Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CN(C)C=O.[C:27]1([CH3:33])[CH:32]=CC=C[CH:28]=1>>[C:27]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:21])=[O:20])([CH3:33])([CH3:32])[CH3:28]
Reactant: O=C(O)CCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
The crude heptadecanedioic acid (0.99 g, 3.3 mmol) was dissolved in toluene (15 ml) at 115° C. N,N-dimethylformamide di-tert-butylacetale (0.79 ml, 3.3 mmol) was added dropwise over 10 min. After refluxing for 1 h more N,N-dimethylformamide di-tert-butylacetale (0.79 ml) was added over 10 min. After refluxing for another 1 h, a last eq of N,N-dimethylformamide di-tert-butylacetale (0.79 ml) was added over 10 min. Reflux was continued for 1 h. On cooling to RT a precipitate appeared, this was filtered off (diacid). The mother liqueour was extracted with water (25 ml) and DCM (25 ml). The organic layer was dried and concentrated. The residue was purified by flash chromatography using DCM/MeOH 15:1 as eluent. Heptadecanedioic acid mono-tert-butyl ester was isolated in 33% yield (0.330 g). HPLC-MS: 379 (M+Na), rt 6.11. 1H-NMR (DMSO-d6): δ 1.22 (br s, 22H), 1.39 (s, 9H), 1.47 (m, 4H), 2.16 (t, 2H), 2.19 ppm (t, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl>>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: ClCCCCCl
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)N(CCCCCl)C1=O

Procedure:
A mixture of 538 g of 5,5-dimethyl-hydantoin (4.2 mols), 290 g of anhydrous potassium carbonate (2.1 mols) and 2,130 g of 1,4-dichlorobutane (16.77 mols) is reacted for 8 hours at 138° to 141° C internal temperature (external temperature 200° C), as described under Example 1 (a). Working up is carried out according to Example 1 (a), and 830.9 g of a brown, viscous crude product (90.5% of theory) are obtained, and are purified by vacuum distillation (boiling point0.2 : 151°-153° C) and subsequent recrystallisation from diethyl ether. The pure product melts at 54.4° to 56.3° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2ncccc12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 692 mg (5.20 mmol) of 3-methyl-1H-pyrazolo[3,4-b]pyridine in 25 mL of acetonitrile under nitrogen was cooled to 0° C. in an ice bath, and was treated with 635 mg (5.20 mmol) of DMAP and 761 μL (5.46 mmol) of triethylamine. A solution of 1.36 g (6.24 mmol) of (BOC)2O in 5 mL acetonitrile was then added dropwise using an addition funnel. Upon completion of addition, the ice bath was removed and the mixture was stirred for an additional 18 hours at room temperature. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil. This crude material was purified by flash chromatography over silica gel with 1:1 ethyl acetate/hexanes to give the title product as a clear oil. 1H NMR (CDCl3): δ 1.74 (s, 9H), 2.60 (s, 3H), 7.29 (m, 1H), 8.02 (dd, 1H), 8.74 (dd, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](F)[N:6]=[C:5]([F:11])[C:4]=1[F:12].[CH3:13][NH:14][CH3:15].O>C(O)C>[CH3:13][N:14]([CH3:15])[C:7]1[C:8]([F:9])=[C:3]([CH2:2][OH:1])[C:4]([F:12])=[C:5]([F:11])[N:6]=1
Reactant: CNC
Reactant: OCc1c(F)c(F)nc(F)c1F
Solvent: CCO
Solvent: O
Product: CN(C)c1nc(F)c(F)c(CO)c1F
Yield: 87.3 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.23 g (0.0050 mole) of dimethylamine in 25 ml of ethanol was refluxed for approximately twenty hours. The reaction mixture was cooled and was poured into water. This mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.9 g of 2-dimethylamino-4-hydroxymethyl-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][S:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:16]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([S:22]([CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2cccnc2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)Cc2cccnc2)cc1

Procedure:
1 g of 3-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl 4-(pyridin-3-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate. 760 mg of methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:21][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]([O:5][C:6]2[CH:7]=[N:8][CH:9]=[N:10][CH:11]=2)[CH:3]=1)=[O:20]
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: Brc1cccc(Oc2cncnc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(Oc2cncnc2)c1)c1cccc(Cl)c1
Temperature: 110 °C
Yield: 9 %

Procedure:
Compound 13 (580 mg, 2.31 mmol, 1.00 eq), 3-chlorobenzamide (539 mg, 3.46 mmol, 1.50 eq), NaOt-Bu (311 mg, 3.24 mmol, 1.40 eq), Pd(OAc)2 (26 mg, 0.12 mmol, 0.050 eq) and Xantphos (134 mg, 0.232 mmol, 0.100 eq) were dissolved in toluene (6 mL) in a flame-dried sealed tube and heated at 110° C. for 18 h. The reaction was cooled to rt, diluted with CH2Cl2 and filtered through a plug of celite. Purification by flash chromatography on silica gel afforded 68 mg (9%) of the title compound as an off white semi-solid: 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.03 (s, 1H), 8.68 (s, 2H), 7.97 (t, J=1.6 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.65 (t, J=9.8 Hz, 2H), 7.59 (t, J=2.0 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.42 (t, J=8.2 Hz, 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H); ES-MS [M+1]+: 326.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][C:14]([CH2:18][CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:33]([CH2:37]I)([F:36])([F:35])[F:34]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:37][C:33]([F:36])([F:35])[F:34])[C:14]([CH2:18][CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: CCc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-3A-1a, 15 mg, 0.039 mmol), Cs2CO3 (52 mg, 0.16 mmol) and CF3CH2I (39 μl, 0.4 mmol) in DMF (1 ml) was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride, and extracted with ethyl acetate (2×). The combined extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (Chromatotron) using a 1 mm silica gel plate and a solvent gradient of 25% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to provide the desired product, 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one 3A-1 (11 mg): MS 467.4 (M+1); 1H NMR (400 MHz, CD2Cl2): δ 7.57–7.43 (m, 4H), 7.44–7.40 (m, 2H), 7.34–7.30 (m, 2H), 5.00–4.80 (br m, 2H), 2.87 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][CH2:25][CH3:26])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CC=O
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (i) (20 mg, 0.052 mmol) in MeOH (0.6 mL) was added acetaldehyde (15 μL 0.27 mmol) at 0° C. Sodium cyanoborohydride (5 mg, 0.078 mmol) was then added and the mixture was stirred at RT for 1 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to give 2-(4-bromophenyl)-5-cyclopropyl-6-(ethylamino)-N-methyl-2H-indazole-3-carboxamide (ii) as a white solid (7 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:19]([CH2:35][NH:36][CH3:37])[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:24][CH2:23]2)[CH:15]=[CH:16][C:17]=1[Cl:18]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:26][CH2:27]2)[CH2:35][N:36]([CH3:37])[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cccc(F)c1

Procedure:
3-Fluorobenzoyl chloride (0.088 mL) was reacted with (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4]bipiperidinyl-2-one (0.30 g) in dichloromethane (78 mL) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 97:3, 94:6) as eluent to give the title compound (0.28 g). Rf=0.36 in methylene chloride:methanol (95:5). MS: m/z=534 (M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam (0.093 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19](=[O:26])[CH:20](Br)C(OC)=O>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]([C:20]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[CH:7]=1)=[O:26]
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: COC(=O)C(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(C)ccc2o1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirring suspension of 5-methylsalicylaldehyde (1.0 mg, 7.5 mmol), K2CO3 (1.55 g, 11.0 mmol), and BU4NBr (322 mg, 1 mmol) in toluene (30 ml) was treated with dimethylbromomalo-nate (1.06 ml, 8.0 mmol). The suspension was heated to reflux with a Dean-Stark trap for 20 h. The brown suspension was cooled to 25° C. and concentrated in vacuo. The residue was taken in DCM and filtered. The filtrate was washed with H2O, 1N NaOH and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (10% ethyl acetate/hexane) to afford the title compound 583 (600 mg, 42% yield). LRMS : 190.2 (Calc.); 191.1 (found).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Br:10]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a chilled (10° C.) solution of 10 g (83 mmol) of 2,3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate solution and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexanes and passed through a pad of silica gel in a 600 mL funnel eluting with hexanes to afford a white solid which was diluted with cold (dry ice-acetone) hexanes and collected by filtration to afford 4.7 g (28%) of 5-bromo-2,3-dihydrobenzofuran as a white solid, mp 45° C.-48° C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2,3-dihydrobenzofuran which was 70% pure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:16][C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=2)[CH2:34][CH2:35]1)[C:22]([NH:24][CH2:25][CH3:26])=[O:23]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OCC)c3)OC(C)C(=O)N4)CC2)c(Cl)c1

Procedure:
Using 398B and 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide 286 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.20 Hz, 3H) 1.29-1.38 (m, 3H) 1.38-1.47 (m, 3H) 2.52-2.59 (m, 4H) 3.05 (br. s., 4H) 3.20-3.31 (m, 2H) 3.43 (s, 2H) 3.99-4.09 (m, 2H) 4.55-4.65 (m, 1H) 6.51 (d, J=1.77 Hz, 1H) 6.60-6.67 (m, 1H) 7.19 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.59, 2.02 Hz, 1H) 7.88 (d, J=2.02 Hz, 1H) 8.44 (t, J=5.56 Hz, 1H) 10.58 (s, 1H). ESI-MS: m/z 487.4 (M+H)+. mp 186.6-198.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[C:24](O)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.B.O1CCCC1>C(=O)([O-])O.[Na+].O1CCCC1.N1C=CC=CC=1>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: O=C(O)c1ccccc1
Agent: B
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cn2cc(Oc3cccc(NCc4ccccc4)c3)ccc2n1)C1CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (20.0 mg, 0.065 mmol), benzoic acid (16.5 mg, 0.135 mmol), HATU (42.3 mg, 0.111 mmol), N,N-diisopropylethylamine (35.0 μL, 0.204 mmol) and pyridine (1.5 mL) was stirred at 60° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (1.0 mL), and the mixture was stirred at room temperature. A solution (2.0 mL, 2.0 mmol) of 1M borane-tetrahydrofuran-complex/tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 39 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (7.7 mg, 30%).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C-:10]#[N:11].[Na+].O>CO>[C:10]([CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:11]
Reactant: COC(=O)CC(=O)CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CC(=O)CC#N
Temperature: 25 °C

Procedure:
10 g of methyl 4-bromo-3-oxobutanoate is dissolved in 100 g of methanol. The resultant solution is cooled to 0° C. and a solution of 4 g of sodium cyanide in 100 g of methanol is added thereto. After completion of the addition, the mixture is warmed gradually to room temperature under stirring. Thereafter, the reaction mixture is poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, concentrated to obtain methyl 4-cyano-3-oxobutanoate.
Reaction SMILES: N[C@H](C(O)=O)CCCCN.N[C@H](C(O)=O)C.N[C@H](C(O)=O)CCCCN.[NH2:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][C:30]1[CH:35]=CC=C[CH:31]=1.N[C@H](C(O)=O)CCCCN>>[NH2:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH:30]([CH3:35])[CH3:31]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
These compounds were prepared from the corresponding compounds I-III by removal of protecting groups with HBr in acetic acid. The benzyloxycarbonyl and t-butyloxycarbonyl groups were simultaneously removed by treatment with 30% Hbr in acetic acid containing anisol (10%) for 15 minutes at room temperature. Yields were about 90%. The molar ratios of the constituent amino acid residues and electrophoretic migrations relative to lysine were for compounds IV: Ala/Lys=1.05 (calc. 1.00), RLys =0.55, for compound V: Phe/Lys=1.06 (calc. 1.00), RLys =0.46, for compound VI: Ala/Lys=1.98 (calc. 2.00); RLys =0.51. Incubation of each of the compounds IV, V and VI with leucine aminopeptidase (E.C. 3.4.11.1) produced quantitatively ε(2-aminobenzoyl)-L-lysisne, (RLys =0.26) and the other expected product as judged by high voltage paper electrophoresis using authentic markers.
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[Li]CCCC.[O-]S(C(F)(F)[F:44])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C>CCCCCC.C1COCC1>[CH2:9]([C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[C:26]([F:44])[CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)[CH2:10][CH3:11]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)CCN(C)C
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(F)(F)F)c(F)c3)cc2)CC1
Temperature: 25 °C

Procedure:
0.01 mol of TMEDA is added to a solution of 0.01 mol of 4-(trans-4-n-propylcyclohexyl)-4'-trifluoromethylbiphenyl in 10 ml of n-hexane. At 0°-5° C. 0.01 mol of n-BuLi is added, and stirring at RT is continued for another half an hour and at 40° C. for half an hour. The mixture is then cooled to 0° C., 20 ml of THF are added, and the fluorinating agent 1-fluoro-2,4,6-trimethylpyridinium triflate (in THF) is added dropwise at this temperature according to scheme 21. Extractive work-up and, as is customary, chromatography and crystallization give 4-(trans-4-n-propylcyclohexyl)-3'-fluoro-4'-trifluoromethylbiphenyl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:40][C:41]1([CH3:48])[CH2:46][CH:45]([NH2:47])[CH2:44][CH2:43][O:42]1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([NH:47][CH:45]2[CH2:44][CH2:43][O:42][C:41]([CH3:48])([CH3:40])[CH2:46]2)=[O:26])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(N)CCO1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NC3CCOC(C)(C)C3)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.677 mmol) in THF (3 ml) were added DMF (0.03ml) and oxalylchloride (0.071 ml, 0.813 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylamine (175 mg, 1.35 mmol), triethylamine (0.313 ml, 2.25 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material.