Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.Cl[CH2:20][CH2:21]Cl.OS(O)(=O)=O>C(O)C>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH2:6][CH2:5]2
Reactant: ClCCCl
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A mixture of 25.0 g. of (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, 100 ml. of 1,2-dichloroethane, 17.5 ml. of ethanol and 1.0 ml. of concentrated H2SO4 was heated at reflux under N2 for 20 hours. The dark mixture was washed with H2O, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and stripped of solvent to give a light yellow solid. Crystallization from ether gave (±)-ethyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate, m.p. 124°-126°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O1CCOCC1.[ClH:37]>CCOCC>[ClH:37].[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A suspension of ethyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (400 mg, 0.963 mmol) in 4 N HCl in dioxane (9.63 mL, 38.5 mmol) was heated to 60° C. for 5 min, then cooled to rt and diluted with 40 mL ether. Filtration through a teflon membrane filter gave the title compound as a yellow solid (310 mg, 91.5% yield). 1H-NMR (DMSO-d6) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.96 to 7.03 (m, 2H), 4.13 (q, J=8 Hz, 2H), 1.15 (t, J=8 Hz, 3H); MS [M+H]+=316.1; LCMS RT=2.39.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=O)[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:18][CH3:19].[CH2:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])C>CO.O.C(OCC)C>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=[C:24]([CH2:23][O:22][CH3:20])[C:25]#[N:26])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:18][CH3:19]
Reactant: CCOCCC#N
Reactant: COc1cc(C=O)c2c(c1OC)OCC=C2
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Yield: 73.6 %

Procedure:
A mixture of sodium methoxide (7.02 g, 0.13 mole), 7,8-dimethoxy-5-formyl-2H-1-benzopyran (57 g, 0.26 mole) and 3-ethoxypropanenitrile (28.35 g, 0.286 mole) in methanol (150 mL) was heated at reflux for 4 hr, allowed to cool and diluted with water (150 mL) and ethylether (500 mL). The layers were separated and the ether portion was washed with water (3×250 mL and 1×100 mL) and dried over magnesium sulfate. The ether solution was concentrated to give 55 g (73%) of an amber oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:17])=[N:14][CH:15]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])=[N:14][CH:15]=1
Reactant: CCOC(=O)COCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCOCC(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.1 %

Procedure:
To a mixed solution of ethyl [[[[5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methoxy]acetate (167 mg, 0.311 mmol) in tetrahydrofuran (6 ml) and water (3 ml), lithium hydroxide monohydrate (16 mg, 0.373 mmol) was added, and the mixture was stirred for 20 hours at room temperature. 1 N hydrochloric acid (0.5 ml) and water were added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:10) was concentrated under reduced pressure. A mixed solution of ethyl acetate-hexane was added to the resulting concentration residue, and then the residue was collected by filtration to obtain the title compound (38 mg, 0.075 mmol, 24%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=O)[CH3:2].[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: CC(C)(C)NO
Product: CCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1OCC

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-diethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 93.7% yield as a solid. m.p. 57.9° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](=[CH:28]/[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])/[C:26]#[N:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCCl>[C:1]([O:5][C:6]([CH:7]1[CH:28]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)([C:26]#[N:27])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1C(C(=O)OC(C)(C)C)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 31.2 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 32a (2.6 g, 11 mmol) was reacted with (Z)-2-(4-chloro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2 g, 7.9 mmol) prepared in Example 32b, AgF (1.3 g, 10 mmol), and triethylamine (2.2 g, 22 mmol) in 1,2-dichloroethane (100 mL) at room temperature for 24 h to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 31%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])=[CH:22][CH:21]=1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(Cl)cc2)c2ccccc2)c1
Yield: 32.9 %

Procedure:
The procedure is analogous to that described in Example 1, but 2.2 g of 2-(2-amino-N-phenylacetamido)-N-(4-chlorophenyl)-N-methylacetamide and 0.87 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 60 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride/methanol (99-1 by volume)], collecting 20 cm3 fractions. Fractions 30 to 43 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 1.0 g of N-(4-chlorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 160° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C#N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc(C#N)c(C)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
5-Bromo-3-methylpicolinonitrile (50, 35 g, 0.18 mol) was added to a solution of sodium methoxide (18 g, 0.54 mol) in methanol (200 mL), and the mixture was heated at reflux for 12 h. The solution was cooled to room temperature and concentrated to one third of its volume. The concentrated solution was diluted with water (150 mL), and the products were extracted with chloroform (3×50 mL). The combined extracts were washed with water (2×50 mL), brine (50 mL), dried with sodium sulfate and filtered through a pad of silica gel, washing with chloroform, to produce 51 as an off-white solid (21 g, 79%): mp 80-81° C. IR (film) 2225, 1645, 1589 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=2.6 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 3.83 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.65, 139.99, 137.68, 125.05, 120.52, 116.76, 55.84, 18.71; EIMS m/z (rel intensity): 148 (M+, 100); CIMS m/z (rel intensity): 149 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:16]([C:17](O)=[O:18])[C:15]([CH3:21])([CH3:20])[S:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.[NH2:34][OH:35].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1.O>[OH:35][NH:34][C:17]([C@H:16]1[C:15]([CH3:21])([CH3:20])[S:14][CH2:13][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:18]
Reactant: COc1ccc(S(=O)(=O)N2CSC(C)(C)[C@@H]2C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CSC(C)(C)[C@@H]2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[4-Methoxybenzenesulfonyl]-5,5-dimethylthiazolidine-4(S)-carboxylic acid (2.0 g, 6.0 mmol) is dissolved in methylene chloride (30.0 mL). To this solution is added oxalyl chloride (1.1 mL, 12.1 mmol) and dimethylformamide (0.50 mL, 6.0 mmol), and the reaction is stirred at room temperature for 2 hours. Meanwhile, in a separate flask, hydroxylamine hydrochloride (1.74 g, 25.0 mmol) and triethylamine (5.0 mL, 36.0 mmol) are stirred in tetrahydrofuran (25.0 mL) and water (2.0 mL) at 0° C. for 15 minutes. After 2 hours, the methylene chloride solution is added in one portion to the second flask, and the combined contents are stirred overnight as the flask gradually warms up to room temperature. The reaction is then diluted with acidic water (pH=~3), and extracted several times with ethyl acetate. The combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (60% ethyl acetate/hexane) to give N-hydroxy-3-[4-methoxybenzenesulfonyl]-5,5-dimethylthiazolidine-4(S)-carboxamide, m.p. 68°-71° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18](I)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:30]#[N:31])=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A solution of N-benzyl-2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (386 mg, 0.716 mmol), Pd2 dba3 (40 mg, 0.043 mmol) and dppf (80 mg, 0.14 mmol) in DMF (6 mL) was degassed with argon before being charged with Zn(CN)2 (100 mg, 0.555 mmol). The mixture was stirred at 70° C. for 20 h. DMF was removed in vacuo. The residue was purified by HPLC to give 4-(benzylamino)-2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg).
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC>[CH2:1]([O:8][CH:9]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: O=CCC(OCc1ccccc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-dibenzyloxypropionate (9, 15 g, 0.0477 mole) and ether (300 mL). The solution was cooled to -78° C. under a dry argon atmosphere and diisobutylaluminum hydride (47.7 mL of 1M solution in hexanes, 0.0477 mole) was added dropwise. The mixture was stirred for 0.5 h at -78° C. followed by quench with methanol (20 mL). The mixture was allowed to warm to 0° C. and washed 2 times with 5% HCl solution (2 @ 250 mL), brine (200 mL) and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 3,3-dibenzyloxypropanal as a colorless oil (12.1 g, 94% yield): 1H NMR d 2.83 (dd, 2H, J=2, 5.3 Hz), 4.61 (d, 2H, J=11.6 Hz), 4.69 (d, 2H, J=11.6 Hz), 5.20 (t, 1H, J=5.5 Hz), 7.27-7.36 (m, 10H), 9.74 (s, 1H); IR (Neat) 3100, 3080, 3045, 2940, 2895, 1735, 1500, 1460, 1390, 1360, 1210, 1110, 1060, 1030, 740, 700. ##STR9##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:8]([F:20])([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][OH:18]
Reactant: OCc1cc(F)ccc1OC(F)(F)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCc1cc(F)ccc1OC(F)(F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 85 %

Procedure:
473 mg (1.36 mmol) of {2-[(4-bromophenyl)(difluoro)methoxy]-5-fluorophenyl}methanol from Example 39A are dissolved in 8 ml of 1,2-dimethoxyethane and, under argon, 362.6 mg (1.91 mmol) of 4-trifluoromethylphenylboronic acid, 67 mg of bis(triphenylphosphine)-palladium(II) chloride and 1.5 ml of a 2 M solution of sodium carbonate in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 5 g of Celite, washed with dichloromethane and concentrated. The resulting crude product is purified by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 532 mg (1.29 mmol, 90% purity, 85% yield) of a colorless oil are obtained.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.[CH3:9][Sn:10]([CH3:25])([CH3:24])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([O:20]C)=[C:13]([O:22][CH3:23])[CH:12]=1>C1COCC1.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>[CH3:9][Sn:10]([CH3:25])([CH3:24])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]2[O:20][CH2:23][O:22][C:13]=2[CH:12]=1
Reactant: COc1cc([N+](=O)[O-])c([Sn](C)(C)C)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of hexamethylditin (1 g, 3.1 mmol), compound 16 (0.7 g, 2.9 mmol) and tetrakis(triphenylphosphine)palladium (100 mg) in anhydrous THF (20 ml) was heated to reflux under nitrogen for 10 h. After cooling to room temperature, THF was evaporated and methylene chloride (30 mL) was added to the residue. To this mixture, aqueous potassium fluoride (7.0M, 1 mL) was added dropwise with vigorous stirring. The mixture was passed through a Celite bed and the filtrate was washed with brine. The methylene chloride layer was dried (anhydrous Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed using 95:5 hexanes:ethyl acetate to give 62 (0.5 g) in 54% yield; 1H NMR (CDCl3) δ0.32 (9H, s), 6.12 (2H, s), 7.04 (1H, s), 7.82 (1H, s); 13C NMR (CDCl3) δ−6.94, 103.27, 105.82, 114.76, 137.19, 147.90, 149.36, 153.36; HRMS (EI) calcd for C10H13NO4Sn—CH3 m/z: 315.9632; found: 315.9638.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].CCN(C(C)C)C(C)C.C1CN([P+](Cl)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:21]([N:23]([CH2:24][CH3:25])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=1)[CH3:22]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Agent: Cl[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To the solution of 6-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinic acid (0.813 g, 3 mmol) in anhydrous DMF (70 mL) was added diethylamine (3.2 mL, 30 mmol) and DIPEA (1.6 mL, 9 mmol) under N2. The mixture was cooled with ice bath and a coupling agent PyCloP (Aldrich#26564, 1.4 g, 3.3 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature overnight, and then rotary evaporated. The residue was dissolved in EtOAc and washed with water, evaporated and purified by flash column chromatography over silica gel eluted with EtOAc to provide the title amide compound as a white solid (0.92 g, 2.82 mmol, yield 94%).
Reaction SMILES: C1(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3CO)=CC=2)(=O)=O)C=CC=CC=1.[C:29]([C:32]1[O:33][CH:34]=[CH:35][C:36]=1[C:37]1[C:38]([OH:57])=[C:39]([C:44]([CH2:47][S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41])(=[O:31])[CH3:30]>>[C:51]1([S:48]([CH2:47][C:44]2[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([OH:57])[C:37]([C:36]3[CH:35]=[CH:34][O:33][C:32]=3[CH:29]([OH:31])[CH3:30])=[CH:46][CH:45]=2)(=[O:50])=[O:49])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(C)=O)c1O
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2CO)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(C)O)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 19, starting from methyl 3-(2-acetylfuran-3-yl)-6-benzenesulfonylmethyl-2-hydroxybenzoate (Intermediate 32).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[O:18][CH2:19][CH2:20][NH:21]C(OCC2C=CC=CC=2)=O)=[N:4][CH:3]=[N:2]1.C(O)=O>[Pd].CO>[NH:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[O:18][CH2:19][CH2:20][NH2:21])=[N:4][CH:3]=[N:2]1
Reactant: O=C(NCCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NCCOc1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Yield: 15.7 %

Procedure:
N-{2-[3-(5-(1H-1,2,4-triazol-5-yl)(1H-indazol-3-yl))phenoxy]ethyl}(phenylmethoxy)carboxamide (0.056 g, 0.123 mmol) was treated with formic acid (2 mL), methanol (0.088 mL) and 10% palladium on carbon (0.060 g) under nitrogen for 3 h. The mixture was filtered though Celite and concentrated. The residue was taken up in aqueous 6 N hydrochloric acid and extracted with ether (3×). The aqueous layer was adjusted to pH 11 and extracted with dichloromethane. The organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (30–80% acetonitrile/water) and gave the title compound (0.0062 g, 16% yield) as the mono trifluoroacetic acid salt. 1H NMR (CD3OD) δ 8.77 (d, 1H), 8.54 (s, 1H), 8.12 (dd, 1H), 7.73 (m, 1H), 7.70 (m, 1H), 7.65 (m, 1H), 7.54 (t, 1H), 7.13 (m, 1H), 4.38 (t, 2H), 3.44 (t, 2H). ES-MS (m/z) 321 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(Cc1ccccc1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(Cc2ccccc2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1

Procedure:
Using the method described in Example 17 from 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid (Intermediate 30) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-phenyl-propionamide was obtained as a white solid (0.26 g, 34%); ES+-HRMS m/e calcd for C26H25N5O4F2 [M+H+] 510.1948 found 510.1949. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (s, 3H) 1.07 (s, 3H) 3.35-3.56 (m, 2H) 3.91 (s, 2H) 4.67 (s, 1H) 5.81 (dd, J=10.7, 4.9 Hz, 1H) 5.92 (d, J=3.0 Hz, 1H) 6.44 (d, J=2.3 Hz, 1H) 7.10-7.20 (m, 1H) 7.24 (t, J=7.1 Hz, 2H) 7.29 (d, J=7.1 Hz, 2H) 7.32-7.40 (m, 2H) 7.40-7.50 (m, 1H) 7.55 (d, J=2.3 Hz, 1H) 8.24 (d, J=3.0 Hz, 1H) 11.00 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:28])[CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([CH2:12][C:11](=[O:28])[N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:6][CH2:7]3)[N:14]=2)=[O:27])=[CH:21][CH:22]=1
Reactant: C1CCNC1
Reactant: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CBr)CC2)cs1)c1ccc(Cl)cc1
Product: O=C(Nc1nc(CC(=O)N2CCN(C(=O)CN3CCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 55.2, N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide was reacted with pyrrolidine to give 4-chloro-N-(4-{2-oxo-2-[4-(2-pyrrolidin-1-yl-acetyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide. Off-white amorphous solid. MS 476.0 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[C:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: O=C1NCCN1
Product: CC(=O)c1cccc(N2CCNC2=O)c1
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 2-imidazolidinone.