Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH2:25][CH2:26][CH2:27][OH:28]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:25][CH2:26][CH2:27][OH:28])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: NCCO
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(NCCO)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 2-amino-ethanol. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (t, J=5.81 Hz, 1H), 7.59 (d, J=9.21 Hz, 1H), 7.47 (s, 2H), 7.27 (t, J=5.21 Hz, 1H), 6.87 (d, J=9.21 Hz, 1H), 4.79-4.81 (m, 1H), 3.55-3.59 (m, 2H), 3.44-3.48 (m, 2H), 3.22-3.23 (m, 2H), 1.98-2.03 (m, 2H), 1.73-1.85 (m, 5H), 1.22-1.31 (m, 2H). m/z: 398.3 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (275 mg, 70%).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16].C(N(CC)CC)C>C(OCC)C>[CH:15]([O:19][C:3](=[O:4])[C:2](=[CH2:1])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: C=C(CCCc1ccccc1)C(=O)Cl
Reactant: CCC(C)O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(CCCc1ccccc1)C(=O)OC(C)CC
Temperature: 25 °C

Procedure:
27 g of 2-methylene-5-phenylvaleric acid chloride are added dropwise to a solution of 100 ml of sec.-butanol and 20 ml of triethylamine in 300 ml of diethyl ether at 25° to 30°. When the addition is complete, the obtained mixture is stirred at room temperature for another hour; 500 ml of ice water are then added and the mixture is shaken thoroughly. The organic phase is collected, dried over sodium sulfate and concentrated. 19.5 g of 2-methylene-5-phenylvaleric acid sec.-butyl ester (b.p. 115° to 126° under 0.01 mm Hg) are obtained.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([CH:23]=[CH2:1])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of methyltriphenylphosphonium bromide (16.1 g, 45.2 mmol, 3.0 eq.) in THF (50 mL) was cooled to −78° C. 1M Sodium bis(trimethylsilyl)amide in THF (38.0 mL, 41.4 mmol, 2.75 eq.) was added and the mixture was stirred for 30 minutes. A solution of (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (3.0 g, 15.0 mmol, 1.0 eq.) in THF (10 mL) was slowly added and the mixture was stirred at −78° C. for 2 hours. The mixture was warmed to room temperature over 3 hours and the reaction was quenched with half saturated NH4Cl (50 mL). The organic layer was washed with saturated aqueous NaCl (50 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting oil was slurried in hexanes (50 mL) and the precipitate was filtered off. The filtrate was concentrated, diluted with hexanes (25 mL), and chilled at −20° C. overnight. The precipitate was filtered off and the filtrate was purified by column chromatography (0-100% EtOAc in hexanes) to yield (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (2.1 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[Br:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 92.7 %

Procedure:
A mixture of 2,3′-dibromoacetophenone (13.5436 g, 48.7 mmol) and potassium thiocyanate (5.2125 g, 53.6 mmol) in 200 mL of absolute ethanol was stirred under nitrogen at room temperature for 5.5 h. The reaction was added to 600 mL of water and the mixture stirred at room temperature for 2 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-(3-bromophenyl)-2-oxoethyl thiocyanate (11.5591 g, 93%) as a white solid, mp 91-93° C.; MS (ES) m/z 253.8 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH:16]([NH2:20])[C:17]([OH:19])=[O:18].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:20][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CC(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of 810 g of 4-chloro-3,5-dinitrotoluene, 384 g of dl-alpha-alanine, and 840 g of sodium bicarbonate was stirred and refluxed in 8 l of 95% ethanol for 18 hours. The mixture was diluted with water, filtered, and the ethanol was distilled off under reduced pressure. 1 l of water was added during the distillation in order to maintain the solids in solution. The aqueous solution was cooled by the addition of 2 kg of ice and acidified with concentrated hydrochloric acid (Congo Red) whilst stirring. The initially formed sticky precipitate crystallized on continued stirring to a dark-yellow solid which was filtered off, washed with water, and air-dried to give 2-(4-methyl-2,6-dinitroanilino)propionic acid (1 A), m.p.: 158°-161° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH2:23](Br)[CH3:24]>>[CH2:23]([O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8]3[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[C:10]=2[N:11]=1)[CH3:24]
Reactant: CCBr
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C

Procedure:
5-Ethoxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 161°-163° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and ethyl bromide by the method described in Example 8.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[NH:19].CC[O-].[Na+]>CCO>[F:16][C:17]([F:22])([F:21])[C:18]1[N:20]=[C:11]([OH:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:19]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1O
Yield: 54.9 %

Procedure:
A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h. The reaction mixture was concentrated and H2O (48 mL) was added. The resulting solid was filtered, washed with Et2O (300 mL) and H2O (200 mL), and dried to give the title compound (21 g, 50% yield); m.p. >220° C. (dec.); 1HNMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:16]([O:24][CH3:25])[N:15]=2)[CH2:10][CH:9]1[C:26](=[O:38])[NH:27][C:28]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]([C:18]1[N:17]=[C:16]([O:24][CH3:25])[N:15]=[C:14]([O:13][CH:11]2[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH:9]([C:26](=[O:38])[NH:27][C:28]3([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH:29]3[CH:31]=[CH2:32])[CH2:10]2)[CH:19]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Compound 3f was dissolved in DCM (20 ml). Triethyl silane (0.6 ml, 3.75 mmol) and TFA (20 ml) were added. The reaction mixture was stirred at RT for 1.5 h. The solvent was co evaporated with toluene and the crude residue was purified by column chromatography (DCM→DCM/MeOH (90/10)) which gave the title compound, (583 mg, 96%), MS (M+H)+476.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:25][O:24][C:23]3[CH:26]=[C:27]4[C:31](=[CH:32][C:22]1=3)[CH2:30][CH2:29][O:28]4)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:33]1[CH:38]=[C:37]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:25][O:24][C:23]4[CH:26]=[C:27]5[C:31](=[CH:32][C:22]2=4)[CH2:30][CH2:29][O:28]5)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[CH:36]=[N:35][CH:34]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
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: COCCOC
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(-c3cncnc3)c2C12COc1cc3c(cc12)CCO3
Yield: 28.3 %

Procedure:
A mixture of 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 0.21 mmol), pyrimidine-5-boronic acid (0.04 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol), 2.00 M sodium carbonate (1.00 mL) and 1,2-dimethoxyethane (10.0 mL) was heated at reflux for 16 h under nitrogen. After the organic solvent was evaporated in vacuo, the black residue was extracted with ethyl acetate (3×35.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluting with ethyl acetate:hexane (35%) to afford the title compound (0.03 g, 26%): mp 263-266° C.; 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.14 (s, 2H), 7.39 (t, 1H), 7.10, (d, 1H), 6.87 (d, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 6.07 (s, 1H), 5.03 (ABq, 2H), 4.62-4.48 (m, 2H), 4.58 (ABq, 2H), 3.01 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.3, 162.5, 161.0, 157.4, 155.9, 151.6, 142.2, 141.7, 132.8, 132.3, 131.3, 129.3, 125.7, 120.6, 120.2, 118.3, 117.0, 112.7, 109.7, 109.4, 93.5, 78.9, 72.5, 57.7, 37.1, 28.9; MS (ES+) m/z 506.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CSCCN1
Solvent: CCC(C)O
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCSCC1
Temperature: 105 °C
Reaction time: 7.5 h
Yield: 87.6 %

Procedure:
In a 100 mL volume glass vessel equipped with a stirrer and a thermometer were placed 4.0 g (14.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 5.0 g (48.5 mmol) of thiomorpholine, and 16 mL of sec-butyl alcohol. The resulting mixture was stirred at 105° C. for 7.5 hours. After the reaction was complete, 16 mL of methanol was added to the reaction mixture. The reaction mixture was refluxed for one hour and cooled to room temperature. Thus precipitated crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 4.38 g (isolated yield: 81%) of 6-methoxy-7-(3-thiomorpholinopropoxy)quinazolin-4-one.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2N=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=[C:47]([C:51]([NH2:53])=[O:52])[CH:46]=2)=C(F)C=1>C(Cl)Cl.CN(C=O)C>[C:51]([C:47]1[CH:46]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:10]=[CH:9][N:8]=1)(=[O:52])[NH2:53]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 17 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to 4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in 10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with saturated aqueous NaCl, the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting ⅓ hexane/EtOAc, then to elute product 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS(ESI+) m/z 427 (M+H)+. HRMS (ESI+) calcd.: 427.1218, found: 427.1214.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH:16](O)=[O:17].[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@:38]([NH2:40])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:19]([O:26][C:27](=[O:67])[N:28]([CH2:64][CH:65]=[CH2:66])[C:29]1[C:34](=[O:35])[N:33]2[C@@H:36]([C:41](=[O:63])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:50]([NH:52][C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)=[O:54])=[NH:51])=[CH:46][CH:45]=3)[CH2:37][C@@:38]([NH:40][CH:16]=[O:17])([CH3:39])[C:32]2=[N:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Reactant: O=CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@]2(C)NC=O
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of DCC (18.6 mg, 0.090 mmol) and formic acid (8.28 mg, 0.180 mmol) in CH2Cl2 that had been stirred at 0° C. for 10 min, was added intermediate 26a (30 mg, 0.045) in a solution of pyridine. The reaction was stirred at 0° C. for 15m then at rt for 2 h. The reaction mixture was concentrated in vacuo, then taken up in brine and extracted with chloroform (6×), dried (Na2SO4) and concentrated. It was purified by SiO2 chromatography (gradient elution, 1–12% MeOH/CH2Cl2) to afford 23.3 mg (75%) of intermediate 42a. MS (ESI) 692.2 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:14][CH:15]=1
Reactant: O=S(=O)(NCc1ccncn1)c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1
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: C1COCCO1
Product: O=S(=O)(NCc1ccncn1)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The sulphonamide from example 2 (1.0 eq), 4-fluorophenylboronic acid and Pd(PPh3)4 were dissolved in dioxane (3 mL/mmol) and an aqueous solution of sodium carbonate (2 mL/mmol) was added. The reaction mixture was heated under reflux overnight and after completion of the reaction the solvent was removed under reduced pressure. The residue was purified by chromatography to yield the title compound as beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]CC)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(C(=O)O)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1(6) (203 mg, 0.79 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 2N sodium hydroxide aqueous solution (2 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. Then, the solvent was removed in vacuo. The residue was diluted with water (30 mL), acidified with 2N hydrochloric acid aqueous solution (pH˜2) and extracted with dichloromethane (50 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 171 mg (94%) of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1)=[O:37]>CN(C=O)C>[CH:8]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]2[N:21]([CH2:35][C:36](=[O:37])[NH:38][C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=3)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=2)=[O:19])[CH2:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])c[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(NC(=O)c2cc([N+](=O)[O-])cn2CC(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 20 h
Yield: 43.9 %

Procedure:
To a solution of 4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide trifluoroacetate salt (30 mg) in DMF (4 mL) was added Cs2CO3 (70 mg). The mixture was stirred for 30 min at RT after which 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide (27 mg) was added. Stirring was continued for 20 h at RT. The mixture was filtered and directly subjected to preparative HPLC(CH3CN/H2O gradient+0.05% TFA) to give 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-nitro-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (15 mg) as its trifluoroacetate salt. MS (ESI+): m/e=449 [M+H]+, chloro pattern.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:26][O:27][NH2:28]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:28][O:27][CH3:26])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 159.9 mg, 0.41 mmol) and methoxyamine hydrochloride (52.3 mg, 0.62 mmol) in methanol (1.2 mL) and pyridine (1.2 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL), washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (168.2 mg, 98%) as a white foam: mp 69–72° C. (foam to gel); (ES)+-HRMS m/e calcd for C18H19Cl2N3O2S (M+H)+ 412.0648 found 412.0652.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-isopropylphenylboronic acid (164 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (59 mg, yield 72%).