Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CCCCCCC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:33]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)nccc3c2)cc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ; 100 mg, 0.227 mmol), (5-chloro-2-methoxyphenyl)boronic acid (63.4 mg, 0.340 mmol), potassium carbonate (94 mg, 0.680 mmol), and pd(ph3p)4 (26.2 mg, 0.023 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (851 μl) and water (284 μl) were added. The vial was sealed and heated to 100° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-40% EtOAc/Heptane, then 70% EtOAc/Heptane) to give 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (91.2 mg, 0.167 mmol, 73.5% yield) as an off-white foam. m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][CH3:32])[C:9]=2[CH2:33][CH2:34][CH3:35])([O:3][CH2:4][CH3:5])=[O:2]>O1CCCC1CCO.[Ni]>[C:1]([CH:6]1[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[C:9]([CH2:33][CH2:34][CH3:35])[C:10]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][CH2:31][CH3:32])=[CH:11][CH:12]=2)[O:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCc1ccccc1OCCCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1CCC
Agent: [Ni]
Agent: OCCC1CCCO1
Product: CCCc1ccccc1OCCCCCOc1ccc2c(c1CCC)OC(C(=O)OCC)CC2=O
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
961 mg (2 mmole) of the compound of Example 30 was dissolved in 30 ml of 50% tetrahydrofuran-ethanol and 96 mg of Raney Nickel was added. The resulting suspension was hydrogenated at 2 psi and room temperature for 30 minutes. After separation of the catalyst by filtration, the solvent was removed by rotary evaporation to yield 855 mg (89%) of the title compound as a clear oil. Calc: C, 72.17; H, 7.94; Found; C, 71.84; H. 8.00.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Temperature: 50 °C
Yield: 86 %

Procedure:
A solution of Intermediate 16 (37.8 g) in ethanol:water (4:1, 375 ml) was treated with sodium hydroxide (18.9 g). The mixture was heated at 50° C. for 5 hours, then concentrated in vacuo, dissolved in water and acidified to pH 2 with aqueous hydrochloric acid (2M). The resultant white solid was removed by filtration and dried under vacuum to afford Intermediate 17 as an off-white solid (29.65 g). LCMS showed MH+=291; TRET=2.17 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[OH-].[Na+]>ClCCl>[F:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[CH2:5][CH2:6][CH:2]([OH:1])[C:3]2=[O:4])=[CH:11][CH:10]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1OCCC1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1C(O)CCN1c1ccc(F)cc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 3-hydroxydihydrofuran-2(3H)-one (5.00 g, 49.0 mmol) and 4-fluoroaniline (6.53 g, 59.0 mmol) was stirred at 150° C. for 1 day. After completion of the reaction, dichloromethane and 10 M sodium hydroxide aqueous solution were added to the reaction solution and the resultant mixture was filtered. To the filtrate, dichloromethane and concentrated hydrochloric acid were added to adjust pH to 1. The obtained solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (6.78 g, yield 71%).
Reaction SMILES: [C:1]([C@@H:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C@H:21]1[C:32]([O:18][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:33]
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: -5 °C
Yield: 87.3 %

Procedure:
A mixture of 310 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol, 310 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid and 1.55 liters of methylene chloride was stirred until total dissolution occured and the mixture was cooled to -5° C. and mixed with a solution of 263.5 g of dicyclohexylcarbodiimide, 3.1 g of 4-dimethylamino-pyridine and 530 ml of methylene chloride. The mixture was stirred at -5° C. for one hour and at room temperature for 3 hours and was vacuum filtered. The filtrate was washed with N hydrochloric acid and then with water, dried and evaporated to dryness under reduced pressure. The residue in 1.185 liters of isopropanol, 80 ml of water and 72 ml of triethylamine was stirred for 36 hours and was vacuum filtered. The product was washed with isopropanol to obtain 518 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3 -tert.-butoxy-1-propenyl]-cyclopropane-carboxylate melting at 114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:16][CH2:17][F:18])[C:12]([O:14][CH3:15])=[O:13].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH2:17][F:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:24][CH:23]=1
Reactant: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of compound from step B (68 mg, 0.189 mmol) and NMM (38 mg, 0.37 mmol) in DCM (7 mL) was added methylsulfonyl chloride (32 mg, 0.283 mmol) dropwise. Then the mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=439.0[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3,5-bis-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 11-aminoundecanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 12 of European Patent Application 136,883 to give (±)-11-[[2-[(acetylthio)methyl]-1-oxo-3phenylpropyl]amino]undecanoic acid, methyl ester.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[CH:11][C:10]2=[C:14]3[C:3]=1[O:4][CH2:5][CH:6]([CH3:17])[N:7]3C(=O)[C:9]2=[O:15].[OH:18]O>[OH-].[Na+]>[F:13][C:12]1[C:2]([F:1])=[C:3]2[O:4][CH2:5][CH:6]([CH3:17])[NH:7][C:14]2=[C:10]([C:9]([OH:15])=[O:18])[CH:11]=1
Reactant: CC1COc2c(F)c(F)cc3c2N1C(=O)C3=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: CC1COc2c(F)c(F)cc(C(=O)O)c2N1
Temperature: 5 °C

Procedure:
A suspension of 6.9 g (28.8 mmol) of 6,7-difluoro-3-methyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1,2-dione (Example 30) in 250 mL of 4.5% aqueous sodium hydroxide is treated dropwise with 16.4 mL of 30% hydrogen peroxide over 1 hour. The reaction is filtered to remove a trace of insoluble material and the filtrate is acidified to pH 4.5 with acetic acid. After cooling to 5° C., the precipitate is removed by filtration, washed with water and dried in vacuo to give 5.5 g of the title compound, mp 200–202° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH:2]=[CH2:3]>[Pd]>[CH3:19][C:16]1[C:17](=[O:18])[C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]=2[O:14][C:15]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C=CCc1c2c(cc3c(=O)c(C)c(C(=O)OCC)oc13)CCCC2
Agent: [Pd]
Product: CCCc1c2c(cc3c(=O)c(C)c(C(=O)OCC)oc13)CCCC2
Yield: 100.6 %

Procedure:
The product of step (e) (16 g) was hydrogenated over palladium on charcoal catalyst, under the conditions of Example 3(b), to give the title ester (16.2 g), as a low melting brown solid.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].[C:12](=S)=[S:13].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>O1CCCC1>[N:7]([CH2:6][CH2:5][CH2:4][Si:3]([O:8][CH3:9])([O:10][CH3:11])[O:2][CH3:1])=[C:12]=[S:13]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[Si](CCCN=C=S)(OC)OC
Temperature: 0 °C
Reaction time: 5 h

Procedure:
In a reaction container mixed were 53.8 g of 3-(trimethoxysilyl)propylamine and 600 ml of dry tetrahydrofuran (THF), with cooling to 0° C. To this solution, 34.2 g of carbon disulfide was added dropwise, and the mixture was stirred at 0° C. for 5 hours in a nitrogen atmosphere. Then, a solution of 61.9 g of dicyclohexyl carbodiimide in 180 ml of dry THF and 3 g of triethylamine were added thereto, and the mixture was allowed to react at 40° C. for 5 hours. THF was removed from the reaction mixture obtained, and the residue was extracted with n-hexane. Then n-hexane was removed from the extract under reduced pressure, and the residue was distilled under reduced pressure, to obtain γ-isothiocyanatopropyltrimethoxysilane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][N:19]=[C:18]([C:22](OC)=[O:23])[CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[C:18]([CH:22]=[O:23])[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(N2CCC(CNC(=O)OC(C)(C)C)CC2)ncn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(C=O)ncn2)CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
A 25 mL round-bottomed flask was charged with methyl 6-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)pyrimidine-4-carboxylate (150 mg, 0.43 mmol, 1 equiv.) and CH2Cl2 (2 mL). The reaction mixture was cooled to −78° C. DIBAL-H 1 M in CH2Cl2 (0.64 mL, 0.64 mmol, 1.5 equiv.) was added in 3 minutes at −78° C. The reaction was stirred for 4 h at −78° C. LC-MS showed some starting material. Another portion of DIBAL-H 1 M in CH2Cl2 (0.5 mL, 0.5 mmol, 1.2 equiv.) was added in 1 min at −78° C. LC-MS after 30 min showed the reaction was complete. The reaction was quenched at −78° C. after 40 min with methanol (1 mL). The solvents were concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 1 N NaOH (6 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The organic layer was dried over Na2SO4. The solvent was evaporated to give the crude desired aldehyde (77.9 mg, 56.8% crude yield) as an yellowish oil. The crude reaction aldehyde was carried on the next step without any further purification. LC-MS m/z 339 (M+1+H2O) and 351 (M+1+MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[C:17]([N:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:24][C:23]([CH:33]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:24][C:23]([CH2:33][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: Cc1ccc(-c2cc(CNCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1
Yield: 89.4 %

Procedure:
Compound 69 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]3[CH:25]=[CH:26][C:13]([NH:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)=[O:37])=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Product: CCc1ccc(NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 23, 4-[4-[[7-(chloro)-4-quinolinyl]amino]benzoyl]piperazine is reacted with p-ethylphenyl isocyanate to give 1-[[(4-ethylphenyl)amino]carbonyl]-4-[4-[[(7-chloro)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=O.[CH3:17][NH2:18]>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][C:14]([NH:18][CH3:17])=[O:16]
Reactant: CN
Reactant: O=C(O)Cc1cc(F)ccc1Br
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (9.4 mL, 129 mmol) is added to a solution of (2-bromo-5-fluoro-phenyl)-acetic acid (20.0 g, 85.8 mmol) in dry toluene (400 mL). The mixture is heated at reflux for 4 hours and the solvent is removed in vacuo. The remanence is redissolved in dry toluene (400 mL) and cooled to 0° C. 40% methylamine (aq.) (17.7 mL, 515 mmol) is added dropwise at 0-5° C. The mixture is then stirred at ambient temperature for 16 hours, poured onto water (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic fractions are washed successively with saturated sodium bicarbonate solution (150 mL) and brine (150 mL), dried (MgSO4) and concentrated in vacuo. This gives 16.2 g (77%) of crystalline 2-(2-bromo-5-fluoro-phenyl)-N-methyl-acetamide.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][C:41]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])=[CH:42][N:43]=1.ClC1SC(C(NC2CC2)=O)=CN=1>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.O>[CH:47]1([NH:46][C:44]([C:41]2[S:40][C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH:14]=3)=[N:43][CH:42]=2)=[O:45])[CH2:48][CH2:49]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(NC1CC1)c1cnc(Cl)s1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)NC4CC4)s3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 130 °C
Yield: 75 %

Procedure:
A mixture of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (150 mg, 0.287 mmol), 78 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide, Pd2(dba)3 (Strem Chemicals, 8 mg, 8.6 μmol), Xphos (Stem Chemicals, cat #15-1152, 9 mg, 17 μmol), potassium phosphate (183 mg, 0.861 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 25 min. LCMS indicated the presence of desired product (M+1=563.0), as well as a significant amount of the starting N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine. To the reaction mixture was added Pd(PPh3)4 (Strem Chemicals, cat #46-2150, 10 mg) and 50 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide. It was heated again at 130° C. for 15 min in an Initiator microwave reactor. The reaction mixture was treated with water (5 mL) and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 20-100% EtOAc in hexanes to give N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)thiazole-5-carb oxamide (60 mg, in 75% purity) as a brown amorphous solid. MS (ESI, pos. ion) m/z: 563.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:25])=[C:4]([C:21]([Cl:24])=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].C=O.[C:28]([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C>[Cl:25][C:3]1[C:2]([NH:1][CH3:28])=[CH:23][CH:22]=[C:21]([Cl:24])[C:4]=1[C:5]([NH:7][C:8]1[C:16]2[O:15][C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: [BH3-]C#N
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CNc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
A mixture of 6-(3-amino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (100 mg), aqueous 37% formaldehyde, sodium cyanoborohydride (70 mg) and acetic acid (5 drops) in acetonitrile (2 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned between dichloromethane and aqueous saturated sodium bicarbonte. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC on silica gel and the obtained oil was crystallized from diisopropyl ether to give 6-(2,6-dichloro-3-methylaminobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (21 mg).