Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][C:23](=O)[CH2:24][CH3:25]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH2:23][CH2:24][CH2:25][CH2:22][CH2:23][CH2:24][CH2:25][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: CCC(C)=O
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OC

Procedure:
A mixture of 28.5 g 3-methoxy-4-(hydroxy)benzoic acid methyl ester, 25.94 g Of finely powdered potassium carbonate, 0.070 g potassium iodide and 285 ml of 2-butanone is heated at reflux temperature for 41 hours. The reaction is cooled and filtered. The filtrate is concentrated in vacuo and recrystallized from hexane to give 40.8 g of the desired product as white crystals.
Reaction SMILES: COC(=O)C[O:5][C:6]1[CH:11]=[C:10](OC)[C:9]([S:14][C:15]#[N:16])=[CH:8][C:7]=1[CH3:17].[CH3:19]OC(=O)COC1C=C(C)C(S)=CC=1C>>[CH3:17][C:7]1[CH:8]=[C:9]([S:14][C:15]#[N:16])[C:10]([CH3:19])=[CH:11][C:6]=1[OH:5]
Reactant: COC(=O)COc1cc(C)c(S)cc1C
Reactant: COC(=O)COc1cc(OC)c(SC#N)cc1C
Product: Cc1cc(SC#N)c(C)cc1O

Procedure:
The title compound was prepared from compound WWA in a manner analogous to compound 1C. 400 MHz 1H NMR (DMSO-d6) δ 7.07 (s, 1H), 6.50 (s, 1H), 4.56 (s, 2H), 3.76 (s, 3H), (s, 1H), 2.26 (s, 3H), 2.17 (s, 3H); MS m/z 252 (m+1). Preparation of (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid methyl ester (Compound WW)
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:24]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-{5-chloro-6-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D86, 140 mg, 0.34 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature under argon for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate (×3). The combined extract was dried (MgSO4) and concentrated under vacuum to leave the title compound as a red oil (94 mg, 83%). M++H=310.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[C:5]([Cl:11])=[CH:4][C:3]=1[OH:12].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:11][C:5]1[C:6]([CH:8]2[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([OH:12])[CH:4]=1
Reactant: Nc1cc(C2CC2)c(Cl)cc1O
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(C2CC2)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of 2-amino-5-chloro-4-cyclopropylphenol (200 mg, 1.01 mmol) in MeOH (20 mL) at RT, AcOH (3 drops) and ethyl glyoxalate (416 mg, 2.02 mmol, 50% in toluene) were added. The mixture was stirred at RT for 2 h and then sodium cyanoborohydride (190 mg, 3.03 mmol) was added to the mixture. The resulting mixture was stirred at 40° C. for 15 h. The mixture was allowed to cool to RT and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (10-20% methanol/dichloromethane) to afford the desired product (290 mg, 100% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 6.66 (s, 1H), 5.93 (s, 1H), 5.07 (t, J=6.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.91 (d, J=6.4 Hz, 2H), 1.92-1.97 (m, 1H), 1.20 (t, J=6.8 Hz, 2H), 0.84-0.87 (m, 2H), 0.51-0.55 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCOCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 237A (0.082 g, 0.19 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.140 mL, 0.28 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and , and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethaneto give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 1 H) 1.24 (m, 2 H) 1.48 (m, 2 H) 3.20 (m, J=18.02, 10.66 Hz, 2 H) 3.81 (m, 2 H) 5.82 (d, J=4.04 Hz, 1 H) 7.04 (m, J=7.72 Hz, 1 H) 7.27 (m, J=8.46, 8.46 Hz, 2 H) 7.52 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 8.04 (d, J=1.47 Hz, 1 H). MS (ESI−) m/z 439 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18].C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:18]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of 4.0 g of ethyl 4-chloroquinolin-3-carboxylate, 2.04 g of 2-hydrazinopyridine and 50 ml of eutectic diphenyl ether-biphenyl is stirred at 110°-130° for 3 hours under nitrogen. After cooling to room temperature it is diluted with diethyl ether, filtered, the solids washed with diethyl ether and dissolved in 100 ml of aqueous sodium hydroxide. The solution is washed with diethyl ether and the pH thereof adjusted to 8.5 by addition of ammonium chloride. The precipitate formed is collected, washed successively with water, methanol and diethyl ether, to yield the 2-(2-pyridyl)-pyrazolo[4,3-c]quinolin-3(5H)-one showing in the IR-spectrum peaks at 887, 865, 853, 788, 780, 765, 756, 737 and 726 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[NH:23])[N:20]([OH:22])[CH3:21])[C:3]=1[S:24]([C:26]([F:29])([F:28])[F:27])=[O:25].[CH2:30]=O>C(#N)C.C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]2[N:20]([CH3:21])[O:22][CH2:30][N:23]=2)[C:3]=1[S:24]([C:26]([F:28])([F:29])[F:27])=[O:25]
Reactant: C=O
Reactant: CN(O)C(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1OCN=C1c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(N-hydroxy-N-methylamidino)-4-trifluoromethylsulfinylpyrazole(1.00 g, 2.07 mmol) was dissolved in 10 ml of acetonitrile, and then aqueous 37% formaldehyde solution 840 mg (10.3 mmol) and 5 drops of acetic acid were added. After the mixture was stirred at 50° C. for 5 hours, aqueous 37% formaldehyde solution 840 mg (10.3 mmol) and, 5 drops of acetic acid were further added, followed by stirring at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo and to the residual oil was added ethyl acetate, and then washed twice with an aqueous saturated sodium hydrogencarbonate solution, once with an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting concentrated residue was purified by silica gel column chromatography [eluent: mixed solvent of ethyl acetate and n-hexane (volume ratio=1:2)] to obtain 260 mg (0.52 mmol) of the title compound as a colorless crystal. Yield 25%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25]>O1CCCC1.O>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(C(O)c2cc(C)c(C)o2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
2-Bromo-4-picoline (1.5 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M hexane solution (5.6 ml) of n-butyllithium was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanol (904 mg, yield 47%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9](=[N:15]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[C:9]([CH2:8][C:7]1[C:6]([CH3:17])=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][C:11]=1[C:10]([OH:14])=[O:25])#[N:15]
Reactant: COc1ccc2c(c1C)CC(=NO)C2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(CC#N)c1C
Temperature: 50 °C

Procedure:
To a solution of 8% 21 mL NaOH was added 5-Methoxy-4-methyl-indan-1,2-dione-2-oxime (2.2 g). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (2.77 g) was added in portions to the mixture. The mixture was heated at 80° C. for another 15 min. After cooled to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and precipitate was formed. The precipitate was washed with water and dried for the next reaction.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([O:15]C)=[O:14])=[C:7]([NH:17][C:18]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[O:19])[CH:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[C:7]([NH:17][C:18]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])=[O:19])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C=Cc1ccc(NC(C)=O)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(C=CC(=O)O)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Reaction time: 15 h
Yield: 12.6 %

Procedure:
0.65 g (1.4 mmol) of methyl 3-{4-acetylamino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate was dissolved in 8 ml of tetrahydrofuran, and 8 ml of H2O and 0.17 g (7.2 mmol) of lithium hydroxide were added. After 15 hours at room temperature, the mixture was made acid with 2 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, concentrated and stirred up with diethyl ether. The resulting precipitate was filtered off with suction and yielded 77 mg (13%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH:11]([C:16]([F:19])([F:18])[F:17])[C:12](=[O:15])[CH2:13]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>CCOCC>[N:21]([CH2:13][C:12](=[O:15])[CH:11]([C:16]([F:19])([F:18])[F:17])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])=[N+:22]=[N-:23]
Reactant: O=C(CC(C(=O)CBr)C(F)(F)F)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)C(CC(=O)OCc1ccccc1)C(F)(F)F
Yield: 81.2 %

Procedure:
Stir a mixture of 290 mg (0.82 mmol) of the bromo-ketoester of Example 5, 91 mg (1.4 mmol) of NaN3, and 4 ml of dry DMF at 25° C. for 1 hour. Dilute the mixture with ether, wash several times with water and then brine, dry over MgSO4, and remove the solvent in vacuo to give 210 mg of the desired azide (VII, R=CF3, R1,R2 =H, R3 =C6H5CH2) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5](=[O:12])[C:6]2=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a stirred solution of 5-fluoroisatin (6.00 g, 36.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (1.60 g, 40.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h followed by the addition of bromodiphenylmethane (10.0 g, 38.0 mmol). The mixture was stirred at 60° C. for 7 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness, the residue was recrystallized from ethyl acetate and hexanes to give 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione (6.30 g, 52%): 1H NMR (300 MHz, CDCl3) δ7.39-7.27 (m, 11H), 7.04-6.97 (m, 2H), 6.46-6.42 (m, 1H); MS (ES+) m/z 354.2 (M+23).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.[CH:47]1([S:50](Cl)(=[O:52])=[O:51])[CH2:49][CH2:48]1>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][S:50]([CH:47]4[CH2:49][CH2:48]4)(=[O:52])=[O:51])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2nc3cc(NS(=O)(=O)C4CC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Yield: 75.9 %

Procedure:
To a stirred solution of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.100 g, 0.254 mmol) in pyridine (1.5 mL) was added dropwise cyclopropanesulfonyl chloride (71.0 mg, 0.510 mmol) at 0° C. The reaction mixture was slowly warmed to 23° C., and maintained at this temperature for 42 h. The reaction was quenched with sat. aq. sodium bicarbonate (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-55% EtOAc/hexanes) to yield the titled compound (96.0 mg, 76%), which was recovered as a 5:4 mixture of regioisomers. MS (ESI/CI): mass calcd. for C20H24ClN5O6S, 497.1; m/z found, 498.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 6.73 (s, 1H), 6.14 (s, 2H), 4.31-4.28 (m, 2H), 3.71-3.64 (m, 2H), 3.51-3.45 (m, 2H), 3.32 (s, 3H), 2.54-2.44 (m, 1H), 1.43-1.35 (m, 3H), 1.21-1.11 (m, 2H), 1.00-0.92 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]2)=[CH:6][C:5]=1[F:21])([OH:3])=[O:2].N1C=CC=CC=1.S(Cl)(Cl)=O.O[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>C(OCC)C>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([O:2][C:1]([C:4]2[CH:9]=[CH:8][C:7]([B:10]3[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][O:11]3)=[CH:6][C:5]=2[F:21])=[O:3])=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: CCCCCC1COB(c2ccc(C(=O)O)c(F)c2)OC1
Reactant: N#Cc1ccc(O)cc1F
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCCCCC1COB(c2ccc(C(=O)Oc3ccc(C#N)c(F)c3)c(F)c2)OC1
Reaction time: 1 h

Procedure:
A mixture comprising 0.004 mole of 2-(4-carboxy-3-flurophenyl)-5-pentyl-1,3,2-dioxaborinane, 0.32 ml of pyridine, 0.32 ml of thionyl chloride in 50 ml of anhydrous diethyl ether is stirred for 1 hour. Then 0.004 mole of 4-hydroxy-2-fluorobenzonitrile and 1 ml of pyridine are added. The mixture is allowed to stand overnight and then filtered. The residue obtained after distilling off the solvent is crystallized from a mixture of hexane and ethyl alcohol. The yield of the compound (VIs) is 60%. M.p. 63° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])[NH2:23])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:36][C:37]([O:39]CC)=[O:38])=[O:5])[CH3:2].[OH-].[Na+].CCO>O>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[C:21]([C:22](=[O:24])[NH2:23])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ncccc3C(N)=O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(F)(F)F)cc2)c2ccc(Oc3ncccc3C(N)=O)cc12
Temperature: 55 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(3-carbamoylpyridin-2-yl-oxy)-2-ethoxycarbonylmethyl-1-(4-trifluoromethoxy-phenyl)indole-3-carboxylic acid ethyl ester (86 mg, 0.15 mmol, see step (a) above), NaOH (aq, 1M, 0.45 mL), EtOH (1 mL) and H2O (1 mL) was stirred at 55° C. for 3 h, cooled, filtered through Celite® and acidified to pH 4 with HCl (aq, 2M). The solid was filtered off, washed with H2O and purified by chromatography and recrystallisation from EtOAc. Yield 36 mg (46%), mp 128-130° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C(OC(=O)C)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COc1cnnc(Cl)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnnc(-c2ccc(F)c(Cl)c2)c1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
3-Chloro-5-methoxy-pyridazine (Bryant, R. D.; Kunng, F. -A.; South, M. S. J. Heterocycl. Chem. (1995), 32(5), 1473-6.) (300 mg, 2.08 mmol), 3-chloro-4-fluorophenylboronic acid (724 mg, 4.15 mmol), Cs2CO3 (2 g, 6.2 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (96.7 mg, 0.093 mmol) were mixed and a solution of tri-tert-butylphosphine (45.4 mg, 0.22 mmol) in degassed dioxane (6 ml) was added. The mixture was heated at 90° C. for 22 hours then cooled to room temperature, ethylacetate was added, the solid was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (hexane-ethyl acetate 4:1) to provide 3-(3-chloro-4-fluoro-phenyl)-5-methoxy-pyridazine (330 mg, 67%) as an orange solid, MS: m/e=239.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[CH:12][CH:13]=1.[OH-].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
To a stirred solution of 66.32A (1.00 g, 3.5 mmol) in THF (70.0 mL) and MeOH (70.0 mL) at 0° C. was slowly added potassium hydroxide (1.9 mL, 3.8 mmol) to maintain the temperature below 6° C. The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then concentrated in vacuo, acidified with 1N HCl, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and to give a white solid 66.32B (0.90 g, 95% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example A7, 15.69 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-[-1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and 1.4 l of a saturated solution of ammonia in methanol yield the title compound.