Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:30][C:29]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc(OC)c1
Temperature: 160 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.400 g (2.60 mmol) of 3,5-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. At ca. 100° C., 1 mL of glacial acetic acid was added to the melt to dissolve. Water (10 mL) was added to precipitate a gum. Decanted and dissolved gum in 35 mL of methylene chloride. The solution was washed with 2×20 mL of water, dried over magnesium sulfate, charcoaled, filtered, and concentrated. The remaining gum was purified silica gel chromatography eluting with chloroform and then with 2:1 hexane:ethyl acetate to obtain the fraction containing the pure product. The eluent was evaporated to near dryness when crystals separated. The crystals were filtered and washed with 0.5 mL of ether; wt 0.059 g; mp 228°-230° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](=[O:35])[CH2:19][C:16]4[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=4)=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1ccncc1
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(=O)Cc2ccncc2)c2[nH]c(C3CCCC3)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (0.47 ml) in tetrahydrofuran (6 ml), cooled to −10° C., was treated dropwise, with a solution of butyl lithium in hexanes (1.2 ml, 2.5M). The resulting solution was stirred for 10 minutes, then cooled to −78° C. and then treated dropwise with a solution of 4-picoline (0.29 ml) in tetrahydrofuran (1 ml). This solution was stirred for 30 minutes then treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [0.274 g, Reference Example 3(t)] in tetrahydrofuran (2 ml). The cold bath was removed and the reaction mixture stirred for 15 minutes at ambient temperature. The mixture was quenched with water, then diluted with ethyl acetate. The organic phase was separated then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (8:92,v/v), to give the title compound (0.126 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.F[B-](F)(F)[CH:23]=[CH2:24].[K+]>C(O)CC.Cl[Pd]Cl.[Fe]>[CH:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([CH:23]=[CH2:24])[C:3]([NH2:20])=[N:4][CH:5]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])([CH3:19])[CH3:18]
Reactant: C=C[B-](F)(F)F
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [K+]
Solvent: CCCO
Product: C=Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N

Procedure:
dichloropalladium; iron (155.6 mg, 0.2132 mmol) was added to a solution of 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (455.6 mg, 1.279 mmol), TEA (323.6 mg, 445.7 μL, 3.198 mmol) and potassium trifluoro(vinyl)boranuide (171.3 mg, 1.279 mmol) in propanol (2 mL). The reaction mixture was heated in a microwave for 40 min at 100 C. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and water. The organic extract was dried over MgSO4 and concentrated in vacuo yielding an oil that was purified by chromatography on silica using 100% DCM to DCM/MeOH 90/10 as elaunt to yield 5-(4-(isopropylsulfonyl)phenyl)-3-vinylpyrazin-2-amine as an orange solid. LC/MS m/z 304.3 [M+1]+.
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+]>O1CCCC1>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH:34]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)CC(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(C)c(C(=O)O)c1)CN2C(=O)CC(C)(C)C
Temperature: 45 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea (0.94 g) was dissolved in tetrahydrofuran (20 ml), aqueous lithium hydroxide monohydrate (0.32 g) solution (10 ml) was added, the mixture was stirred at 40-50° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:methanol=30:1), to thereby obtain 0.56 g of the title compound as colorless powder (Yield: 61%).
Reaction SMILES: [CH2:1](C(C)=O)[CH:2](C)C.[CH2:8]([N:10]([CH2:18][CH3:19])[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].C(Br)C>O>[CH2:18]([N:10]([CH2:8][CH3:9])[C:11]1[CH:12]=[C:13]([O:17][CH2:1][CH3:2])[CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CCN(CC)c1cccc(O)c1
Reactant: CC(=O)CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCBr
Solvent: O
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A 1 liter reactor is charged with 150 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate. The mixture is stirred for 30 minutes, then 72.7 g of ethyl bromide are added and the autoclave is closed. The reaction mixture is heated first for 3 hours to 115°-129° C. and then for a further 5 hours at 140°-142° C. (pressure: 4 bar). After cooling to c. 25° C. and addition of water, the product is isolated with the organic phase, which is washed with water and concentrated by evaporation, to give 80.67 g (97.2% yield) of 3-diethylaminophenetol with a titre of 94.8%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:2]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc(NC2CCCNC2)ccn1
Product: c1ccc(CN2CCCC(Nc3ccncc3)C2)cc1

Procedure:
Reaction of N-(piperidin-3-yl)pyridin-4-amine with the benzaldehyde using the method of Example 8 affords the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:22][CH3:23])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([O:20][CH3:21])[CH:12]=3)[CH:5]=[CH:6][C:7]=1[OH:8].C1N=CN([C:29](N2C=NC=C2)=[O:30])C=1>C1COCC1>[CH2:22]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:20][CH3:21])[CH:12]=2)[C:17]([C:18]#[N:19])=[C:9]1[C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:29](=[O:30])[NH:1][C:2]=2[CH:3]=1)[CH3:23]
Reactant: CCn1c(-c2ccc(O)c(N)c2)c(C#N)c2ccc(OC)cc21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCn1c(-c2ccc3oc(=O)[nH]c3c2)c(C#N)c2ccc(OC)cc21
Temperature: 65 °C
Yield: 80.9 %

Procedure:
2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This is heated at 65° C. for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (89 mg, 81%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C1COCC1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(N)cc3CC[C@@H]12
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Reaction time: 4 h

Procedure:
A 620 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-amino-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was dissolved in 100 ml of THF, and an equivalent amount of 3-nitrobenzoyl chloride (500 mg) was added. The reaction mixture was stirred for 4 h, and was then evaporated to dryness under vacuum. The residue was purified by chromatography on silica gel, eluting with 10% methanol in ethyl acetate, and the product-containing fractions were evaporated and the resulting solid was crystallized from dichloromethane/hexane to obtain 595 mg of the desired product, m.p. 240°-242°. FDMS: m/e=393. α[D]589
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH2:11](Br)[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[CH3:12]
Reactant: CCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cccc2[nH]ccc12
Reaction time: 18 h

Procedure:
4-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Reaction SMILES: [NH:1]([C@@H:8]([CH2:24][O:25]C(C)(C)C)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C.CCCCCC>[ClH:36].[ClH:36].[NH:1]([C@@H:8]([CH2:24][OH:25])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC[C@H](Nc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(-c2ccncc2)cc1)[C@H](CO)Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of (2S)-2-anilino-3-tert-butoxy-N-[4-(4-pyridinyl)phenyl]propanamide (70 mg) in ethyl acetate (0.42 mL) was added 4N hydrogen chloride-ethyl acetate (1.8 mL) and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was diluted with n-hexane (2.5 mL) and the solid was collected by filtration and washed with n-hexane (2.5 mL) to give (2S)-2-anilino-3-hydroxy-N-[4-(4-pyridinyl)phenyl]propanamide dihydrochloride (72 mg) as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][C:9]1[C:10]([F:17])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[F:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)c(F)c1
Yield: 70.9 %

Procedure:
Potassium carbonate (7.8 g, 56.4 mmol) was added to a solution of 1,2,3-trifluoro-5-nitrobenzene (5 g, 28.2 mmol) and benzyl alcohol (3.2 g, 29.6 mmol) in N,N-dimethylformamide (70 mL). The resultant mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by column chromatography to give 2-(benzyloxy)-1,3-difluoro-5-nitrobenzene (5.3 g, 71% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, J=8.4 Hz, 2H), 7.46-7.37 (m, 5H), 5.39 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][O:20][CH2:19][CH2:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Reactant: BrCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3ccccc3c2n1CCOCCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.0 g, 3.7 mmol) in N,N-dimethylformamide was added dropwise to a suspension of sodium hydride (0.19 g of a 60% dispersion in mineral oil, 4.8 mmol) in N,N-dimethylformamide (20 ml). The reaction was maintained for 2 hours followed by the dropwise addition of benzyl 3-bromopropyl ether (0.72 ml, 4.1 mmol). The reaction was stirred overnight at 100° C., quenched by pouring over ice, and extracted with ethyl acetate. The organic fractions were washed with water, dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide 0.45 g of 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.17 h

Procedure:
1.58 g of sodium hydride (60% content) was suspended in 19.80 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 19.83 g of a tetrahydrofuran solution containing 2.50 g of 2-nitroaniline was dropwise added over 1 hour, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 2.77 g of benzoyl chloride was added dropwise over 0.5 hr at room temperature and stirred for 2 hours. The reaction mixture was added to water and separated. The separated organic layer was washed with sodium hydroxide solution and saline to obtain an organic layer, which was analyzed by high performance liquid chromatography to find the yield of the desired product was 82%.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:7][CH:8]=[C:9]([C:15](=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18](F)[C:17]=2F)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]1.[H-].[Na+]>CN(C=O)C>[F:22][C:20]1[C:19]([F:23])=[C:18]2[O:1][CH2:2][C:3]3([CH2:6][CH2:5][CH2:4]3)[N:7]3[CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:26])[C:16]([CH:21]=1)=[C:17]23
Reactant: CCOC(=O)C(=CNC1(CO)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC21CCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A solution of ethyl 3-[1-(hydroxymethyl)cyclobutylamino]-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (1.52 g, 4.05 mmol) in DMF (10 mL) was added to an ice-cooled suspension of 60% NaH in oil (356 mg, 8.91 mmol) in DMF (10 mL), under argon atmosphere. The reaction mixture was stirred for 4 hours and poured into ice-water. The product was extracted with AcOEt, dried over MgSO4 and the crude product was purified by column chromatography (Hexane: EtOAc 2:1→AcOEt) to yield the title compound (604 mg, 44%) as a white solid. Mp 255-256° C. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J=7.3 Hz), 1.91-2.07 (2H, m), 2.16-2.22 (2H, m), 2.65-2.76 (2H, m), 4.24 (2H, q, J=7.3 Hz), 4.62 (2H, s), 7.62 (1H, dd, J=10.4, 7.9 Hz), 8.80 (1H, s). ESIMS (+): 336 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)(O)=[O:4].C(Cl)(=O)C([Cl:21])=O>O1CCCC1.CCOCC>[Cl:21][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)=[O:4]
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C

Procedure:
To a suspension of 1.94 g (0.08 mol) of sodium hydride in 100 ml of tetrahydrofuran is added with stirring under argon dropwise a solution of 17 g. (0.08 mol) of 2-(6-carboxyhexyl)cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to given 16.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([OH:28])=O)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([N:31]([CH3:32])[CH3:30])=[O:28])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C(=O)O)n1
Reactant: CNC
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C(=O)N(C)C)n1
Yield: 23.42 %

Procedure:
(S)—N4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylic acid (0.2 g, 0.428 mmol) and dimethylamine hydrochloride (0.029 g, 0.357 mmol). The product was purified by Flash-chromatography. Yield 23.42%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 3.05 (s, 3H), 3.45 (s, 3H), 4.37 (m, 2H), 4.46 (m, 1H), 6.94 (d, 1H), 7.84 (d, 1H), 7.89 (dd, 1H), 7.95 (d, 1H), 8.04 (d, 1H), 8.30 (d, 1H), 8.43 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:49]=[C:40]1[C:41]2[C:42](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43](=[O:44])[N:39]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 85.4 %

Procedure:
In a manner similar to that of Example 17a, by reaction of 600 mg (1.4 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 500 mg (1.7 mmol) of N-(5-bromopentyl)phthalimide and 230 mg (1.66 mmol) of potassium carbonate in 50 ml of acetone. 770 mg of ethyl 4′-[5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentyloxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a beige-colored solid (yield=85%).
Reaction SMILES: Cl[C:2]1[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]1([NH:30][C:31](=[O:34])[NH:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][C:8]=1[Cl:12])[N:11]=[C:2]([N:32]([C:31]([NH:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:34])[NH2:33])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:4]2
Reactant: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: NNC(=O)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nc2cc(Cl)c(Cl)cc2nc1N(N)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,6,7-trichloro-2-(methylsulfonyl)quinoxaline (312 mg, 1.0 mmol) in DMF (10 ml) was added caesium carbonate (489 mg, 1.5 mmol) followed by 4-phenylsemicarbazide (182 mg, 1.2 mmol). The reaction was stirred overnight at room temperature. The product was purified by flash column chromatography using ethyl acetate:hexane 1:1 obtaining the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18](Cl)[C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:23]=4)[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1.[C:37]1([C:43]2[NH:44][CH:45]=[CH:46][N:47]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([N:44]4[CH:45]=[CH:46][N:47]=[C:43]4[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:19]4[S:20][CH:21]=[C:22]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:23]=4)[CH:16]=3)[NH:11][C:10](=[O:31])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(Cl)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(c3nc(-c4ccccc4)cs3)n3ccnc3-c3ccccc3)ccc2[nH]c1=O
Temperature: 60 °C
Yield: 5.1 %

Procedure:
A mixture of intermediate (20) (0.0245 mol), 2-phenyl-1H-imidazole (0.0368 mol) and K2CO3 (0.0735 mol) in acetonitrile (150n) was stirred at 60° C. The solvent was evaporated till dryness. The residue was taken up in DCM and water. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.8 g (5.1%) of ethyl 4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-[(2-phenyl-1H-imidazol-1-yl)(4-phenyl-2-thiazolyl)methyl]-3-quinolinecarboxylate.