Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:18]([Zn]CC)[CH3:19]>>[CH2:18]([C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:19]
Reactant: CC[Zn]CC
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Product: CCc1cc(C(=O)OC)cnc1OCC(F)(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (610 mg, a white solid) from methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1.0 g, 3.2 mmol, Step-1) and diethylzinc (6.4 mL, 6.4 mmol, 1M solution in n-hexane) instead of dimethylzinc by the similar manner in Step-3 of Amine-27.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:8]([N+:14]([O-:16])=[O:15])=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 42.1 g (200 mmol) of 3-chloro-2,4,5-trifluorobenzoic acid (E.P.O. No. 0 183 129) in 100 ml of sulfuric acid was added concentrated nitric acid (50 ml) dropwise such that the reaction temperature stayed below 40° C. The reaction mixture was heated at 60° C. for 18 hours, then poured cautiously onto 500 g of ice water. The aqueous solution was extracted with ether, and the ether extracts were washed with water, dried over magnesium sulfate, and concentrated to give 26.5 g of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid.
Reaction SMILES: [ClH:1].O.C([O:7][C:8]([C@H:10]1[CH2:13][C@@H:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=4)[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:11]1)=[O:9])(C)(C)C.C(OCC)C>O1CCOCC1>[ClH:1].[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([C:25]2[O:24][N:23]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C@@H:12]4[CH2:13][C@H:10]([C:8]([OH:9])=[O:7])[CH2:11]4)=[CH:17][CH:18]=3)[N:26]=2)=[CH:32][CH:31]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CN[C@H]4C[C@@H](C(=O)OC(C)(C)C)C4)cc3)no2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CN[C@H]4C[C@@H](C(=O)O)C4)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl (4.0 M in dioxane, 21.6 mL) and water (3.6 mL) was added to a solution of 3-{4-[5(4-isobutyl-phenyl)-[1,2,4]oxadiazole-3-yl]-benzylamino}-cis-cyclobutanecarboxylic acid tert-butyl ester (4.0 g, 8.67 mmol) in dioxane (20.0 mL) and stirred at room temperature for 1 hour. Diethyl ether (50.0 mL) was added to the reaction mixture and the resulting slurry was stirred for 2 hours and filtered to yield the title compound (2.8 g, 79% yield) as a solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+].CO>>[C:16]([C:15]1[C:8]2[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:5])[C:7]=2[OH:31])[N:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:14]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)#[N:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(C#N)c(-c3ccc(F)cc3)n(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-7-methyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 445 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@H:10]([O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:24])=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](OC(=O)c1cccnc1)C(=O)O

Procedure:
A total of 17.8 g of nicotinoyl chloride hydrochloride was dissolved in 150 ml of pyridine and 50 ml of dimethylformamide and the solution treated slowly with stirring at a temperature not over 15° with 22.2 g of benzyl-(R)-α-hydroxy-isovalerate (prepared from (R)-2-hydroxy-isovaleric acid and benzyl chloride in a manner analogous to that described for the preparation of the corresponding compound in Example 1). After stirring for two hours at room temperature, the mixture was evaporated under reduced pressure. The residue was taken up in ether, washed three times with water and extracted six times with ice-cold 3-N hydrochloric acid. The hydrochloride phases were immediately allowed to run into saturated sodium bicarbonate solution and the base which was thus released was extracted three times with ether. After washing and drying, it was evaporated under reduced pressure and there were obtained 27 g of a resin which contained benzyl-(R)-2-(nicotinoyloxy)-isocaproate. The resin was then hydrogenated in 200 ml. of ethanol with 2 g. of 5% palladium-on-charcoal until 2 equivalents of hydrogen had been taken up. After filtration and evaporation, the residue was taken up in 10% potassium bicarbonate, washed twice with ether and adjusted to pH 3 with citric acid. After extraction with ether, washing, drying and evaporation of the extract, there was obtained a crystallizing oil. Recrystallization from ethyl acetate/petroleum ether yielded 14 g of (R)-2-(nicotinoyloxy)isocaproic acid; mp 101°-103°; [α]D25 =+18.8° (c = 1.0 in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:13][C:14]([F:26])([F:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1F)=[O:16].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:11][NH:12][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[C:14]([F:25])([F:26])[F:13]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(CNc2cc(F)ccc2C(=O)C(F)(F)F)cc(OC)c1
Yield: 100.9 %

Procedure:
A solution of (3,5-dimethoxyphenyl)methanamine (0.88 g, 5.20 mmol), 2,2,2-trifluoro-1-(2,4-difluorophenyl)ethanone (1.0 g, 4.80 mmol) and diisopropylethylamine (1.6 mL, 9.6 mmol) in acetonitrile was stirred at 40° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water and brine, dried, and concentrated under reduced pressure to yield 1.73 g of a yellow oil. The residue was purified by PTLC (20% ethyl acetate in hexanes) to give 527 mg (35%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 9.27 (br t, 1H), 7.83 (br s, 1H), 6.47-6.40 (m, 5H), 4.42 (d, 2H), 3.79 (s, 6H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(O)c1cccnc1
Reaction time: 1.5 h
Yield: 103 %

Procedure:
To a solution of the product from step (b) (1.30 g) in ethanol (50 ml) was added sodium borohydride (105 mg). The mixture was stirred for 1.5 h then evaporated. Water was added and the mixture extracted twice with ethyl acetate. The combined organic layers were washed (brine) and dried (MgSO4). The solvent was evaporated off to give the sub-title compound (1.35 g) as an oil.
Reaction SMILES: C([O:5][C:6](=[O:23])[C@@H:7]([NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C@@H:7]([CH:8]([CH3:11])[CH2:9][CH3:10])[C:6]([OH:23])=[O:5])=[O:22]
Reactant: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)[C@H](NC(=O)c1ccccc1OC)C(=O)O
Yield: 85.8 %

Procedure:
(2S)-2-(2-Methoxybenzoylamino)-3-methylpentanoic acid tertbutyl ester (341 mg, 1.06 mmol) was dissolved in trifluoroacetic acid/CH2Cl2 (1:1, 10 ml). After 2 h at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography (eluant: 1% acetic acid, 2% methanol, 97% chloroform) to give a colourless oil identified as the title compound (242 mg, 0.91 mmol, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=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.C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:17]=[C:16]([C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1ccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)cc1
Yield: 58.7 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 4-cyanophenylboronic acid (74 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) in a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (94 mg, 59%) m/z, 321.0 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN(C)CCN
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN(C)C)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(2-dimethylamino-ethyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N,N-dimethyl-1,2-ethanediamine in an analogous manner to Example 1396. Product isolated as a yellow foam (32 mg, 59%). LCMS (m/e) 538 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.22 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.09 (s, 1H), 7.61 (d, 1H, J=7.7 Hz), 7.47-7.41 (m, 1H), 7.38 (s, 1H), 7.30-7.16 (m, 2H), 7.14-7.07 (m, 1H), 7.06-7.00 (m, 2H), 3.65-3.55 (m, 4H), 3.38 (s, 3H), 3.04-2.92 (m, 4H), 2.89-2.78 (m, 6H), 2.64 (t, 2H, J=5.7 Hz), 2.36 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([C:35]([CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:36])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(C(=O)C4CCC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclobutanecarbonyl chloride (1 mole) with triethylamine (1 mole) in dimethylformamide, stirring 16 hours at 25°C gave the desired product.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Yield: 69.2 %

Procedure:
A solution of acryloyl chloride (0.017 mL, 0.21 mmol) in CH2Cl2 (0.6 mL) was added to a mixture of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 65, 87 mg, 0.19 mmol) and DIPEA (0.063 mL, 0.38 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was then stirred at 0° C. for 4 h. (during this time a further 0.5 eq acryloyl chloride was added). The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3, then with water, and then dried (MgSO4). Purification by FCC, eluting with 0-6% methanolic ammonia in CH2Cl2 gave the title compound (67 mg, 69%) as a yellow solid; 1H NMR: (102° C.) 2.30 (3H, s), 2.56-2.59 (4H, m), 2.93-2.96 (4H, m), 3.78 (3H, s), 5.67-5.7 (1H, m), 6.16 (1H, d), 6.44-6.51 (1H, m), 6.95 (1H, s), 7.11 (1H, t), 7.35 (1H, t), 8.20 (1H, s), 8.32 (1H, d), 8.66 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.91 (1H, s), 8.96 (1H, br s); m/z: ES+ MH+ 510.5.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([OH:39])[C:36]3[C:31](=[CH:32][C:33]([CH3:40])=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:48]([O:52][C:53](=[O:56])[CH2:54]Br)([CH3:51])([CH3:50])[CH3:49]>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:41])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH2:54][C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:56])[C:36]3[C:31](=[CH:32][C:33]([CH3:40])=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 650 mg of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 7.7 ml of DMF, 414 mg of cesium carbonate and 248 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 590 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18]C)=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([OH:18])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(CSc2ccc(O)cc2)cc(OC)c1O
Temperature: -78 °C
Yield: 62.8 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (3 g, 9.8 mmol), prepared as described in Example 1, was dissolved in 60 ml of dry methylene chloride, and cooled to -78° C. A solution of borontribromide (2.8 ml, 29.5 mmol) in 10 ml of methylene chloride was added dropwise to the above solution. The mixture was stirred to room temperature, and immediately cooled to 0° C. Water (50 ml) was then added dropwise, and the methylene chloride layer was separated. The crude product, obtained after being dried over magnesium sulfate and concentrated, was purified on silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give 1.8 g (63% yield) of 4-hydroxy-3,5-dimethoxybenzyl 4-hydroxyphenyl thioether as a white solid.
Reaction SMILES: [N:1]1([C:4]2[C:5](=[O:18])[C:6]3[C:7]([CH3:17])=[C:8]([CH2:15][OH:16])[NH:9][C:10]=3[C:11](=[O:14])[C:12]=2[CH3:13])[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].[K+].[Br-]>C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>[C:28]([O:16][CH2:15][C:8]1[NH:9][C:10]2[C:11](=[O:14])[C:12]([CH3:13])=[C:4]([N:1]3[CH2:3][CH2:2]3)[C:5](=[O:18])[C:6]=2[C:7]=1[CH3:17])(=[O:30])[CH3:29]
Reactant: CC1=C(N2CC2)C(=O)c2c([nH]c(CO)c2C)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCc1[nH]c2c(c1C)C(=O)C(N1CC1)=C(C)C2=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a mixture of 10 mg of indole 1b (0.04 mmole), 5 mg (0.04 mmole) dimethylaminopyridine (DMAP) in 5 ml of chloroform, was added 100 mg of acetic anhydride. The reaction was stirred at room temperature for 25 min and then added directly to a silica gel chromatography column employing chloroform as the eluant. The purified indole 1c was recrystallized from chloroform/hexane: 11 mg (95%) yield; mp 210-212° C.; TLC (chloroform/methanol, 90:10) Rf=0.68; 1HNMR (CDCl3) δ 9.38 (1H, bs, indole proton), 5.03 (2H, s, 2-methylene), 2.32 (4H, s, ethylene), 2.31 (3H, s, 3-methyl) 2.08 and 2.05 (6H, 2s, methyls); IR (KBr pellet) 3207, 2924, 1734, 1664, 1624, 1566, 1500, 1361, 1350, 1242, 1209, 1155, 1020, 962, 817, 781 cm−1; MS (EI mode) m/z 288 (M+), 245 (M+-CH3—C═O), 228, 213, 201, 185. Anal. Calcd (C15H16N2O4) C, H, N.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28](O)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1>ClCCl>[CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[O:17])([CH2:27][C:28]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)=[O:29])[C:7]1=[O:31])[CH3:2]
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Reactant: Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(CO)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
The carboxylic acid intermediate (234 mg) was dissolved in dichlormethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (131 mg) and para-toluidine (73 mg) were added in that order. The mixture was stirred at 15-30° C. for 18 hours and concentrated. After diluting the residue with ethyl acetate and washing it with dilute hydrochloric acid and saturated bicarbonate water, it was dried on anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane/ethyl acetate=2/1) to obtain 204 mg of a white powder (90% ee, 80% yield from ester intermediate).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 55.1 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.59 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.50 g, 55%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1cccc(B(O)O)c1F
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-fluoro-3-methoxy-phenylboronic acid (CAS RN 352303-67-4) and using preparative HPLC for the chromatographic purification. Off-white solid (42%). MS (ESI): m/z=472.8 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>CO>[N:13]1[CH:12]=[N:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2ncnc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 38 %

Procedure:
To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130° C. for 12 hours. The mixture was then concentrated to give a residue. To the residue was added MeOH (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to give methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate in 18% yield, 6 g. To a solution of methyl[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room temperature. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6) δ: 7.56-7.58 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), 9.04-9.06 (m, 1H), 13.5-14.0 (s, 1H).