Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc(-n2ccnc2)c1
Yield: 101.6 %

Procedure:
A solution of 1-(3-nitrophenyl)-1H-imidazole (6.5 g, 34 mmol) in glacial acetic acid (50 ml) was treated with 10% palladium on charcoal (320 mg) and hydrogenated at 50 psi until hydrogen uptake ceased (ca. 3 hours). The mixture was filtered through a glass microfibre filter paper (Whatman GF/A) and evaporated to dryness. The residue was azeotroped twice with toluene to give 3-(imidazol-1-yl)phenylamine as a yellow oil (5.5 g, 100%) which was used without purification. m/z (ES+) 360 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(C2=NN(Cc3ccc(F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Fluorobenzyl bromide (8 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=1.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(-c2ccccn2)c1Br
Yield: 69.1 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol) and N-bromosuccinimide (432 mg, 2.43 mmol) in trifluoroacetic acid (6 mL) was heated to 150° C. for 30 minutes via microwave. Concentration under reduced pressure afforded a yellow oil which was diluted with ethyl acetate (80 mL), washed with a saturated aqueous solution of sodium bicarbonate (20 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1:3 mixture ethyl acetate and hexane afforded ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (0.217 g, 0.672 mmol, 69% yield). The product had an HPLC retention. time=2.65 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=299.02. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.15 Hz, 3H), 4.52 (q, J=7.28 Hz, 2H), 7.43-7.48 (m, 1H), 7.90 (td, J=7.78, 1.76 Hz, 1H), 8.11 (d, J=8.03 Hz, 1H), and 8.84 (d, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12]C=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:14][CH2:15]O.[CH3:17]C(O)=O>[Pd]>[CH3:17][C:15]1([CH3:14])[CH2:12][CH2:13][CH:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: C1=C(Nc2ccccc2)CCCC1
Reactant: CCO
Reactant: CC(=O)O
Agent: [Pd]
Product: CC1(C)CCC(Nc2ccccc2)CC1
Reaction time: 8 h
Yield: 90 %

Procedure:
In a Parr hydrogenation flask, cyclohexenylaniline (46.4 g, 0.247 mol) is dissolved in 30 mL of 3:1 EtOH/AcOH and 10% Pd on carbon (0.5 g) is added. The reaction is shaken under H2 (60 psi) overnight. The mixture is filtered through a pad of celite and concentrated under vacuum. The crude product is dissolved with CH2Cl2 and neutralized with saturated aqueous bicarbonate. The organic layer is washed with water, dried over MgSO4 and concentrated to give a the 4,4-Dimethylcyclohexyl aniline as a light yellow oil (42.2 g, 90%).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32][CH3:33])=[C:25]([C:27]4OC=CC=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(NC2C3C(=CC=CC=3)C(CC3C=NC(OC)=C(Br)C=3)=NN=2)=CC=1)(C)(C)C.C([Sn](CCCC)(CCCC)C1[S:73][CH:74]=[CH:75][N:76]=1)CCC>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32][CH3:33])=[C:25]([C:27]4[S:73][CH:74]=[CH:75][N:76]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:34][CH:35]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1Br
Product: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1nccs1

Procedure:
Can be obtained analogously to Ex. 18a from 1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine and 2-tributylstannyl-thiazol (supplier: Frontier Scientific; Logan/USA). MS: (M+H)+=482; HPLC(Grad20-100) tRet=14.6.
Reaction SMILES: [C:1]([C:3]([C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36])=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][N:16](COCC[Si](C)(C)C)[C:13]3=[N:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:2].C(O)(C(F)(F)F)=O.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:1]([C:3]([C:35]([N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)=[O:36])=[CH:4][C:5]1[CH:34]=[CH:33][C:8]([NH:9][C:10]2[N:11]=[C:12]3[C:18]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Reaction time: 8 h

Procedure:
To a 20 ml vial 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazine-7-carboxamide (65 mg, 0.11 mmol was dissolved in DCM (3 ml) added TFA (3 ml, 0.11 mmol) was added. The reaction mixture was stirred overnight. HCl (1 ml, 0.11 mmol) and methanol (3 ml) were added and the reaction mixture was stirred at overnight and then neutralized to pH 6-7 with NaHCO3. The organics were extracted with EtOAc, washed with water, dried with Na2SO4, filtered and evaporated solvent to give 45 mg of 2-[4-(2-cyano-3-morpholino-3-oxo-prop-1-enyl)anilino]-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]#[N:30])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:70]=[N+:71]=[N-:72])(C)C>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]4[N:26]([CH2:27][CH2:28][C:29]#[N:30])[N:72]=[N:71][N:70]=4)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NCCC#N)s3)C[C@H]2OC)nc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnnn4CCC#N)s3)C[C@H]2OC)nc1Cl
Yield: 39.6 %

Procedure:
THF (2 mL) was added to cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-N-(2-cyanoethyl)-4-methyl-1,3-thiazole-5-carboxylic acid amide obtained in Example (261a) (36 mg, 0.08 mmol). While the mixture was stirred, triphenylphosphine (124 mg, 0.47 mmol), diisopropyl azodicarboxylate (0.24 mL, 0.45 mmol, 1.9 M solution in toluene) and trimethylsilyl azide (7.3 g, 55.4 mmol) were added, followed by stirring at 30° C. for four days. The reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0/10, 2/8) and preparative thin layer chromatography (developing solvent: ethyl acetate/hexane=10/1) to obtain 16 mg of the title compound as a white solid (41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].O>CN(C)C(=O)C.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.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:34]3[CH:35]=[CH:36][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)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: [K+]
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (6.92 g, 30.75 mmol), potassium carbonate (7.34 g, 53.09 mmol) and 4-methanesulfonylbenzeneboronic acid (5.31 g, 26.55 mmol) in N,N-dimethylacetamide (90 mL) and purge for 15 min. Add water (35 mL) and the mixture further purged for 15 min. Add tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 mmol) and heat for 2 hr. 10 min. at 110° C. Allow to cool to 65° C., add water (30 mL) and t-butyl methyl ether (70 mL) and stir for 0.5 hr. Filter off the solid and dry in a vacuum oven to give 3′-(4-methanesulfonylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (8.3 g, 86%). MS (ES): m/z=419 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-:14].[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:14][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C(O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g (60.2 mmol) of hydroxyphenylacetic acid methyl ester (Aldrich) is dissolved in 75 ml of acetone. 18.4 g (133 mmol) of solid potassium carbonate is added. 17.8 ml (123 mmol) of bromoacetic acid ethyl ester is added in drops under reflux within 15 minutes, it is kept at this temperature for another 4 hours, and it is stirred overnight at room temperature. Precipitate is filtered out, the solution is evaporated to the dry state and chromatographed on silica gel (hexane/ethyl acetate 3:1). The fractions that contain the product are combined and concentrated by evaporation.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[NH:37][CH:38]=[CH:39][N:35]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ncc[nH]3)C3CCCc4cccnc43)cc2)nc1
Reaction time: 40 h
Yield: 28.8 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (174 mg, 0.38 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (75 mg, 0.78 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol) and the mixture was stirred for 40 h. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 (30 mL) and aqueous 1 N sodium hydroxide (30 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) afforded the imidazole derivative (48 mg, 24%) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH2:10]([OH:14])[CH2:11]C#C.[CH:15]1C=CC=C[CH:16]=1>>[CH3:1][C:2]1([CH3:9])[CH:3]2[CH:15]=[CH:16][CH:6]([C:5]([CH2:11][CH2:10][OH:14])=[CH:4]2)[C:7]1=[O:8]
Reactant: CC1(C)C=CC=CC1=O
Reactant: c1ccccc1
Reactant: C#CCCO
Product: CC1(C)C(=O)C2C=CC1C=C2CCO
Temperature: 25 °C

Procedure:
A mixture of 50 g of 6,6-dimethylcyclohexadienone and 50 g of 3-butyn-1-ol in 300 ml of benzene is placed in an autoclave and heated to 210°-210° C. for 3 hours. The autoclave is then cooled to room temperature and the reaction mixture is removed, the solvent stripped and the residue distilled under vacuum through a 3" microvigreaux column yielding 65 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octa-5,7-dien-2-one having the structure: ##STR26##
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Cl)[C:14](=[CH2:16])[CH3:15]>C(O)C>[CH3:15][C:14](=[CH2:13])[CH2:16][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C(C)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: C=C(C)CC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h

Procedure:
Sodium (5.08 g.) was dissolved in dry ethanol (300 ml.). Diethyl malonate (35 g.) was added and the mixture was stirred for 2 hours. Methallyl chloride (20 g.) was added and the mixture was refluxed with stirring for 4 hours. The mixture was cooled, the solid filtered off and the solvent was removed in vacuo. 2N Hydrochloric acid solution was added and the mixture was extracted with diethyl ether. The ethereal extracts were washed with sodium hydrogen carbonate solution, water and then dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. Distillation gave diethyl 2-methyl-prop-2-enylmalonate as a colourless liquid (28.2 g. b.p. 120°-126° 20 mm.).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:22][C:23]([C:26]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:27])=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cc2c(s1)CCCCN2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine of Step A (0.300 g) and N,N-diisopropylethyl amine (0.5 mL) in dichloromethane (25 mL) was cooled to 0°. To this was added a solution of 4-biphenyl carbonyl chloride (0.518 g) in dichloromethane (5 ml). The solution was stirred overnight as it warmed to room temperature, then washed with 0.1N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash chromatography of the residue on silica gel provided the title compound as a white solid (0.490 g), m.p. 164-166° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.[CH:26]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: O=C(O)C1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(Oc3c(F)cc(F)cc3F)CC2)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3c(F)cc(F)cc3F)CC2)CC1)C1CCC1

Procedure:
According to the synthesis of example 19 the title compound was prepared from Trans(4-{2-[4-(2,4,6-trifluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amine and Cyclobutanecarboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 439.0 (M+H+).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:6]([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].C(N([CH2:44][CH3:45])CC)C.[CH2:46]([Si:48](Cl)([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:47]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[CH:6]([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:48]([CH2:44][CH3:45])([CH2:49][CH3:50])[CH2:46][CH3:47])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:34])([O:35][Si:48]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:46][CH3:47])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:48]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:46][CH3:47])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(C)=O)C=CC1C
Reactant: CCN(CC)CC
Reactant: CC[Si](Cl)(CC)CC
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(C)=O)/C=C/C1C)O[Si](CC)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(C)=O)C=CC1C)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (8E,12E,14E)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (54 mg, 0.1 mmol), 4-dimethylaminopyridine (124 mg, 1 mmol), and triethylamine (102 mg, 1 mmol) in methylene chloride (2.5 mL) was cooled to 5° C. A solution of triethylsilyl chloride (152 mg, 1 mmol) in methylene chloride (0.5 mL) was added dropwise to the reaction mixture, and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with water. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:19->1:14) to obtain the title compound (77.1 mg, 88%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:31](I)([CH3:33])[CH3:32].O>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:31]([CH3:33])[CH3:32])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(SC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC(C)C)c(SC)c1
Yield: 62.8 %

Procedure:
A suspension of the ethyl (RS)-(4-cyano-phenylamino)-(4-hydroxy-3-methylsulphanyl-phenyl)-acetate (198 mg, 0.58 mmol) described in Example 168.1, Cs2CO3 (227 mg, 0.64 mmol) and isopropyl iodide (58 μl, 0.58 mmol) in acetone (3 ml) was heated under reflux for 4 h. Water was added and the mixture was extracted with CH2Cl2. Die organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 2:1). Ethyl (RS)-(4-cyano-phenylamino)-(4-isopropoxy-3-methylsulphanyl-phenyl)-acetate (140 mg, 63%) was obtained as a colorless oil; MS: 443 ([M+OAc]+).
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24](N(OC)C)=[O:25])[CH:13]=C(C)C=2C(=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Mg+].[Br-].[CH2:35]1[CH2:39][O:38][CH2:37][CH2:36]1>>[C:24]([C:14]1[N:15]=[C:16]2[C:36]([C:37](=[O:38])[CH:9]=[C:8]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:17]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:35]([CH3:39])[CH:13]=1)(=[O:25])[CH3:32]
Reactant: CON(C)C(=O)c1cc(C)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Reactant: C[Mg+]
Reactant: C1CCOC1
Agent: [Br-]
Product: CC(=O)c1cc(C)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Yield: 74 %

Procedure:
To a suspension of 7-anilino-N-methoxy-N,4-dimethyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide (100 mg, 0.24 mmol) in THF (5 mL) at 0° C. was added MeMgBr (3M in Et2O, 322 uL, 0.97 mmol). The suspension became a red solution. As the reaction proceeded the solution lost its red color. After 1 h the reaction was quenched with saturated NH4Cl, diluted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by a Biotage silica gel chromatography using EtOAc to afford 7-acetyl-2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one as a light yellow solid (65 mg, 74%): LCMS RT: 2.63 min, MH+: 370.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:35])[CH2:33][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[N:13]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(-c2nccc(NS(=O)(=O)c3ccc(Cl)cc3)n2)cc1
Product: CC(C)c1ccc(-c2nccc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3ccc(Cl)cc3)n2)cc1

Procedure:
{(4-Chloro-benzenesulfonyl)-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-amino}-acetic acid tert-butyl ester was prepared (97 mg) from 4-chloro-N-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzenesulfonamide (100 mg, 0.26 mmol) (Prepared in Example 158) and bromoacetic acid tert-butyl ester by following the general procedure S (method 1). LCMS m/z: 503 (M+1)+.