Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[C:14]([CH:23]=[CH2:24])=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:26])([CH3:25])[C:9]2=[O:27])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[CH2:23]([C:14]1[C:13]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[O:11][C:12]=2[CH:17]=[C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=1)[CH3:24]
Reactant: [H][H]
Reactant: C=Cc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Yield: 104 %

Procedure:
To a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 156, 200 mg) in ethanol (20 mL) was added 10% palladium-carbon (water content: ca. 50%, 200 mg), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; chloroform→chloroform/ethyl acetate=10/1) to give N-[5-ethyl-4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (209 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([N:7]([CH3:25])[CH2:8][CH2:9][NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:17]3C=[CH:19][C:20](OC)=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1([N:32](C)CCNC(=O)CN2C3C=C(OC)C=CC=3N=C2)CCCCC1>>[CH:1]1([N:7]([CH3:25])[CH2:8][CH2:9][NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:17]3=[N:32][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=[CH:14]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncn(CC(=O)NCCN(C)C3CCCCC3)c2c1
Reactant: COc1ccc2c(c1)ncn2CC(=O)NCCN(C)C1CCCCC1
Product: CN(CCNC(=O)Cn1cnc2cccnc21)C1CCCCC1

Procedure:
N-[2-(Cyclohexyl-methyl-amino)-ethyl]-2-(5-methoxy-benzoimidazol-1-yl)-acetamide (3x1)/N-[2-(Cyclohexyl-methyl-amino)-ethyl]-2-(6-methoxy-benzoimidazol-1-yl)-acetamide (3x2) (ratio 1:1): LC-MS (Method A, retention time=1.478 min. MS calc'd for C19H29N4O2 (MH+): 345.2. Found 345.5.
Reaction SMILES: C([NH:8][C@H:9]([C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)=[O:12])[CH3:10])(OC(C)(C)C)=O.Cl>C(OCC)C>[Cl:38][C:34]1[CH:33]=[C:32]([NH:31][C:29]2[N:28]=[CH:27][N:26]=[C:25]3[NH:24][N:23]=[C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH2:8])=[CH:16][CH:17]=4)[C:30]=23)[CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: Cl
Solvent: CCOCC
Product: C[C@H](N)C(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 100 mg (0.177 mmol) of 3-[4-(N-{N-Boc-L-alanyl}-aminomethyl)-phenylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Example 85) and 4 ml of 3N methanolic hydrochloric acid is stirred at 20° C. for 15 hours and then about 5 ml of diethyl ether are added. Filtration and washing the filter residue with diethyl ether yield 4(3chloro-phenylamino)-3-[4-(N-{L-alanyl)-aminomethyl)-phenylamino]-1H-pyrazolo[3,4-d]-pyrimidine.1.9 hydrochloride having a water content of 6.36%; m.p. 220° C. (decomp.); ESI-MS: (M+H)+=437; [a]D20=−1.4=2.0° (c=0.508%, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[C:18]([CH3:20])[C:19]=1[O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Cc1cc(Cl)c(C)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 130 °C
Yield: 47.5 %

Procedure:
Into a solution containing 9.10 grams (51.1 mmol) of 4-chloro-1-naphthol and 10.12 grams (46.0 mmol) of 3-chloro-2,5-dimethyl-1-nitrobenzene in 22 milliliters of dimethylsulfoxide at room temperature and under a nitrogen atmosphere was added 8.89 grams (64.4 mmol) of anhydrous potassium carbonate. The resulting mixture was heated to a temperature of 130° C. and maintained at that temperature for a period of 6 hours. The reaction mixture was then filtered and the filtrate was diluted with 20 milliliters of methanol and allowed to cool to room temperature. Crystallization occurred during this cooling period. The filtrate was further cooled in an ice bath, filtered and the collected crystals washed with cold methanol. Recrystallization from a hexane-ethyl acetate mixture afforded 7.92 grams of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethyl-1-nitrobenzene as a white solid having a melting point of 135° C.-137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-]>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[CH:1]/[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=3)[N:3]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(/C=C/c2ccc3cc(C(=O)O)ccc3n2)cc1
Yield: 24.8 %

Procedure:
A mixture of 2-methyl-6-quinolinecarboxylic acid (200 mg, 0.936 mmol), 4-methoxybenzaldehyde (228 mg, 0.936 mmol), acetic anhydride (630 mg, 6.18 mmol) and a catalytic amount of zinc chloride was heated at 140° C. for 12 h with stirring. The cooled reaction mixture was extracted with water and ethyl acetate. The organic layer was collected, dried (MgSO4) and the solvent was removed under reduced pressure to give dark brown solid. This material was applied to a silica gel column and the product was eluted with ethyl acetate/n-hexane (1/4). Fractions containing the required product (RF=0.20 ethyl acetate/n-hexane 2/1, fluorescent under UV lamp) were collected and the solvents were removed under reduced pressure. The residue as a yellow solid was triturated with n-hexane and filtered to give the title compound (71 mg, 25%), m.p.=274-277° C. (sublimed around 240° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([NH:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]([CH2:35][CH2:36][OH:37])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N(CCO)Cc2ccccc2)cc1Cl

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(benzylamino)ethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxyethyl)terephthalamide. MS (Q1) 520 (M)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][N:16]=[C:15]([O:20]C)[C:14]=4[C:13]([C:22]4[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1COCC1.Cl>O>[O:20]=[C:15]1[C:14]2[C:13]([C:22]3[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=3)=[N:12][N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:19]=2[CH:18]=[CH:17][NH:16]1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 4-(1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (20.0 mg) obtained in Step B of Example 148 in a mixed solvent of THF (5 mL) and water (0.50 mL) was added 6N hydrochloric acid (0.032 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16.1 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.NN.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][NH:9][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCO1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
2-(tetrahydro-2H-pyran-2-ylmethoxy)-1H-isoindole-1,3(2H)-dione (6.8 mmol, 1.77 g) was combined with hydrazine (6.8 mmol, 0.21 mL) in anhydrous THF (15 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 2 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (6.8 mmol, 1.40 g) and diisopropylethylamine (8.1 mmol, 1.42 mL) was added. After stirring at room temperature for 24 hours, the reaction was concentrated to a yellow solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a yellow solid and purified by silica gel chromatography (2:1 hexanes/ethyl acetate). The purified product was combined with ether and filtered to remove the residual phthalimide-hydrazine biproduct. The final product was crystallized using hexanes and ethyl acetate to provide 141 mg (7%) of white crystals. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.83 (2H,d), 7.05 (1H,s), 6.97 (2H,d), 4.01-3.86 (3H,m), 3.86 (3H,s), 3.63-3.57 (1H,m), 3.42-3.36 (1H,m), 1.88-1.78 (1H,m), 1.59-1.43 (4H,m), 1.3-1.15 (1H,m).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:14]1>O1CCCC1.[Cl-].[Na+].O>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(=S)NC1(c2ccccc2)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Benzoyl isothiocyanate (15 mL, 112 mmol) is added to a 0° C. solution of benzyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (34.7 g, 106 mmol) in tetrahydrofuran (347 mL). The mixture is warmed to room temperature and stirred for 1 hour. Brine (300 mL) is added, the aqueous layer is separated, the organic layer is dried over magnesium sulfate, and concentrated to give the title compound (51 g, 98%). ES/MS (m/e): 390 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.[C:21](OCC)(=[O:23])C.O1CCCC1>C(O)(=O)C>[Cl:1][C:2]1[N:7]2[C:8]([CH:21]=[O:23])=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2nccn12
Reactant: CCOC(C)=O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1cnc2cccc(Cl)n12
Yield: 37 %

Procedure:
A solution of 5-chloroimidazo[1,2-a]pyridine (997 mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) was stirred at 90° C. for 5 hours. After the reaction mixture was allowed to cool, ethyl acetate-tetrahydrofuran (4/1; 200 ml) was added and the mixture was washed with saturated aqueous solution of sodium chloride. The organic layer was neutralized with 2N-aqueous solution of sodium hydroxide, dried over MgSO4, and concentrated. The resulting crystals were rinsed with diethyl ether to provide the title compound (440 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][C:29]([N:24]6[CH:28]=[CH:27][CH:26]=[N:25]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5cccn5)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(1H-pyrazol-1-yl)phenylboronic acid (Combi-Blocks, San Diego, USA, 24 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.79 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.60-8.56 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.99-7.93 (m, 3H), 7.80-7.75 (m, 1H), 7.63-7.56 (m, 3H), 6.59-6.53 (m, 1H), 3.95 (s, 31-1), 3.57 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [K].[C:2]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])([CH3:5])([CH3:4])[CH3:3].Cl[C:13]1[C:18]2[CH:19]=[C:20]([CH3:22])[S:21][C:17]=2[CH:16]=[CH:15][N:14]=1>C(O)(C)(C)C>[C:2]([NH:6][CH2:7][CH:8]([OH:11])[CH2:9][O:10][C:13]1[C:18]2[CH:19]=[C:20]([CH3:22])[S:21][C:17]=2[CH:16]=[CH:15][N:14]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2c(Cl)nccc2s1
Reactant: CC(C)(C)NCC(O)CO
Agent: [K]
Solvent: CC(C)(C)O
Product: Cc1cc2c(OCC(O)CNC(C)(C)C)nccc2s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.49 g of potassium are dissolved with heating in 60 cc of tert.butanol. After cooling, 1.5 g of 1-tert.butylamino-2,3-dihydroxypropane was added and subsequently 1.85 g of 4-chloro-2-methylthieno[3,2-c]pyridine was added. After stirring for one day at room temperature, heating is effected to 50° for a further day. The reaction solution is concentrated in a vacuum, the residue is taken up in 1 N hydrochloric acid and ether, the aqueous phase is neutralized with 2 N soda solution and extracted with methylene chloride. After drying over magnesium sulphate and concentrating, the title compound is obtained as an oil, which yields the hydrogen maleate having an M.P. of 210°-213°, with maleic acid in tetrahydrofuran.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][CH2:17][C:18]([NH:20][CH2:21][C@H:22]([OH:37])[CH2:23][O:24][C:25]1[C:30]([CH3:31])=[CH:29][C:28]([C:32](=[NH:35])[NH:33]O)=[CH:27][C:26]=1[Cl:36])=[O:19]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:33]=[C:32]([C:28]3[CH:29]=[C:30]([CH3:31])[C:25]([O:24][CH2:23][C@@H:22]([OH:37])[CH2:21][NH:20][C:18](=[O:19])[CH2:17][OH:16])=[C:26]([Cl:36])[CH:27]=3)[N:35]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(Cl)c3)no2)cc1C
Yield: 50.7 %

Procedure:
The title compound (31 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (S)-2-hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2-chloro-6-methyl-phenoxy]-propyl)-acetamide (39 mg, 117 μmol) according to Method A; LC-MS: tR=0.53 min; [M+1]+=523.14; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 2.22 (s, 3H), 2.40 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 3.20-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.74 (s, 2H), 3.83 (d, J=5.8 Hz, 2H), 3.86-4.01 (m, 3H), 5.32 (d, J=5.3 Hz, 1H), 5.55 (t, J=6.0 Hz, 1H), 7.70 (t br, J=6.0 Hz, 1H), 7.82 (s, 1H), 7.86-7.89 (m, 1H), 7.89-7.90 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[CH2:30][C:31]#[N:32])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH2:40]([O:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH3:41]>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]([NH:28][C:29](=[O:33])[C:30]([C:31]#[N:32])=[CH:44][C:43]([O:42][CH2:40][CH3:41])([CH3:47])[CH3:46])[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCOC(C)(C)C=O
Reactant: C[C@H](Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(C)(C)C=C(C#N)C(=O)N[C@H](C)Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 85 °C
Yield: 7.7 %

Procedure:
To a sealed tube was added N-[(1R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-ethyl]-2-cyano-acetamide (105 mg, 0.24 mmol), piperidine (0.01 mL, 0.12 mmol), 2-ethoxy-2-methyl-propanal (0.07 mL, 0.47 mmol) and ethanol (4 mL). The tube was capped, and heated to 85° C. for 60 hrs. The reaction was cooled and evaporated. The resulting crude oil was dissolved in DCM (30 mL) and washed with water (30 mL) and brine, then dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (10 g column, 3%-7% MeOH/DCM) to obtain 10 mg (8%) of the title compound. MS (pos. ion) m/z: 544 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:26]=2)[N:21]=1.C(Cl)Cl>CO.C(Cl)Cl>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:24]2[CH:23]=[C:22]3[C:27]([CH:28]=[CH:29][C:20]([O:19][CH3:18])=[N:21]3)=[CH:26][CH:25]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2n1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.305, 1.2 mmol) as in EXAMPLE 24, Part B using 2-methoxyquinoline-7-sulfonyl chloride (0.30 g, 1.16 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. 2-Methoxy-quinoline-7-sulfonic acid {1-[3-cyanobenzyl]-2-oxopyrrolidin-3-(S)-yl}amide is obtained as a solid (0.27 g, 0.62 mmol) upon chromatography (CH2Cl2 to 3% MeOH/CH2Cl2).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.O1CCCC1>CN(C)C1C=CN=CC=1.CCCCCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:26]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: O=C(O)CCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCCCCCCBr)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
A mixture of benzoin (26.15 g), 8-bromooctanoic acid (25.0 g), 4-dimethylaminopyridine (1.35 g), 1,3-dicyclo-hexylcarbodiimide (25.4 g) and dry tetrahydrofuran (350 ml) was stirred under nitrogen at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane (350 ml), washed with 5% aqueous hydrochloric acid (3×175 ml), saturated sodium hydrogen carbonate solution (2×200 ml), saturated sodium chloride solution (220 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chro-matography on silica gel eluted with a hexane: dichloromethane gradient gave a yellow oil. This oil was stirred in hexane to give 2-oxo-1,2- diphenyl-ethyl 8-bromooctanoate (27.1 g, 52.7%) as a pale yellow solid m.p. 60°-61° C.
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:9][CH:8]([CH3:10])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[O:31][C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6]([OH:39])=[O:5]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (S)-3-methyl-2-{4′-[(benzoxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester was added 4 mL of TFA/CH2Cl2 (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 90 mg of (S)-3-methyl-2-{4′-[(benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.6, 6.8 Hz, 6 H) 1.9 (m, 1 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.6 (m, 1 H) 7.6 (m, 1 H) 7.8 (m, 6 H) 8.0 (m, 2 H) 8.1 (m, 3 H) 11.4 (s, 1 H).
Reaction SMILES: O[C:2]1([CH:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>S(Cl)(Cl)=O>[C:2]1(=[C:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCC2)cc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2CCCC2)c2ncc[nH]2)cc1
Yield: 48.2 %

Procedure:
6.9 g of crude 4-[1-hydroxycyclopent-1-yl-1-(imidazolyl)methyl]benzonitrile is refluxed in 82 ml of thionyl chloride to 0.5 hour. Then the mixture is concentrated to dryness under vacuum, combined with 2 N sodium hydroxide solution, extracted with dichloromethane, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus producing 3.1 g of 4-[1-cyclopentylidene-1-(imidazolyl)methyl]benzonitrile as the free base, mp 108°-110°.