Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[CH3:10][N:11]([CH3:26])[C:12]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH:23]([CH3:25])[CH3:24]>>[CH3:10][N:11]([CH3:26])[C:12]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:15]([CH:16]([OH:17])[C:1]#[CH:2])=[CH:14][C:13]=1[CH:23]([CH3:25])[CH3:24]
Reactant: C#C[Mg]Br
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1N(C)C
Solvent: C1CCOC1
Product: C#CC(O)c1cc(C(C)C)c(N(C)C)c(C(C)C)c1
Yield: 192.8 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 28 ml (14 mmol) of 0.5M ethynylmagnesium bromide/THF with 1.2 g (5 mmol) of 4-dimethylamino-3,5-diisopropylbenzaldehyde. 2.5 g of 1-(4-dimethylamino-3,5-diisopropylphenyl)prop-2-yn-1-ol are obtained in the form of a whitish solid (yield=90%).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[S:27]1[CH:31]=[CH:30][N:29]2[CH:32]=[N:33][CH:34]=[C:28]12>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:33]3[CH:34]=[C:28]4[S:27][CH:31]=[CH:30][N+:29]4=[CH:32]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: c1cn2cncc2s1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3)[C@H](C)[C@H]12
Yield: 25 %

Procedure:
The same procedure as in Example 1 was repeated except that 91 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 155 mg of imidazo[5,1-b]thiazole were used, thereby obtaining 21.6 mg of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH:9]1[C:24](=[O:36])[NH:25][C:26]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH:27]1[CH:29]=[CH2:30])=O)(C)(C)C.[ClH:37].CCOCC>>[ClH:37].[ClH:37].[CH2:34]([O:33][C:31]([C:26]1([NH:25][C:24]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)[CH2:12][NH:8]2)=[O:36])[CH2:28][CH:27]1[CH:29]=[CH2:30])=[O:32])[CH3:35]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3ccccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: C=CC1CC1(NC(=O)C1CC(Oc2nccc3ccccc23)CN1)C(=O)OCC
Yield: 100 %

Procedure:
A stirred slurry of 2-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.40 g, 10.9 mmol) was treated with 2N HCl/ether (Aldrich)(250 mL) for 24 h. The reaction mixture was concentrated in vacuo to give 5.3 g (˜100%) of 1-{[4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride as a white solid: LC-MS (Method A, retention time: 2.40 min), MS m/z 396 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([O:26][CH2:27][CH3:28])=[C:17]([C:29](O)=[O:30])[C:16]=1[C:32](O)=[O:33])[CH3:13]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:27]([O:26][C:18]1[C:17]2[C:29](=[O:30])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=3)[C:32](=[O:33])[C:16]=2[C:15]([O:14][CH2:12][CH3:13])=[C:24]2[CH:23]=[CH:22][C:21]([F:25])=[CH:20][C:19]=12)[CH3:28]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2cc(F)ccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOc1c2c(c(OCC)c3cc(F)ccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2=O
Temperature: 180 °C
Yield: 44 %

Procedure:
4-Aminophenylacetic acid (418 mg, 2.77 mmol) was added to 1,4-bis(ethyloxy)-6-fluoro-2,3-naphthalenedicarboxylic acid (810 mg, 2.5 mmol) and powdered molecular sieves (4 Å, 200 mg) in NMP (4.5 ml) and heated in a microwave at 180° C. for 10 minutes. The reaction mixture was cooled and diluted with EtOAc, filtered through celite, washed with water, brine, dried over magnesium sulphate and concentrated in vacuo to yield a yellow solid. This was recrystallised from methanol (˜50 ml) and the white solid filtered, washed with methanol and dried in vacuo in an oven to give the title compound as a white solid (490 mg, 1.1 mmol). The filtrate was concentrated in vacuo and the yellow oil purified by reverse phase chromatography eluting with acetonitrile:water (1:20-1:0) to give the title compound as a white solid (107 mg, 0.24 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1.[CH3:13][NH2:14]>CO>[O:11]1[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:14][CH3:13])=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: BrCCc1ccc2c(c1)CCO2
Reactant: CN
Solvent: CO
Product: CNCCc1ccc2c(c1)CCO2

Procedure:
A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (1.5 g -- see Preparation 20) in 33% methylamine in methanol (40 ml) was heated at 100° C. in a stainless steel pressure vessel for 6 hours then concentrated in vacuo. The residue was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (50 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×50 ml). The aqueous layer was concentrated in vacuo to give a solid which was triturated with boiling 2-propanol. The mixture was filtered and the filtrate concentrated in vacuo to give a solid which was purified by column chromatography o silica eluting with dichloromethane containing methanol (0% up to 1%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless solid, yield, 0.31 g, m.p. 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A stirred solution of 5.2 g (0.017 mol) of 3-(2-chloro-5-trifluoromethylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 4 g (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 mL of water and the oil globules which separated slowly solidified on standing. Filtration yielded 4 g of crude product which was recrystallized from benzene/ligroin yielding 3.3 g (62.9%) of fine white crystalline product, mp 132°-133° C.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[C:12]([Si:16]([O:6][CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC=CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CC=CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.9 %

Procedure:
Cyclopent-3-en-1-ol (10 g, 118.9 mmol) was dissolved in DMF (100 mL) at 0° C., then 1H-imidazole (17.29 mL, 261.5 mmol) was added, followed by tert-butyl(chloro)-dimethylsilane (21.5 g, 142.7 mmol). The mixture was warmed to room temperature and stirred for 14 h. The mixture was diluted with ethyl acetate (300 mL), washed with 5% aqueous LiCl solution (2×100 mL) and brine (50 mL), then dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by chromatography, eluting with 0-10% EtOAc in hexane, to afford the title compound (17.2 g, 73%) as a colourless clear liquid. δH (250 MHz, CDCl3) 5.66 (s, 2H), 4.53 (tt, J 7.0, 3.6 Hz, 1H), 2.57 (dd, J 15.2, 6.8 Hz, 2H), 2.27 (dd, J 15.3, 3.6 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]1([N:11]2[C:15]([C:16]3[CH:17]=[C:18]([CH:22]4[CH2:31][C:30]([CH3:33])([CH3:32])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:34](O)=[O:35])[CH:28]=5)[NH:23]4)[CH:19]=[CH:20][CH:21]=3)=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:8]1([N:11]2[C:15]([C:16]3[CH:17]=[C:18]([CH:22]4[CH2:31][C:30]([CH3:32])([CH3:33])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:34]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:35])[CH:28]=5)[NH:23]4)[CH:19]=[CH:20][CH:21]=3)=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (1.3 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A43. A solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (544.6 mg, 1.4 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B43. Solution B43 was added to Solution A43 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (195.7 mg, 30%) as a white solid: MS (ESI) M+1=467.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Brc1cncnc1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, light brown solid, MS (ISP): m/e=310.4 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 20 using 5-bromopyrimidine instead of 3-bromo-pyridine.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[C:7]([CH2:9][C:10]1([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)[CH2:13][NH:12][CH2:11]1)#[N:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([CH2:3][C:4]([N:12]1[CH2:13][C:10]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[N:23][N:22]4[C:25]([C:28]5[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36])[CH:31]=[CH:32][CH:33]=5)=[CH:26][N:27]=[C:21]4[CH:20]=3)[CH:16]=[N:15]2)([CH2:9][C:7]#[N:8])[CH2:11]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanoacetic acid (3.1 mg, 0.036 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (11.9 mg, 0.0241 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.036 mmol) in N,N-dimethylformamide (0.6 mL), followed by triethylamine (10. μL, 0.072 mmol). The reaction mixture was stirred at r.t. for 1 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=563.2.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[CH3:33][S:34]([O:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]3[N:4]([CH2:17][CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3]([CH2:1][CH3:2])=[N:16][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1)(=[O:36])=[O:35]
Reactant: CCc1nc2cnc3cc(O)ccc3c2n1CCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.5 g, 4.5 mmol), chloroform (45 mL), and triethylamine (0.697 mL, 5.00 mmol) were combined. Methanesulfonyl chloride (0.348 mL, 4.50 mmol) was added dropwise to the mixture; a flocculent precipitate formed. The reaction was stirred for 72 hours and then quenched with methanol. The volatiles were removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with a dichloromethane:methanol gradient) to provide 0.628 g of 2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate as a white solid.
Reaction SMILES: Cl[Si:2]([Cl:18])(Cl)[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([Li])[CH:23]=[C:24]([CH3:26])[CH:25]=1>C(OCC)C>[Cl:18][Si:2]([C:3]1[CH:4]=[C:5]([C:13]([CH3:15])([CH3:16])[CH3:14])[CH:6]=[C:7]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:8]=1)([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:13])[CH:4]=1)[C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: [Li]c1cc(C)cc(C)c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: Cc1cc(C)cc([Si](Cl)(c2cc(C)cc(C)c2)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (74 mL) of trichloro(3,5-di-tert-butylphenyl)silane (12.95 g, 40.00 mmol), a solution of 3,5-dimethylphenyllithium (11.09 g, 98.96 mmol) in diethyl ether (95 mL) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure to quantitatively obtain chloro(3,5-di-tert-butylphenyl)bis(3,5-dimethylphenyl)silane.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:16][C:13]1[C:14]2[CH:15]=[C:7]3[C:6]4[CH:19]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[CH:3]=[CH:4][C:5]=4[O:18][CH2:17][N:8]3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)cc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 2-chloro-11-fluoro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (30 mg, 0.11 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (55 mg, 0.11 mmol), K3PO4.3H2O (88 mg, 0.33 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), X-Phos (11 mg, 0.022 mmol) was stirred in dixane/H2O (5 mL, 4:1) at 110° C. for 12 hours. Then the mixture was cooled to 25° C., water was added to it. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=3:1) to provide the product of Compound 43 (25 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.94˜7.97 (m, 2H), 7.83˜7.86 (m, 2H), 7.62 (s, 1H), 7.37˜7.40 (m, 1H), 7.09˜7.24 (m, 5H), 6.93 (s, 1H), 6.80˜6.85 (m, 1H), 5.95 (s, 2H), 5.85 (br, 1H), 3.16 (s, 3H), 3.00˜3.01 (d, J=5.2 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 614.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][O:20][CH2:30][O:31][CH3:32])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCO)CC1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In dichloromethane (60 ml), 4-tert-butoxycarbonyl-1-[(3-hydroxy-1-propyl)sulfonyl]piperazine (3.00 g) was dissolved. To the resulting solution, diisopropylethylamine (2.72 ml) was added, followed by the addition of methoxymethyl chloride (1.11 ml) under ice cooling. After stirring at room temperature for 15 hours, the reaction mixture was diluted with dichloromethane, washed with water, 5% aqueous citric acid solution and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (3.32 g, 97%) was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([CH2:6][OH:7])[NH2:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:5][CH:4]([CH2:6][OH:7])[CH:3]([C:8]([F:10])([F:9])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][C:23]=1[N+:32]([O-:34])=[O:33]
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(CO)C(C(F)(F)F)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To a solution of 4,4,4,4′,4′,4′-hexafluoro-dl-valinol (0.50 g, 2.37 mmol), triethylamine (0.43 mL, 3.08 mmol) and CH2Cl2 (17.5 mL) at 0° C. was added a previously dissolved mixture of 4-chloro-3-nitro-benzenesulfonyl chloride (0.606 g, 2.37 mmol) in CH2Cl2 (5 mL). After 15 min, the ice bath was removed and the reaction allowed to warm up to 25° C. After 16 h, the reaction was then diluted with CH2Cl2 (20 mL) and poured into a separatory funnel containing a saturated NaHCO3 solution. The organic phase was separated, washed sequentially with 1N HCl solution, distilled water, brine, dried over MgSO4 and evaporated to afford the crude product which was purified using Biotage Flash™ chromatography, eluent: 3:1 hexanes-ethyl acetate, to afford the product as a solid (0.134 g, 13%). MS (−ESI) 428.9 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH2:1])[CH:11]=[CH:10]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: Nc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc2cc(N)ccc2c1
Temperature: 60 °C
Yield: 88.1 %

Procedure:
3 grams (g) (18.85 millimoles (mmol)) of 6-aminonaphthalene-2-ol is dissolved in 100 milliliters (mL) of acetone, and 4 g (20.7 mmol) of 1-bromooctane and 13.0 g (94.2 mmol) of potassium carbonate (K2CO3) are added thereto. The reaction mixture is stirred under reflux at 60° C. for 24 hours, and cooled down to room temperature (25° C.). The obtained reaction mixture is concentrated, and purified by silica gel column chromatography (n-hexane:EtOAc=3:1 volume ratio), to give 4.5 g (16.6 mmol) of 6-octyloxynaphthalene-2-amine. The yield is 88%.
Reaction SMILES: [NH2:1]C1C=CC(S(N(CC)CC)(=O)=O)=CC=1.C([O:18][C:19](=O)[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)C.C[Al](C)C>ClC(Cl)C>[C:27]1([CH:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:19]([NH2:1])=[O:18])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(c1ccccc1)c1ccncc1
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Product: NC(=O)C(c1ccccc1)c1ccncc1
Yield: 299.6 %

Procedure:
As described in Example 1, 4-Amino-N,N-diethyl-benzenesulfonamide (242 mg, 1.06 mmol, 2.0 equiv) was coupled with phenyl-pyridin-4-yl-acetic acid ethyl ester (128 mg, 0.53 mmol, 1.0 equiv) using trimethylaluminum (0.53 mL, 0.53 mmol, 2 equiv) in dichloroethane (20 mL). Standard work-up and purification of the residue by rotary chromatography (5% methanol/methylene chloride) provided N-(4-Diethylsulfamoyl-phenyl)-2-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide (337 mg)
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30]CC)=[O:29])=[CH:20][N:21]3C(C)(C)C)=[CH:16][CH:15]=2)[CH2:10]1)=O)(C)(C)C.Cl>C(O)C>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([OH:30])=[O:29])=[CH:20][NH:21]3)=[CH:16][CH:15]=2)[CH2:10]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Agent: Cl
Solvent: CCO
Product: NC1CCN(c2ccc3c(=O)c(C(=O)O)c[nH]c3n2)C1
Temperature: 0 °C

Procedure:
A solution of Example 73D (120 mg) in ethanol (5 mL), and 6M HCl (5 mL) was heated in a sealed tube at 130° C. for 18 hours then cooled, concentrated to remove the ethanol, diluted with diethyl ether, cooled to 0° C., and filtered; and the filtrant was washed with ether, dried, and purified by reverse phase HPLC. NMR (300 MHz, DMSO-d6) δ 8.54 (s), 8.32 (m), 6.83 (m), 4.12 (m), 3.98 (m), 3.83 (m), 2.55 (m), 2.27 (m).