Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCCC1.CO.[C].[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(O)ccc1N
Reaction time: 8 h

Procedure:
1-Benzyloxy-3-methoxy-4-nitrobenzene (11.0 g) was dissolved in tetrahydrofuran (100 ml)-methanol (100 ml), and then 10% palladium carbon (5.0 g) was added thereto, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the reaction mixture was filtered to remove the catalyst, which was washed with tetrahydrofuran, ethyl acetate and methanol in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (5.88 g, quantitatively) as brown powder.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3]([OH:5])=O.[CH3:23][O:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[CH2:2][C:3]([N:25]([O:24][CH3:23])[CH3:26])=[O:5]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Gly-OH, 1 g (3.36 mmol), 361.0 mg (3.70 mmol) of CH3ONHCH3 and 447.3 mg (3.53 mmol) of HOBt were dissolved in DMF. Under ice cooling, 677 mg (3.53 mmol) of WSCI.HCl and 1.94 mL (11.1 mmol) of DIEA were added to the solution, followed by stirring overnight. After the reaction solution was concentrated, 10% aqueous citric acid solution was added and the precipitated solid was extracted with AcOEt. The organic layer was washed with 10% aqueous citric acid solution, 5% NaHCO3 aqueous solution and satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The oily Fmoc-Gly-N(CH3)OCH3 product obtained by concentrating the solvent was dissolved in THF. Under ice cooling, 332 mg (0.726 mmol) of LiAlH4 was added by small portions to the solution over 15 minutes. After stirring at 0° C. for 30 minutes, 150 mL of diethyl ether and 150 mL of 20% citric acid aqueous solution were sequentially added to the reaction solution, which was then vigorously stirred for an hour. The organic layers were collected and the aqueous layer was again extracted with 150 mL of diethyl ether. The pooled organic layer was washed sequentially with 5% NaHCO3 aqueous solution, water, 10% citric acid aqueous solution, water and then satd. sodium chloride aqueous solution, and dried over anhydrous Na2SO4. The organic layer obtained was concentrated to give Fmoc-Gly-al as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: NCCc1ccccc1F
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4ccccc4F)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 2-(2-fluorophenyl)ethanamine were processed as described in Example 33C to provide the title compound. MS (ESI) m/z 455 (M+H)+.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:13]([NH2:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>>[CH:1](/[S:9]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:13](=[O:22])(=[O:14])[NH2:23])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(NS(=O)(=O)/C=C/c2ccccc2)cc1
Yield: 80 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and sulfanilamide (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 171-173° C., was obtained in 80% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:10]([CH:12]([CH3:15])[CH:13]=[CH2:14])[CH3:11].[Li]CCCC.C1COCC1.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>C1COCC1>[CH3:37][C:32]1([CH3:38])[C:33]([CH3:36])([CH3:35])[O:34][B:30]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH:10]([CH:12]([CH3:15])[CH:13]=[CH2:14])[CH3:11])[O:31]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C=CC(C)C(C)Oc1ccc(C)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)C(C)Oc1ccc(C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-methyl-1-((3-methylpent-4-en-2-yl)oxy)benzene (820 mg, 3.05 mmol) in THF (15.200 mL) at −78° C. was added 1.6M n-BuLi/THF (2.285 mL, 3.66 mmol) and the mixture was stirred for 30 min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.746 mL, 3.66 mmol) was then added and after 30 min, bath removed and reaction allowed to warm to rt. After 3 h, partitioned between EtOAc and water. EtOAc layer was dried (Na2SO4), filtered and concentrated. Crude was used as-is in the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C2CCCCO2)[N:19]=[C:18]3[C:30]([NH:32][C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)=[O:31])[CH:12]=[N:13][CH:14]=1.C([SiH](CC)CC)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:30]([NH:32][C:33]2[CH:34]=[N:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=2)=[O:31])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(-c3cncc(F)c3)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1n[nH]c2ccc(-c3cncc(F)c3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
TFA (10 mL) was added to a solution of 5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXX) (0.420 g, 0.86 mmol) and triethylsilane (0.345 mL, 2.16 mmol) in DCM (10 mL) and stirred 5 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and air dried at room temperature. The solids were suspended in DCM:MeOH (1:1) mixture and boiled to get a clear solution. The solution was cooled to room temperature. The solids formed were filtered washed with DCM and dried under vacuum at room temperature to get 5-(5-fluoropyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (2) as a white solid (72.9 mg, 0.18 mmol, 21% yield). 1H NMR (DMSO-d6) δ ppm 14.13 (br. s, 1H), 11.11 (s, 1H), 9.27 (d, J=1.8 Hz, 1H), 8.84 (m, 1H), 8.63 (dd, J=6.8, 1.8 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.53 (m, 1H), 8.14-8.11 (m, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.90-7.83 (m, 2H); ESIMS found for C19H11F4N5O m/z 402.30 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]([CH3:38])[CH2:35][CH2:36][N:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]([CH3:38])[CH2:35][CH2:36][N:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(C3=NCCN3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(C3=NCCN3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1-methyl-imidazolin-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:46])[N:31]([CH:43]([CH3:45])[CH3:44])[CH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[CH:27]=[C:26]([Cl:47])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:47][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:25]=1)[C:30]([N:31]([CH:43]([CH3:44])[CH3:45])[CH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]([F:40])([F:42])[F:41])(=[O:37])=[O:38])=[O:46]
Reactant: CC(C)N(CCCNS(=O)(=O)C(F)(F)F)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCCNS(=O)(=O)C(F)(F)F)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A solution of (2-{3-chloro-5-[isopropyl-(3-trifluoromethanesulfonylamino-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.038 g) in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml) stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.024 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:9][CH2:10]O)=[N:5][N:6]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[F:19][C:14]1[CH:13]=[C:12]([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[N:6]=[C:2]([NH2:1])[N:3]=[C:4]23)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nnc(N(CCCO)c2ccc(F)c(F)c2)[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2n(n1)CCCN2c1ccc(F)c(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-((5-amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl)amino)propan-1-ol (31 mg, 115 μmol) in tetrahydrofurane (1.15 mL) was added at 0° C. under an atmosphere of nitrogen triphenylphosphine (45.3 mg, 173 μmol). The reaction was stirred for 15 minutes and then DEAD (31.0 mg, 28.2 μL, 173 μmol) was added. The reaction was stirred for 30 minutes at 0° C. and then at room temperature over night. The same procedure was repeated with additional triphenylphosphine (45.3 mg, 173 μmol) and DEAD (31.0 mg, 28.2 μL, 173 μmol). Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a colorless solid (14 mg, 48%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 252.3 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[O:11]=[C:6]1[C:5](=[O:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:26](=[O:27])[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[O:29])[CH:3]=2)[NH:7]1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCOCC
Product: O=C1Nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)cc2C1=O

Procedure:
The title compound is prepared from 5-amino1H-indole-2,3-dion [Helv. Chim-Acta 19, 1327. (1936)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 205-206° C. (diethylether)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[O:24])=[CH:18][C:14]=1[C:15](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[O:24])=[CH:18][C:14]=1[C:15]1[NH:11][C:6]2[C:7]([N:10]=1)=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(Cl)c(-c2nc3ncc([N+](=O)[O-])cc3[nH]2)c1)c1ccco1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 5-nitropyridine-2,3-diamine (1-2) (6 g, 38.93 mmol, 1.00 equiv) and 2-chloro-5-(furan-2-amido)benzoic acid (I-3) (10.4 g, 39.15 mmol, 1.00 equiv) in PPA (100 mL) was stirred overnight at 130° C. The reaction was then poured into water/ice and the pH value of the mixture was adjusted to 9 with sodium carbonate. The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (31) to give 3.9 g (26%) of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)furan-2-carboxamide (I-3) as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8]1([C:14]([CH3:24])([CH3:23])[CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH:16]2O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][C@H:18]1[CH2:17][C@@H:16]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[C@H:15]([C:14]([CH3:24])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:23])[CH2:20][CH2:19]1
Reactant: CCC(=O)C(=O)O
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2.28 g 2-oxobutyric acid (2, 22.11 mmol, 1.3 eq), 4.04 g (−)-8-phenylmenthol (18, 17.02 mmol, 1.0 eq) and 169.9 mg para-toluenesulfonic acid monohydrate (0.884 mmol, 0.52 eq) in 48 mL benzene was heated to reflux for 20 h 35 min. After cooling down to room temperature, the solution was washed twice with 50 mL saturated aqueous sodium hydrogencarbonate solution, and subsequently with 50 mL water and 50 mL brine. The organic phase was dried over 5 g sodium sulfate and was filtered. The filter cake was washed with 10 mL benzene. The organic phase was evaporated to dryness in a rotary evaporator (40° C., 20 mbar) yielding the title compound (4.98 g, 92% by weight) as colorless solid.
Reaction SMILES: N[C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC#N.[BrH:44].N([O-])=O.[Na+]>O>[Br:44][C:2]1[C:11]([Cl:12])=[CH:10][C:9]([N:13]([C:18]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:21]3[C:22]([C:32](=[O:35])[NH:33][CH3:34])=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:24][C:20]=3[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1 L 3-necked flask equipped with a magnetic stirrer was added 58.0 g (99.0 mmol) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate followed by 500 mL of MeCN and then 500 mL of 48% aqueous HBr. The dark brown solution was cooled to 0° C. in an ice water/brine bath and treated with a solution of 8.20 g (119 mmol) of sodium nitrite in 50 mL of water over a 5 minute period. After 30 minutes LCMS indicated complete consumption of the starting material. The solution was treated with 18.5 g (129 mmol) of CuBr over 2 minutes and then warmed to 50° C. After 30 minutes at 50° C. LCMS indicated complete reaction. The solution was cooled to RT and partitioned between 1 L of EtOAc and 1.5 L of water. The phases were separated and the aqueous solution extracted with EtOAc (2×200 mL). The combined EtOAc solutions were washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated aqueous brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration through a pad of silica gel and the filtrate concentrated to dryness at reduced pressure to give 64.3 g of crude methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a reddish-brown foam. The crude product was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (q, J=4.29 Hz, 1H) 8.16 (s, 1H) 7.92-8.03 (m, 2H) 7.79 (d, J=2.73 Hz, 1H) 7.65 (d, J=2.73 Hz, 1H) 7.41 (t, J=8.93 Hz, 2H) 7.24 (s, 1H) 3.81-3.89 (m, 3H) 3.45-3.53 (m, 3H) 2.85 (d, J=4.59 Hz, 3H) 2.04-2.16 (m, 1H) 0.71-1.07 (m, 3H) 0.40 (br. s., 1H). LCMS (ESI): 649 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C([O-])(O)=O.[Na+].[Cu]I>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=1
Reactant: C#CCO
Reactant: Brc1cnc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: OCC#Cc1cnc2ccccc2c1
Yield: 88.3 %

Procedure:
To a dry 2-L three-necked flask previously purged with nitrogen was charged 3-bromoquinoline (118.77 g, 570 mmol), propargyl alcohol (71.9 g, 1.28 mol, 2.25 equiv), triethylamine (1500 mL), copper(I) iodide (3.62, 19 mmol, 0.033 equiv) and dichlorobis(triphenyl-phosphine) palladium(II) (6.67 g, 9.5 mmol). The mixture which resulted was mechanically stirred and heated to reflux for 3 hours. Upon cooling the triethylamine solution was mechanically stirred and heated to reflux for 3 hours. Upon cooling, the triethylamine solution was filtered and washed with triethylamine (300 mL). The filtrate was then concentrated under reduced pressure to provide solids which were suspended in 5% aq. NaHCO3 (600 mL) and extracted with ethyl acetate (1×600 mL). The solids which were left after filtration were treated in the same manner. The combined ethyl acetate extracts were stirred with silica gel (15 g) and decolorizing carbon (3 g) before being filtered through a bed of celite. The filtrate was concentrated under reduced pressure to provide a tan colored solid which was vacuum oven dried at 45° C. overnight. The 3-(3-quinolyl)-2-propyn-1-ol was isolated in 92.14 g (88.3% yield). MS(CI): (M+H)+ at 184; 1H NMR (300 MHz CDCl3) δ: 4.56 (s, 2H), 4.70 (s, broad, 1H), 7.57 (m, 1H), 7.70 (m, 1H), 7.77 (d, 1H), 8.10 (d, 1H), 8.10 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][S:14][C:15]3[N:19]([CH3:20])[CH:18]=[N:17][N:16]=3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][C:18]1[N:19]([CH3:20])[C:15]([S:14][CH2:13][C:11]2[O:10][N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:12]=2)=[N:16][N:17]=1
Reactant: Cn1cnnc1SCc1nc(-c2cccc(Cl)c2)no1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cn1c(Br)nnc1SCc1nc(-c2cccc(Cl)c2)no1
Temperature: 70 °C
Yield: 57.5 %

Procedure:
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole was mixed with 30 ml of chloroform/pyridine(25/1) at room temperature. Then bromine in chloroform (0.5 ml) was added dropwise and the reaction mixture was heated at 70° C. overnight. The reaction mixture was diluted with chloroform and washed with saturated NH4Cl twice and the organic layer was dried with sodium sulfate, concentrated, the residue was triturated with diethyl ether to give the title compound (1.5 g, 57.5%, yellow solid). 1H-NMR(CDCl3) d(ppm): 8.05 (s, 1H), 7.94 (d, 1H), 7.47(d, 1H), 7.43 (t, 1H), 4.66 (s, 2H) and 3.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([O:18]C2C=CC=CC=2)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])=[CH:43][CH:42]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[N:48]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[O:55])=[CH:42][CH:43]=2)[CH2:49][CH2:50][CH2:51][N:52]([CH3:53])[CH3:54])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
1-Benzyloxy-3-(phenoxycarbonylamino)benzene (Reference Compound No. 5-1, 3.7 g, 12 mmol) was added to a solution of the mixture containing N-(2-t-butoxycarbonylaminophenyl)-4-(3-dimethylaminopropylaminomethyl)benzamide (Reference Compound No. 4-5, 10 g, 24 mmol) in DMSO (30 mL), and then the reaction mixture was stirred at room temperature for 15 hours. Water (300 mL) was added thereto, the whole was extracted with ethyl acetate (250 mL) twice, and then the organic layer was washed with brine (250 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.1 g of the title reference compound as a white amorphous product. (Yield 15%)
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:46]2[CH2:47][CH2:48][N:43]([C:35]3[N:34]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:44][CH2:45]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(Cn2c(N3CCNCC3)nc3ccccc32)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4n3Cc3ccccc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 10 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-benzyl-2-(piperazin-1-yl)-1H-benzimidazole.