 g. of methyl 5-ethoxy-6-propyloxybenzothiophene-2-carboxylate and 0.34 g. of potassium hydroxide in ethanol was heated to reflux for two hours. The solution was poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N sodium hydroxide. The alkaline solution was acidified with hydrochloric acid and was then extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated in vacuo to provide the desired title product, m.p. 192°-194° C., in an overall molar yield of 36% from 5-ethoxy-6-hydroxybenzothiophene-2-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([CH3:24])[CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].ClCCl>C(O)C.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C@H:18]([CH3:24])[CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC[C@@H](C)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C[C@H](CO)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 65 °C
Yield: 56.5 %

Procedure:
5.64 g of crude (S)-acetic acid 3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-2-methyl-propyl ester (asserted 14.1 mmol) were stirred in 26.6 ml of ethanol. A solution of 2.83 g of sodium hydroxide in 6 ml of water was added and the reaction was heated at 60-70° C. for 5 h. After cooling to room temperature, 50 ml of water and 50 ml of dichloromethane were added. The dichloromethane layer was separated and the aqueous phase was extracted with a further portion dichloromethane. The combined dichloromethane extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum to give an orange oil. The crude product was purified by flash column chromatography eluting with dichloromethane-methanol (9:1). The fractions containing the product were combined and evaporated to give an orange oil (2.76 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:22][C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O>[CH2:30]([O:32][CH2:33][N:22]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[S:3][CH2:1][CH3:2])[CH3:31]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2[nH]1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCn1c(-c2ccccc2SCC)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (270 mg) and DMF (10 ml), 60% of sodium hydride (in oil) (80 mg) and chloromethyl ethyl ether (118 μl) were sequentially added under ice-cooling. The mixture was heated to room temperature, and stirred for 5 hours. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 180 mg of 3-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 33) and 70 mg of 1-ethoxymethyl-2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-1H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 34)).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:15][C:16]#[N:17]>>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:15][C:16]#[N:17])[CH2:4][CH2:3]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: N#CCBr
Product: N#CCN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Hydroxy-4-phenyl-piperidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=217.2: AtRet=1.51.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(CO)NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc(C(N)=O)cn1)NCc1ccccc1

Procedure:
Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1(a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:6](=O)[C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:6]1[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Temperature: 0 °C
Yield: 86.9 %

Procedure:
To methyl 2-(5-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (3 g, 10.09 mmol) was added POCl3 (25 mL, 268 mmol). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid was filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (2.77 g, 84%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.58 (3H, s), 3.71 (3H, s), 4.04 (2H, s), 7.29 (1H, s), 7.43-7.58 (3H, m), 8.07 (2H, d, J=7.0 Hz).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][C:10]=2[CH2:24][CH3:25])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[S:11][C:10]=2[CH2:24][CH3:25])[O:8][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a mixture of cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methanol (648 mg) synthesized above, methyl 4-hydroxybenzoate (321 mg), 1,1′-(azodicarbonyl)dipiperidine (888 mg) and tetrahydrofuran (20 mL) was added tributylphosphine (877 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the precipitate was removed by filtration, and washed with diisopropyl ether. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 2N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at 50° C. for 2 hr. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, the organic solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (413 mg, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(Cl)Cl.C(O)(=O)C>[Br:11][CH2:9][C:8](=[O:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: CON=C(C(=O)O)C(=O)CBr
Reaction time: 0.5 h

Procedure:
In 3 liters of methylene chloride was dissolved 460 g of the 2-methoxyimino-3-oxobutyric acid obtained by the procedure of Example 1. To the solution was added 46 ml of a 25% hydrogen bromide solution in acetic acid. To the resultant solution was added dropwise over 2 hours at 7° to 15° C. a solution of 372 g of bromine in 372 ml of methylene chloride. Nitrogen was then blown into the mixture violently at 7° to 8° C. for 30 minutes so as to eliminate the byproduct hydrogen bromide. Silica gel (Kieselgel 60, 70 to 230 mesh, manufactured by Merck; 80 g) and activated carbon (Shirasagi of larger grain A grade, manufactured by Takeda Chemical Industries; 30 g) were added to the supernatant obtained. The mixture was stirred at 10° to 15° C. for 30 minutes and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, the oily residue was dissolved in 685 ml of xylene, and the solution was allowed to stand at 5° C. for 15 hours. The resultant crystalline precipitate was collected by filtration, washed with 100 ml of a 1:1 (v/v) mixture of xylene and n-hexane and then with 200 ml of n-hexane, and dried under reduced pressure to give 434 g of 4-bromo-2-methoxyimino-3-oxobutyric acid. The filtrate (mother liquor) was concentrated under reduced pressure and the oily residue was crystallized by addition of 238 ml of a 100:15 (v/v) mixture of xylene and n-hexane to give 82.3 g of 4-bromo-2-methoxyimino-3-oxobutyric acid as a second crop.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:35]([O-])(=[O:37])[CH3:36].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:35]([O:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH:5]=[CH:4]1)(=[O:37])[CH3:36]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (5.0 g) in a mixture of acetic acid (60 ml) and acetic anhydride (60 ml) containing p-toluenesulfonic acid (2.5 g) is maintained at room temperature for eighteen hours. Sodium acetate (2.5 g) is added and the mixture is concentrated in vacuo at 35°-40° C. The residue is diluted with water (150 ml) and the solid that separates is isolated by filtration, washed with water and dried in vacuo to afford the title compound as a solid (5.0 g) with consistent spectral data. An examination (silica gel, chloroform: ethyl acetate, 95:5) reveals the presence of a small amount of starting steroid as the only significant impurity. This material is used without purification in the next step. A specimen crystallized from acetone-hexane melts at 173°-174° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]1([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[CH:14]1([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:24]2)=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(NC1CCCCC1)C1CCCNC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC1CCCCC1)C1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (12.3 mg) and N-cyclohexylpiperidine-3-carboxamide (TFA salt, 18 mg) from Step 2 in 0.2 mL acetonitrile was added triethylamine (19.3 μL). The reaction mixture was stirred at RT for 2 hours and directly purified by HPLC to give 13.2 mg of desired product. LCMS: m/z 396.1 (M+H)+; 813.3 (2M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C)C=O.ClCCl>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=1[NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:11]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: Nc1ccc(F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ccc(F)cc1NC(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
Method 3,4—Step a To a mixture of the solids 5-Bromo-2-chlorobenzoic acid (7.00 g, 29.79 mmol), 4-Fluoro-benzene-1,2-diamine (4.65 g, 36.94 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (11.89 g, 31.28 mmol), triethylamine (TEA) (4.60 mL, 32.77 mmol), dichloromethane (120 mL) and dimethylformamide (DMF) (30 mL) were added. The reaction mixture was stirred at room temperature overnight, water was added (30 mL) and stirred until the formation of a precipitate. The precipitate was filtered off, washed with dichloromethane (3×10 mL) and dried to afford 6.90 g of the title compound (69%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH2:20]([Li])[CH:21]([CH3:23])[CH3:22]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2]
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [Li]CC(C)C
Product: CCc1cccc(CC(C)C)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(2-Ethyl-6-isobutyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and isobutyl lithium in analogy to procedure Example 5 a): colourless liquid; NMR (CDCl3, ppm): 0.88 t, 18H (2×(CH3)2C), 1.20 t, 3H(CH3—CH2), 1.88 septett, 1H(CH(CH3)2), 2.08 m, 2H(NCH(CH(CH3)2)2), 2.48 t, 1H(NCH), 2.68 d, 2H (aryl -CH2CH), 2.88 q, 2H(CH3-CH2), 7.00 d, 1H and 7.08 d, 1H and 7.19 t, 1H (aryl-H), 8.49 1H (═CHN).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][CH3:22])=[O:14].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH3:22])[CH:1]=[O:3])=[O:14]
Reactant: O=CO
Reactant: CNc1ccccc1C(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1ccccc1C(=O)CCl
Reaction time: 3 h

Procedure:
A mixture of formic acid (2.3 ml) and acetic anhydride (3.6 ml) was heated at 50 to 60° for 2 hours, cooled to 0 to 5° and dichloromethane (10 ml) added. A solution of 2-chloro-2'-(methylamino)acetophenone (1.6 g) in dichloromethane (25 ml) was added and the solution then stirred at 10°-20° for 3 hours. The solution was cooled to 0 to 5° and water (50 ml) followed by aqueous sodium bicarbonate (1M, 50 ml) was added. The layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The combined dichloromethane layer and extract were dried over magnesium sulphate and the solvent was removed by distillation to give the novel compound 2'-(2-chloro-acetyl)-N-methylformanilide in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2]([CH:37]=[CH:36][CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Brc1ccc(-n2cccn2)nc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=CC=Cc1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:20][OH:21]>O>[OH:21][N:20]=[C:11]([CH:2]1[CH:3]([C:8]([OH:10])=[O:9])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)[OH:12]
Reactant: NO
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1C2C=CC(C2)C1C(O)=NO
Temperature: 25 °C

Procedure:
30 ml of water was added to 24.6 g of 5-norbornene-2,3-dicarboxylic acid anhydride, and while cooling the reaction temperature below 20° C., 10.6 g of sodium carbonate and then 13.9 g of hydroxylamine hydrochloride were added. The mixture was reacted at room temperature for 1 hour and then reacted at a temperature of 60° to 70° C. for 1 hour. After cooling to room temperature, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide thus formed was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](=[CH:8][O:9]C)[CH2:4][CH2:3]1.Cl>C1COCC1.C(OCC)C.[Cl-].[Na+].O.O>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: COC=C1CCC(C)(C)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g, 0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred at room temperature for 24 hr. The reaction mixture was diluted with a mixture of ethyl ether, hexanes, brine and water. The mixture was separated and the aqueous phase was extracted with ethyl ether. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde as a yellow oil, used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][N:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:37][CH2:38][N:34]([CH3:33])[C:35]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 65.4 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (205 mg) described in Preparation Example 240 and 1-methylimidazolidin-2-one (59 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (139 mg) was obtained.