Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)=[C:11]([C:27]#[N:28])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(=[O:31])C>C(O[Pd]OC(=O)C)(=O)C>[C:27]([C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=[C:13]2[C:12]=1[NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]2=1)(=[O:31])[NH2:28]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Product: CCOC(=O)c1ccc2[nH]c3c(C(N)=O)cc(-c4ccc(Cl)c(Cl)c4)cc3c2c1
Temperature: 25 °C

Procedure:
Ethyl 4-(3′,4′-dichloro-3-cyanobiphenyl-4-ylamino)benzoate (410 mg, 0.997 mmol), diacetoxypalladium (560 mg, 2.492 mmol) in glacial acetic acid (20 mL) in a microwave tube (20 mL) were heated in microwave reactors at 160° C. for 4 h. The reaction was cooled to room temperature. The catalyst was filtered off and solid was washed with acetic acid several times. The filtrate was concentrated under reduced pressure and the residue was co-evaporated with toluene (3×). The resulting residue was suspended in ethyl acetate. The solid was collected by filtration and air dried to afford 75.4 mg of ethyl 8-carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazole-3-carboxylate. MS (ESI) m/z 425.1(M−H). 1H NMR (DMSO-d6) δ ppmH NMR (DMSO-d6) d ppm 11.87 (1H, s), 9.00 (2H, m), 8.41 (1H, br. s), 8.40 (1H, d, J=1.22 Hz), 8.30 (1H, d, J=2.14 Hz), 8.06 (1H, dd, J=8.55, 1.53 Hz), 8.01 (1H, dd, J=8.24, 2.14 Hz), 7.82 (1H, d, J=8.55 Hz), 7.78 (1H, d, J=8.55 Hz), 7.65 (1H, br. s.), 4.38 (2H, q, J=7.22 Hz), 1.39 (3H, t, J=7.17 Hz).
Reaction SMILES: N#N.[CH3:3][C:4]([Si:7]([CH3:21])([CH3:20])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1)([CH3:6])[CH3:5].C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.O1CCCC1>[Si:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:4]([CH3:3])([CH3:5])[CH3:6])([CH3:20])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Under nitrogen flush, in a 2-necked 100 ml round-bottomed flask equipped with a reflux condenser (flammed for 5 minutes under vacuum and then 3 cycles of N2/vacuum), (1,1-dimethylethyl)(dimethyl){[(3-{[(methyloxy)methyl]oxy}phenyl)methyl]oxy}silane (Intermediate 103, 1.5 g, 5.31 mmol) was dissolved in hexane (20 ml) to give a colourless solution. Butyllithium 1.6N in hexane (4.31 ml, 6.9 mmol) was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours stirring in those conditions, the pale yellow reaction mixture was added to a solution of ethyl chloroformate (1.015 ml, 10.62 mmol) in tetrahydrofuran at −78° C. After 30 min, the reaction was quenched with a 2M aqueous solution of hydrochloric acid while the pH was allowed to reach ˜2 and diluted with 10 ml of ethyl acetate. Two phases were separated and the organic layer was dried over Na2SO4 and evaporated under vacuum affording the crude product as a yellowish oil that was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (1.396 g) as a yellow pale oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: COc1cc(Cl)c(B(O)O)cc1F
Product: COc1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 63 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (3.8 g, 14.3 mmol) and 2-chloro-5-fluoro-4-methoxyphenylboronic acid (Preparation 1) (3.8 g, 18.6 mmol) were treated substantially as described in Part A of Example 19a to give 3.5 g (63%) of 2-benzyloxy-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.4 Hz, 1 H), 7.45–7.42 (m, 2H), 7.40–7.29 (m, 3H), 7.04 (d, J=7.6 Hz, 1 H), 7.00 (d, J=10.8 Hz, 1 H), 6.91 (d, J=5.4 Hz, 1 H), 5.54 (s, 2 H), 3.91 (s, 3 H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[C:1]([C:3]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of tert-butyl 4-cyanopiperidine-1-carboxylate (500 mg; 2.38 mmol) and 2-(chloromethyl)pyridine (334 mg; 2.62 mmol) in toluene (3.6 ml) cooled in an ice bath was added a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene; 5.7 ml; 2.86 mmol) over 10 minutes. The reaction mixture was allowed to warm to ambient temperature with stirring for 1.5 hours. The reaction was poured into brine (25 ml) and extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (30 ml), dried over MgSO4, filtered and evaporated to give a orange oil. The crude product was chromatographed on silica eluted with 50% EtOAc in isohexane to give the desired product a colourless oil. (375 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:43]([CH2:45][NH2:46])[OH:44]>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:46][CH2:45][CH2:43][OH:44])=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), ethanolamine (0.141 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven which gave the title compound (0.161 g, 69% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.61 (t, 1H), 8.56 (s, 1H), 8.08 (AB quartet, 2H), 7.93 (dd, 1H), 7.62 (d, 1H), 7.40 (t, 2H), 4.76 (t, 1H), 3.54 (q, 2H), 3.80 (q, 2H); ES-MS (m/z) 300 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:21]#[N:22])=[C:18]([CH:19]=[CH2:20])[C:13]=3[C:12]3[CH:23]=[CH:24][CH:25]=[N:26][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:21]#[N:22])=[C:18]([CH2:19][CH3:20])[C:13]=3[C:12]3[CH:23]=[CH:24][CH:25]=[N:26][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1c(C#N)ncc2c1c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1c(C#N)ncc2c1c1cccnc1n2S(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 103.5 %

Procedure:
A mixture of 9-benzenesulfonyl-5-vinyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (60 mg 0.16 mmol) and 10% palladium on carbon (20 mg) in THF (4 mL) and IMS (3 mL) was stirred under an atmosphere of hydrogen for 3 h. The reaction vessel was then purged with nitrogen then the reaction mixture was filtered through celite. The celite pad was washed with DCM and then ethyl acetate and the combined filtrate was concentrated in vacuo to yield the title compound as a beige solid (60 mg, 99%). LCMS (Method B): RT=3.78 min, M+H+=363.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.[Li]CCCC.[Cl:20][CH2:21][C:22](N(OC)C)=[O:23].C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[Cl:20][CH2:21][C:22]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:9])[N:7]=1)=[O:23]
Reactant: CON(C)C(=O)CCl
Reactant: Cc1ncn(C(C)C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)CCl)n(C(C)C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a 10 L four necked flask was charged 1-Isopropyl-3-methyl-1H-1,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to −40° C. and 2.5 M n-butyllithium BuLi in n-hexanes (1.41 L) was added while keeping the internal temp. below −20° C. The resulting yellow suspension was stirred at −40° C. for 1 hour before being transferred. To a 20 L flask was charged 2-chloro-N-methoxy-N-methylacetamide 10 (485 g) in THF (4 L). The resulting solution was cooled to −40° C. at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp. below −20° C. At this point a yellow orange solution was obtained which was stirred at −30° C. for 1 hour. Propionic acid (520 mL) was added keeping the internal temp. below −20° C. The resulting off-white to yellowish suspension was warmed to −5° C. over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20 w % K3PO4 solution (1 L), 20 w % K2HPO4 solution (2 L), and 20 w % NaCl solution (1 L). The organics was reduced to ca 4 L via distillation under vacuum to afford 2-chloro-1-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used “as is” in the next step.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[N:4]([CH2:12][C:13]([NH2:15])=[O:14])[C:3]1=[O:16]>CC(O)=O.[Zn]>[F:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:16])[N:4]2[CH2:12][C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CN1C(=O)C(Br)(Br)c2c(F)cccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)CN1C(=O)Cc2c(F)cccc21
Reaction time: 1 h

Procedure:
Zinc dust (4.46 g, 0.068 mol) is added to a stirred solution of the crude 2-(3,3-dibromo-4-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 3 (theorical: 6.32 mmol) in AcOH (20 ml) at 0° C. After 1 hour, the reaction mixture is filtered through a Celite pad. The filtrate is diluted with AcOEt and cold water. The pH is adjusted to 7 and the layers are separated. The aqueous phase is extracted again with AcOEt. Organic layers are dried over Na2SO4 and concentrated. Several attempts to cristallize in AcOEt failed. The crude reaction mixture is purified by reverse phase HPLC (LC-MS, acetonitrile/H2O). 2-(4-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 9 is obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[O:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[O:33][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=5)=[CH:30][CH:31]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 95.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (24 mg, 0.085 mmol), 5-(3-chlorophenyl)-2-furoic acid (9.5 mg, 0.043 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.085 mmol), HOBT (12 mg, 0.085 mmol) and DIPEA (15 μl, 0.085 mmol) in DMF (4 ml) were stirred at room temperature for 4 h. The DMF was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organic fraction was concentrated under vacuum and the residue purfied by preparative HPLC to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-5-(3-chlorophenyl)-2-furamide (20 mg, 95%). NMR; δH [2H6]—DMSO 10.25,(1H, s), 8.64,(1H, t), 8.11,(1H, t), 7.96-7.94,(3H, m), 7.75,(1H, dd), 7.66,(1H, d), 7.52,(1H, t), 7.49-7.44,(3H, m), 7.39,(1H, d), 7.34-7.31,(2H, m), 3.18,(2H, t), 2.23,(3H, s), 1.06,(1H, m), 0.45,(2H, m), 0.26,(2H, m). LCMS: retention time 3.88 min, MH+485.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[N:4]=1)=O.[C:17]([N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:3]([CH2:1][NH:41][C:37]2[N:36]([C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:40]=[CH:39][N:38]=2)=[N:4]1
Reactant: Nc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(C=O)nn(C)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(CNc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Step A (204 mg, 1 mmol) is dissolved in toluene (10 mL) with N-trityl-2-aminoimidazole (357 mg, 1.1 mmol) and heated to reflux with a Dean-Stark trap. Four aliquots of toluene (3 mL each) are removed via distillation at 1.5 hour intervals, being replaced by dry toluene each time, and then the solution is left to reflux for 18 hours. The reaction is cooled to room temperature and sodium triacetoxyborohydride (1 gram, 5 mmol) is added in one portion. The reaction is stirred at room temperature for 24 hours, poured into water, and the layers separated. The aqueous layer is extracted with ethyl acetate and the combined organic layers are washed with saturated bicarbonate, water, and brine, dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH3:28][O:29][NH2:30].CN1CCCCC1.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:30][O:29][CH3:28])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: CON
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CCOc1cc(C(CC(=O)NOC)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (500 mg, 1.41 mmol) and N,N′-carbonyldiimidazole (250 mg, 1.54 mmol) in methylene chloride (30 mL) under nitrogen was stirred at room temperature for 30 minutes. To the solution was added O-methyl hydroxylamine hydrochloride (175 mg, 2.09 mmol) followed by the addition of 1-methyl piperidine (0.26 mL, 2.14 mmol). The mixture was stirred at room temperature for 2 hours and then was heated to reflux for 14 hours. The cooled reaction mixture was washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL), and then dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave a solid which was stirred with ether (10 mL) for 30 minutes. This suspension was filtered and the solid was washed with ether (2×10 mL) to give 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamide as a white solid (360 mg, 67% yield): mp, 138.0-139.5° C.; 1H NMR (CDCl3) δ1.41 (t, J=6.9 Hz, 3H, CH3), 2.95 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.53 (dd, J=11.2, 14.5 Hz, 1H, CHH), 3.62 (s, 3H, CH3), 3.84 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 4.23 (d, J=17.1 Hz, 1H, NCHH), 4.46 (d, J=17 Hz, 1H, NCHH), 5.49 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.78-6.99 (m, 3H, Ar,), 7.27-7.51 (m, 3H, Ar), 7.78 (dd, J=7.4 Hz, 1H, Ar), 10.08 (br s, 1H, NH); 13C NMR (CDCl3) δ14.66, 37.52, 49.48, 54.94, 5.91, 64.01, 64.41, 111.37, 112.12, 119.26, 122.75, 123.54, 128.04, 131.38, 131.68, 132.58, 141.44, 148.56, 149.15, 167.81, 169.47. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C, 65.23; H, 6.52; N, 6.88.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16]C=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1OC(=O)C.[CH3:18][O-:19].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:18]([OH:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(-c2ccccc2)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(-c2cccc(Br)c2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1.07 g (3.67 mmole) of 3-bromo-4-acetoxybiphenyl in 10 mL methanol at ambient temperature under a nitrogen atmosphere was added 0.92 mL of 4.4 M sodium methoxide in methanol solution (4 mmole). The mixture was stirred for 20 minutes and partitioned between Et2O/ice-H2O/2N HCl (aq.) and the organic phase separated, washed with saturated NaCl solution, and then ice-H2O/saturated NaHCO3 (aq) solution, dried over Na2SO4, filtered, and evaporated. The product was dried in vacuo to give 1.05 g of crude 3-bromo-4'-hydroxybiphenyl which was used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=1.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][C@:45]([C:50]#[C:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=2)([OH:49])[CH2:44]1>CC(N(C)C)=O>[Cl:58][C:54]1[CH:53]=[C:52]([C:51]#[C:50][C@:45]2([OH:49])[CH2:46][CH2:47][CH2:48][C@H:43]([NH:42][C:37](=[O:39])[C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:41][CH:40]=3)[CH2:44]2)[CH:57]=[CH:56][CH:55]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CCC[C@@](O)(C#Cc2cccc(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)N[C@H]2CCC[C@@](O)(C#Cc3cccc(Cl)c3)C2)cc1
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A solution of TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate)(29.9 mg, 0.093 mmol) in DMA (0.23 ml) and DIPEA (36 μl, 0.213 mmol) was added to solid 4-methylbenzoic acid (11.6 mg, 0.085 mmol) under argon atmosphere at room temperature. After stirring for 20 min., a solution of (1S,3S)-3-amino-1-(3-chloro-phenylethynyl)-cyclohexanol (21.2 mg, 0.085 mmol) in DMA (0.43 ml) was added and the crude reaction mixture was purified without further treatment after stirring for 24 h on a preparative LC/MS system, yielding the title compound (25.1 mg, 0.068 mmol).
Reaction SMILES: [F:1][C@:2]([CH3:29])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[F:1][C@@:2]([CH3:29])([C:3]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:5])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7]
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (R)-2-fluoro-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (69%). MS: m/e=532(M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NCCCO
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCCO)c(Cl)c32)c(F)cc1F
Temperature: 45 °C
Reaction time: 43 h
Yield: 46.7 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1-propanol (75 mg) and triethylamine (200 mg) were added to pyridine (350 mg), and the mixture was stirred at 45° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (120 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (80 mg) as a colorless powder.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccccn1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromopyridine