Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CCCCC1C=C(/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:38])=[O:37])[CH:30]=[C:31]([S:32]([O-:35])(=[O:34])=[O:33])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:46])=[O:45])C=CC=1)(O)=O.[Na+:70].[Na+].[Na+].B([C:76]1[CH:77]=[C:78]([CH2:82][CH2:83][C:84]([OH:86])=[O:85])[CH:79]=[CH:80][CH:81]=1)(O)O>>[C:84]([CH2:83][CH2:82][C:78]1[CH:77]=[C:76](/[C:14](=[CH:48]\[CH:49]=[C:50]2/[C:51]([CH3:69])([CH3:68])[C:52]3[C:53](=[N:67]/2)[N:54]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:64])=[O:65])[CH:55]=[C:56]([Cl:58])[CH:57]=3)/[CH:15]=[CH:16]/[C:17]2[C:25]([CH3:27])([CH3:26])[C:24]3[C:23]4[CH:28]=[C:29]([S:36]([O-:39])(=[O:37])=[O:38])[CH:30]=[C:31]([S:32]([O-:35])(=[O:33])=[O:34])[C:22]=4[CH:21]=[CH:20][C:19]=3[N+:18]=2[CH2:40][CH2:41][CH2:42][CH2:43][S:44]([O-:47])(=[O:45])=[O:46])[CH:81]=[CH:80][CH:79]=1)([OH:86])=[O:85].[Na+:70].[Na+:70].[Na+:70]
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCC(=O)O)c1

Procedure:
Compound 30 is prepared analogously to compound 28 (Example 37), except that 3-(3-boronophenyl)propionic acid is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([NH2:19])=O)=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]#[N:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2cc(-c3ccccc3)n(Cc3ccc(C(N)=O)o3)c2cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2cc(-c3ccccc3)n(Cc3ccc(C#N)o3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution of 5-(6-chloro-5-methoxy-2-phenylindol-1-ylmethyl)furan-2-carboxamide (194 mg) in dichloromethane (2.5 mL) were successively added triethylamine (0.355 mL) and trifluoroacetic anhydride (0.177 mL) under ice-cooling. This mixture was stirred at room temperature for 8 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (143 mg). 1H-NMR (CDCl3) δ ppm: 3.95 (3H, s), 5.23 (2H, s), 6.00-6.10 (1H, m), 6.50-6.60 (1H, m), 6.98 (1H, d, J=3.6 Hz), 7.16 (1H, s), 7.25-7.35 (1H, m), 7.40-7.55 (5H, m).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12](O)=O)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CO[NH2:18].[Na+].[Cl-].CS(Cl)(=O)=O.Cl.C([O-])([O-])=O.[K+].[K+].[Na].[NH4+].[Cl-]>O.CC(O)(C)C.CCOC(C)=O.CC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]1[CH2:12][NH:18][C:10]1=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a solution of Boc-L-serine (10.3 g, 50 mmol) in 75 mL of H2O:t-BuOH (2:1) is added methoxyamine hydrochloride (23 g, 75 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol). After 2 hours, the solution is saturated with NaCl. The solution is extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is dissolved in 50 mL of pyridine and cooled to 0° C. To the solution is added methane sulfonyl chloride (7.44 g, 65 mmol). After 1 hour, the solution is poured into 100 mL of cold 1 N HCl (aq.). The solution is diluted with EtOAc. The layers are separated and the organic layer is washed with 1 N HCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The resulting crude material is dissolved in 50 mL of acetone and added dropwise to a solution of K2CO3 (20.7 g, 150 mmol) in 900 mL of acetone at reflux. After 1 hour, the solution is cooled to ambient temperatures. The solution is filtered through Celite. The collected organic solution is washed with 1 N HCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The resulting solid is dissolved in 20 mL of THF and added dropwise to an ammonia solution containing sodium (2.6 g, 113 mmol) at -78° C. After the blue color has dissipated, the solution is stirred for an additional 10 minutes. To the reaction mixture is added NH4Cl (13.4 g, 250 mmol) and the solution is allowed to warm to ambient temperatures. The solution is filtered. The collected solution is concentrated. The resulting residue is recrystallized from EtOAc to give the title compound (2 g, 11 mmol) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)=[CH:18][C:17]=1[F:38])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=3)=[CH:28][C:29]=2[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([F:36])[CH:31]=2)=[CH:18][C:17]([F:38])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2ccnc(F)c2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2ccnc(F)c2)cc1F
Reaction time: 0.08 h
Yield: 29 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-2′-fluoro-[4,4′-bipyridin]-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 6.8 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.7 mg (10 mol %) of Pd(PPh3)4, 10 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(C1C=CC=CC=1)(=O)CCCCCCCCCC.S(Cl)([Cl:42])(=O)=O>C(Cl)(Cl)Cl>[Cl:42][C:5]1[C:4]([OH:8])=[C:3]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCC(=O)c1c(O)cccc1O
Reactant: O=S(=O)(Cl)Cl
Agent: CCCCCCCCCCC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(=O)c1c(O)ccc(Cl)c1O

Procedure:
In a 100 ml three-neck flask was placed 50 ml of 2',6'-dihydroxyundecanophenone and after dissolving the undecanophenone in 50 ml of chloroform, the solution thus formed was stirred under ice-cooling. To the solution was added dropwise 10 ml of a chloroform solution of 1.4 ml of sulfuryl chloride over a period of 15 minutes. Thereafter, the mixture was stirred for 2 hours at room temperature and then after adding thereto n-hexane, the mixture was washed twice with water. After drying the reaction mixture with magnesium sulfate, the product was concentrated and the residue thus obtained was recrystallized from methanol to provide the light yellow crystals of 3'-chloro-2',6'-dihydroxyundecanophenone having a melting point of 76°-77° C. The structure was confirmed by carrying out analysis such as mass spectrography and nuclear magnetic resonance spectra.
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][P:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]=2[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[CH2:15][P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: C[SiH](Cl)Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1

Procedure:
409.7 g (0.6 mol) of 2,2'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 1.5 1 of xylene and 715 ml (3.0 mol) of tri-n-butylamine in the absence of air and moisture, and 345.1 g (3.0 mol) of methyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 12 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 200 ml of degassed acetone. 378 g (97%) of colorless crystals of melting point 160° to 161° C. are obtained.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18](O)=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([Cl:25])=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 100 %

Procedure:
The 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (12) (5.582 g, 16.7 mmol) prepared above was refluxed with dimethylformamide (1 drop), thionyl chloride (3.57 ml,50 mmol) and toluene (22 ml) for 1.5 hours. When the solvent was removed under reduced pressure, 5.89 g of the objective compound (6) was obtained.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:29])[CH2:6][N:7]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[CH3:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1.CO.O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH:15]([N:7]([CH2:6][C:5]([OH:29])=[O:4])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:16])=[CH:22][CH:21]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)C(C)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(c1ccc(-c2ccccc2)cc1)N(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
LiOH (140 mg, 3.3 mmol) was added to a stirred solution of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid methyl ester (202 mg, 0.54 mmol) in THF:MeOH:H2O (3:1:1, 10 mL), and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added, the product was acidified with aqueous citric acid solution and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 190 mg (97.9% yield) of [(1-biphenyl-4-yl-ethyl)-tert-butoxycarbonyl-amino]-acetic acid.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:45])([CH2:43][CH3:44])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([NH:41][CH3:42])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C:26]4[CH:30]=[N:31][N:32](COCC[Si](C)(C)C)[C:25]3=4)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:45])([CH2:43][CH3:44])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([NH:41][CH3:42])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C:26]4[CH:30]=[N:31][NH:32][C:25]3=4)=[CH:22][CH:23]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(N3CCCc4cnn(COCC[Si](C)(C)C)c43)cc2)NC)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(N3CCCc4cn[nH]c43)cc2)NC)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-N,N-dimethyl-2-{1-(methylamino)-2-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}-1H-imidazole-1-sulfonamide (1 eq) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was purified by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 407.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:31]=[CH:30][CH:29]=[C:27]([NH2:28])[CH:26]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To the reaction vessel containing methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate (2.0 g, 4.56 mmol, 1 eq), 3-ethynylaniline (0.715 mL, 1.5 eq), and bis(triphenylphosphine)palladium(II) dichloride (320 mg, 0.1 eq) in anhydrous DMF (10 mL) under anhydrous nitrogen atmosphere was added triethylamine (2.54 mL, 4 eq) and copper(I) iodide (173 mg, 0.2 eq). The reaction mixture was stirred at RT for 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was separated, washed with aq NH4Cl (1×) and brine (1×), followed by drying with anhydrous Na2SO4. The upper clear liquid was decanted, concentrated, and the brown oily residue was subject twice to a gradient column chromatography (EtOAc-Hex from 1:3 to MeOH-EtOAc-Hex 1:30:6). Concentration of the product eluting fractions provided the title compound as a white foam (1.32 g, 68%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[S:12]([NH2:22])(=[O:21])([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+]>>[S:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:2][C:3]([NH:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4])=[CH:16][CH:15]=1)(=[O:13])(=[O:21])[NH2:22]
Reactant: O=C(CCl)NC1CCCCC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccc(NCC(=O)NC2CCCCC2)cc1

Procedure:
2-Chloro-N-cyclohexylacetamide (8.7 g) and sulfanilamide (17.2g) were heated for 30 min. at 160°C. The mixture was then added to 2N NaOH and extracted with ethyl acetate to yield 8.2 g, product, m.p. 223° - 225°C
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH:39][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: NCc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
To a solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (500 mg, 3.5 mmol) in DMF (5 mL) were added HATU (1.98 g, 5.2 mmol, 1.5 equiv.) and 2-chlorobenzylamine (622 μL, 5.2 mmol, 1.5 equiv.). The reaction mixture was stirred for 2 h. The reaction mixture was purified twice on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 34%). LRMS (M+H+) m/z 268.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[CH:30]=1)[NH:27][C:26](=[O:35])[CH2:25]2.NC1C=C(F)C=C2C=1NC(=O)C2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:35])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Agent: Nc1cc(F)cc2c1NC(=O)C2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4c(NC(C)=O)cc(F)cc43)c(C)c2C1=O
Yield: 30.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide which was prepared by the acetylation of 7-amino-5-fluoro-1,3-dihydro-indole-2-one (prepared according to U.S. Pat. No. 6,114,371, US1997-810659) as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-acetamide (36 mg, 30.8%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:22]=[C:21]([C:24](=[O:26])[CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: CSc1ccc(C(C)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Product: CSc1ccc(C(C)=O)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (150 mg, 0.59 mmol) and 1-(4-(methylthio)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone to give 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylthio)phenyl)ethanone. Mass Spectrum (ESI) m/e=378.1 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O1CCCC1.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([NH:2][OH:3])=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.30 g, 3.5 mmol) in water (5 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in tetrahydrofuran (5 mL) and the obtained mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), extracted with ethyl acetate, the extract was washed with water, brine, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-isopropanol (9:1) as eluent to give the title compound (0.087 g, 34%). M.p. 125-126° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.26-2.42 (4H, m); 2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d, J=15.8 Hz); 7.07 (4H, t, J=8.6 Hz); 7.37 (4H, dd, J=8.4 and 5.6 Hz); 7.57 (1H, d, J=15.8 Hz); 7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d, J=8.0 Hz); 9.19 (1H, s); 10.93 (1H, s). HPLC analysis on Alltima C18 column: impurities 2% (column size 4.6×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 70:30; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector: UV 215 nm). Anal. Calcd for C26H25F2N3O4S*0.3 Et2O*0.2 iso-PrOH*0.1CHCl3 (an exhaustively dried material contains all the indicated traces of solvents (PMR)), %: C, 59.87; H, 5.35; N, 7.51; S, 5.73. Found, %: C, 59.85; H, 5.36; N, 7.29; S, 5.60.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:20]([N:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:25]Cl)([CH3:22])[CH3:21].[OH-].[K+].C(O)(C)C>O.C(OCC)(=O)C>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH2:25][CH2:24][N:23]([CH:27]([CH3:29])[CH3:28])[CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC(C)N(CCOC(=O)c1cccc2cc(-c3ccccc3)oc12)C(C)C
Yield: 84.9 %

Procedure:
A mixture of 1.16 g of 2-phenylbenzofuran-7-carboxylic acid, 1.0 g of 2-(diisopropylamino)ethyl chloride hydrochloride, 0.66 g of potassium hydroxide and 20 ml of isopropanol is refluxed for 1 hour. After cooling, ethyl acetate and water are added to the reaction mixture. The organic layer is collected, washed with a saturated sodium chloride solution and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1.51 g 2-(diisopropylamino)ethyl 2-phenylbenzofuran-7-carboxylate as colorless oil.