Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1[N:18]([C:19]2[S:20][C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:22][C:23]=2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:17]([CH3:38])=[N:16][N:15]=1>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([C:23]1[CH:22]=[C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[S:20][C:19]=1[N:18]1[C:17]([CH3:38])=[N:16][N:15]=[C:14]1[CH2:13][NH:12][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:32]
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1

Procedure:
3,4-Dichlorobenzoyl chloride and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3,4-dichlorobenzoylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>P(=O)(O)(O)O>[C:11]([C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: c1csc(-c2cccs2)c1
Agent: O=P(O)(O)O
Product: CC(=O)c1ccc(-c2cccs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.40 g of 2,2'-bithiophene was dissolved in 8 ml of acetic anhydride and refluxed under nitrogen gas atmosphere. 6 drops of phosphoric acid (85%) was added and reacted for 5 hours. The reaction mixture was poured onto 200 g of crushed ice cubes and stirred for 1 h. The solid deposited was collected and vacuum distilled, 5-acetyl-2,2'-bithiophene 1.98 g was obtained at 148° C./0.8 mm-Hg and the melting point was 112°-113° C. The residue was recrystallized from dioxane and 0.25 g of 5,5'-diacetyl-2,2'-bithiophene with melting point of 236°-9° C. was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[CH2:13]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1
Reactant: CCCCc1ccc(C=O)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1ccc(CNCCCCCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-heptanoic acid methyl ester hydrochloride, prepared of Preparation 1, (1.12 g, 5.9 mmol), 4-butyl-benzaldehyde (0.915 g, 5.65 mmol) and triethylamine (0.83 mL, 5.98 mmol) in 20 mL MeOH was stirred at room temperature for 3 hours. After cooling to 0° C., NaBH4 (0.342 g, 9.04 mmol) was added and the reaction was stirred for 15 minutes at room temperature. The mixture was quenched with 1:1 NaHCO3:H2O and the MeOH was removed in vacuo. The resulting residue was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step A (1.4 g). 1H NMR (400 MHz, CDCl3) δ 7.08-7.38 (m, 4H), 3.62 (s, 2H), 3.29 (s, 3H), 2.52-2.66 (m, 4H), 2.25 (t, 2H), 1.53-1.63 (m, 6H), 1.25-1.40 (m, 6H), 0.85 (t, 3H); MS 306 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([OH:29])=[O:28])=[CH:5][CH:4]=1)#[N:2].[CH:30]1N=[CH:33][N:32]([C:35](N2C=NC=C2)=O)[CH:31]=1.CN(C)CCO.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[C:11]([CH3:26])=[C:10]2[C:27]([O:29][CH2:30][CH2:31][N:32]([CH3:35])[CH3:33])=[O:28])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)CCO
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)CC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg (0.1 mmol) of the compound of Example 47 in 0.3 ml dry dimethylformamide are added 48.6 mg (0.3 mmol) N,N-carbonyldiimidazole. After allowing the reaction mixture to stand for one hour, the reaction mixture is diluted with water and extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is evaporated off in vacuo. To the residue are added 0.5 ml (443 mg, 4.98 mmol) 2-(dimethylamino)ethanol and 10 μl (0.07 mmol) triethylamine. The reaction mixture is stirred at 100° C. for one hour. Then the reaction mixture is filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][C:21]([NH2:23])=[O:22].O>CN(C=O)C>[O:13]=[C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[O:7][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Potassium carbonate (2.67 g, 19.31 mmol) was added to a solution of N-hydroxyphthalimide (3.0 g, 18.39 mmol) in anhydrous DMF (37 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. The reaction mixture was cooled to 0° C. and 2-bromoacetamide (2.79 g, 20.23 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature overnight. The reaction mixture was poured into rapidly stirring water and the precipitated solid was collected by filtration and dried to afford 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetamide (2.0 g, 49%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 7.85-7.88 (4H, m); ESI MS m/z 221 [C10H8N2O4+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:12]2[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCC1CCC(c2ccccc2-c2cccc(OC(=O)CC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Under a nitrogen atmosphere, 1.6 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)phenyl)phenol (1) dissolved in 10 mL (mili-litter) of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.42 g of 3-((4-propylcyclohexyl)phenyl)phenyl propanoate (2).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:27][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 mg (0.275 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide (Example 73A) were reacted according to the General Method 1. Yield: 63.9 mg (48% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].C(OC(C)C)(C)C>O1CCCC1.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: Cc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 81.1 %

Procedure:
To a solution of 4-methyl-1,2-phenylenediamine (1) (25 g) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1′-carbonyldiimidazole (36.5 g) in dichloromethane (375 mL). After stirring at room temperature for 6.5 hr, diisopropylether (375 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration. The precipitate was washed with diisopropyl ether, and dried under reduced pressure to give 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.6 g).
Reaction SMILES: CO.C[O-].[Na+].[O:6]1CCC[CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>O>[CH3:7][O:6][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: Clc1ccc(Cl)nn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 7.4 mL, 3.69 mmol) was slowly added to an anhydrous tetrahydrofuran (12 mL) solution having 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) dissolved therein, stirred at room temperature for one hour, followed by adding water. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-methoxy-6-chloropyridazine (108a, 436 mg, 90%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10]S(C=CC2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[NH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:27].[Na+].[CH3:29][C:30]([CH3:32])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:29]=[CH:30][C:32]2[CH:25]=[CH:26][C:4]([N+:1]([O-:2])=[O:27])=[CH:5][CH:6]=2)=[NH:9])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: N=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [OH-]
Reactant: CC(C)=O
Agent: [Na+]
Product: N=C(NC=Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Yield: 68 %

Procedure:
A solution of 4-nitro-N-(4-nitrostyrylsulfonyl)benzamidine (15.0 g., 0.04 mole) and 100 ml. of 2 N sodium hydroxide in 200 ml. of acetone is stirred for 25° C. for a period of 1 hr. Acetone is removed under reduced pressure, the mixture filtered and the filter cake washed with water and dried affording 8.4 g. (68% yield) of 4-nitro-N-(4-nitrostyryl)benzamidine free base, m.p. 214°-216° C. 4-Nitro-N-(4-nitrostyryl)benzamidine hydrochloride obtained in the usual manner has a melting point of 243°-244° C. (dec.). The free base taken up in methanol and acidified with isethionic acid provides 4-NITRO-N-(4-NITROSTYRYL)BENZAMIDINE ISETHIONATE, m.p. 206.5°-208° C., (corr.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:5]2=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: COc1ccccc1-c1n[nH]c2nc(Cl)ncc12
Reactant: Nc1ccccc1
Product: COc1ccccc1-c1n[nH]c2nc(Nc3ccccc3)ncc12
Yield: 69 %

Procedure:
The compound was prepared from 6-chloro-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 6) and aniline (Aldrich) in an analogous manner as described in Example 32 (175° C.) and the title compound was obtained in 69% yield. MS (M+H)+, 318.2.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[C:14](OCC)(=O)C.[CH3:20][S:21]([O:24]C)(=[O:23])=[O:22]>C(O)C>[CH3:20][S:21]([O-:24])(=[O:23])=[O:22].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CCOC(C)=O
Reactant: COS(C)(=O)=O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CCO
Product: CO[Si](CCC[N+](C)(C)C)(OC)OC
Product: CS(=O)(=O)[O-]

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 24 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 3.0 g of methyl methanesulfonate was dissolved in 26 g of ethanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, ethanol was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and methyl methanesulfonate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in ethanol to obtain a 38.1% ethanol solution of trimethoxysilylpropyltrimethylammonium methanesulfonate.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].N1C=CC=CC=1.Cl[C:16]([O:18][CH:19]=[CH2:20])=[O:17]>O1CCCC1>[CH:19]([O:18][C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:17])=[CH2:20]
Reactant: O=C1CCC(=O)N1O
Reactant: C=COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=COC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 10.0 (87.0 mmol) of N-hydroxy succinimide, 6.9 g (87.0 mmol) of pyridine, and 100 mL tetrahydrofuran was added. To the reaction mixture 9.25 g (87.0 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl, and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting liquid chromatographed (silica gel, chloroform) to yield 10.0 g (54.0 mmol, 62.1% yield) of an oil. FTIR (neat, capillary) 3516.50, 3132.04, 3099.40, 3003.94, 2960.21, 1830.80, 1823.25, 1792.36, 1734.05, 1671.98, 1653.62, 1646.30, 1429.97, 1380.77, 1368.60, 1306.35, 1260.89, 1241.83, 1201.12, 1162.09, 1154.49, 1134.29, 1087.59, 1049.93, 1005.21, 990.18, 948.77, 941.86, 908.06, 897.29, 892.42, 812.37, 769.04, 756.85, 724.90, 707 81. NMR (CDCl3) 6.73-7.09 (1H,q), 4.61-5.24 (2H,m), 2.78 (4H,S). ##STR16##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:16]
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(C#N)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a suspension of 4-chloro-6-(methyloxy)-3-quinolinecarboxamide (0.92 g, 3.9 mmol) in CH2Cl2 (8 mL) and Et3N (4 mL) at 0° C. was added TFAA (2.0 mL, 14 mmol) over 5 min. The reaction was warmed to rt and then stirred at this temperature for 2 h (complete by LCMS). The reaction solution was partitioned between water and CH2Cl2 and the organic phase was collected. The aqueous phase was further extracted with CH2Cl2. The organic layers were combined and washed with brine and dried over MgSO4. The solution was filtered and the solvent was removed in vacuo. The resulting material was redissolved in EtOAc and the product was precipitated via the addition of hexane. The solid material was collected by filtration and washed with cold hexanes and water to remove remaining Et3N. Isolated 580 mg (65%) of pure product as an off-white solid: LC/MS (ES) m/e 219 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:38]([C:35]1[CH:34]=[CH:33][C:32]([S:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]2[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:22][CH2:23][CH2:24][CH2:25][N:26]=3)=[CH:15][CH:16]=2)=[O:11])[C:6]([OH:42])=[O:5])(=[O:31])=[O:30])=[CH:37][CH:36]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)s2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
0.27 g (0.43 mmol) of the compound obtained in step b) were dissolved in dichloromethane (1 ml). Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred for 2 h at room temperature. After evaporation of the solvents lyophilization gave the title compound (0.25 g, 86%) as a white amorphous solid.
Reaction SMILES: [SH:1][CH2:2][C:3](OCC)=[O:4].[H-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1Br>CN(C=O)C.CCOC(C)=O>[O:4]=[C:3]1[CH2:2][S:1][C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]=2[NH:10]1
Reactant: CCOC(=O)CS
Reactant: COC(=O)c1ccc(Br)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-mercaptoacetate (1.473 ml) in DMF (48 ml) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was diluted with EtOAc (1 litre), washed with water (3×300 ml), dried and evaporated to about 10 ml. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>C1COCC1>[OH:34][CH2:33][C:32]([NH:31][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)([CH3:37])[CH2:35][OH:36]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: CC(N)(CO)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 72 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (105 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-25% EtOAc/CH2Cl2 Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 160-162°, LC MS m/z=453 (MH+) Retention time=1.75 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[OH:16].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[O:16][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: C1=COCCC1
Reactant: CC(C)(C)C(=O)Nc1cc(O)c(F)cc1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)cc1F
Temperature: 25 °C
Reaction time: 4.3 h
Yield: 85 %

Procedure:
2.15 g (9.39 mmol) of the resulting 2,4-difluoro-5-pivaloylaminophenol was dissolved in 40 ml of dichloromethane, 4.3 ml of 3,4-dihydro-2H-pyrane and 44 mg of camphorsulfonic acid were added and the mixture was stirred at room temperature for 4.3 hours. The reaction solution was added to a 5% aqueous solution of potassium carbonate and the mixture was extracted with chloroform. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent Was distilled off under reduced pressure and the residue was triturated with n-hexane to give 2.51 g (85%) of 2,4-difluoro-5-pivaloylamino-O-(2-tetrahydropyranyl)phenol.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1.OO.C(O)(=[O:33])C>>[CH3:1][S:2]([CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)=[O:33]
Reactant: CC(=O)O
Reactant: CSCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: OO
Product: CS(=O)Cc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 63 from 4'-[(2-methylthiomethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and hydrogen peroxide/acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1C
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 321.6 mg.