Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH4+:5].[Cl-].[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](OC)=[O:33])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]([N:17]1[CH2:22][C@@H:21]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:20][C@H:19]([C:32](=[O:33])[NH2:5])[C@@H:18]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](C(N)=O)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
Under an atmosphere of N2, a 2.0M solution of Me3Al in PhMe (Aldrich, 140 ml, 280 mmol) was added dropwise to a stirred and ice-cooled suspension of NH4Cl (14.92 g, 279 mmol) in dry PhMe (280 ml). After the addition was complete, the reaction mixture was allowed to stirr at room temperature for 30 minutes; at this point, solid NH4Cl disappeared completely, and the clear, homogeneous mixture resulted. To this was added a solution of (2R*,3S*,5S*)-1-benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (13.88 g, 27.89 mmol) in dry PhMe (30.0 ml) dropwise at room temperature: on the addition, the reaction mixture became turbid. This was stirred and heated at a bath temperature of 50 C. overnight (ca. 20 hours). The turbid white reaction mixture was ice-cooled; and H2O (80.0 ml, 4.40 mol) was added carefully, wherein H2 gas evolved violently. The resultant white precipitates were filtered off by the aid of Celite, and washed with AcOEt (80 ml×5). The combined filtrate and AcOEt washings were washed with sat. NaCl aq. solution (×2), dried (MgSO4), and concentrated in vacuo to give a viscous colorless oil (13.76 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 100 g). Elution with n-hexane-AcOEt (5:1/2:1/1:1) gave title compound (11.10 g, 82.4%) as a colorless syrup. IRmax (film): 3405(s), 3340(s), 3200(s), 3100(w), 3070(m), 3045(m), 1735(m), 1675(br., v.s), 1610(s), 1498(s), 1160(s), 1100(s), 836(s), 775(s), 737(s) cm-1 ; 1H-NMR δ: 7.42-7.18(m, 10H), 5.83(d, J=5.1 Hz, 1H), 5.67(br.s, 1H), 5.47(br.s, 1H), 5.20(d, J=12.5 Hz, 1H), 5.13(d, J=12.5 Hz, 1H), 3.91(br.d, J=13.9 Hz, 1H), 3.63(dd, J=10.0, 6.8 Hz, 1H), 3.53(dd, J=10.0, 7.7 Hz, 1H), 3.08(dd,J=13.9, 7.7 Hz, 1H), 2.98(ddd,J=17.6, 5.1, 4.8 Hz, 1H), 2.25-1.91(m, 3H), 0.87(s, 9H), 0.02(s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[O:22])[CH2:17][CH2:16]2)[C:12]([Cl:34])=[CH:11][N:10]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[O:22])[CH2:19][CH2:20]2)[C:12]([Cl:34])=[CH:11][N:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 4-(2-((2-aminophenyl)amino)-5-chloropyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide (0.043 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.004 mL, 0.052 mmol) and DIEA (0.018 mL, 0.11 mmol) and the mixture was stirred at 0° C. for 1 h. The crude reaction mixture was loaded onto silica gel and purified using 0-7% MeOH/DCM gradient to give the title compound (10 mg, 43%). MS (ES+) C25H23ClF3N7O2 requires: 545. found: 546 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]Br.O>ClC1C=CC=CC=1>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(O)C(Br)c1ccc(Cl)cc1
Temperature: 105 °C
Yield: 95 %

Procedure:
In a stirred reactor with reflux condenser (connected to a caustic scrubber) 171 g 4-chlorophenyl acetic acid are pre-charged in 750 g chlorobenzene and 41 g phosphortrichloride (0.3 Mol) are added. The mixture is heated to 100-110° C. and 280 g bromine (1.75 mole) are added within 1 hour through a dropping funnel. The reaction mixture is stirred for another 3-4 hour at 110-115° C. until the conversion of the 4-chlorophenyl acetic acid is complete (control by LC). The reaction mixture is cooled to 50° C. and 100 ml water is added. Excess bromine is destroyed by addition of NaHSO3 solution. The reaction mixture is adjusted to pH 1 with aqueous NaOH solution and then the organic product phase is separated from the aqueous phase. The chlorobenzene phase contains 237 g bromo-(4-chloro-phenyl)acetic acid by LC analysis (yield=95% of theory based on 4-chlorophenylacetic acid). The “bromoacid” bromo-(4-chloro-phenyl)acetic acid can be isolated partly by concentration to a 50% solution and crystallisation/filtration at 0° C. About 200 g of bromo-(4-chloro-phenyl)acetic acid can be isolated in a crystallised form. Melting point=92-93° C. 1H-NMR (CDCl3) δ (ppm): 5.3 (s, 1H); 7.4 (4H, Ar); 9.7 (1H, OH)
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH2:30][CH2:31][OH:32])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][N:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:32][CH2:31][CH2:30][N:22]1[C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([C:17]2[O:16][N:15]=[C:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[N:18]=2)[CH:20]=[N:21]1)(=[O:3])=[O:2]
Reactant: OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1ncc(-c2nc(-c3cc(F)ccc3F)no2)c1-c1ccccc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Mesyl chloride (280 μL; 3.6 mmol) was added to a solution of 2-(4-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5-phenyl-1H-pyrazol-1-yl)ethanol (663 mg; 1.8 mmol), obtained from step 1, and triethylamine (502 μL; 3.6 mmol) in dry DCM (5 mL) at 0° C. The tube was sealed and allowed to warm to room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate and the organic fraction passed through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a pale yellow solid (785 mg; 97%). 1H NMR (CDCl3, 400 MHz) δ 8.31 (1 H, s), 7.69-7.64 (1 H, m), 7.59-7.81 (3 H, m), 7.50-7.45 (2H, m), 7.21-7.10 (2 H, m), 4.64 (2 H, t, J=5.2 Hz), 4.38 (2 H, t, J=5.2 Hz), 2.90 (3 H, s). LC/MS: 447 (M+H)+. HPLC (Method A) Rt=3.69 min (Purity: 99.4%).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1.C(=O)(O)[O-].[Na+]>>[O:7]([CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCOc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Product: OCC1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture of 2-bromoethyl phenyl ether (20.1 g), piperidin-3-yl-methanol (11.5 g), sodium bicarbonate (8.4 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was treated with water (50 ml), 2M sodium hydroxide solution (20 ml) and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine and then extracted with 2M hydrochloric acid. The combined acidic extracts were washed with dichloromethane then basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give 1-(2-phenoxyethyl)piperidin-3-ylmethanol as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([C:20](=[O:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([OH:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)O)n3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of Example 100C (1.7 g, 0.0047 mol) in a mixture of methanol and tetrahydrofuran (1:1) was added sodium borohydride (0.36 g, 0.0094 mol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (ethyl acetate/hexane, 10˜50%) to give 1.43 g of product as a white solid (84% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 1.70 (d, J=6.62 Hz, 3H) 2.87 (s, 1H) 4.45-4.61 (m, 1H) 5.27 (q, J=6.62 Hz, 1H) 6.87-6.98 (m, 2 H) 7.16-7.25 (m, 2H) 7.94 (s, 1H). MS (ESI), M/Z: 364.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:23]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:5][N:6]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
To a mixture of 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g) and pyridine (1 g) in N,N-dimethylformamide (30 ml) was added dropwise the propionylchloride (1.1 g) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 3.5 hours. The reaction mixture was poured into ice water and the mixture was adjusted to pH 8 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-propionylamino-5-(4-nitrophenylthio)thiazole (2.5 g, yield: 78.7%). mp: 227°-229° C. (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15]N(C)[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH2:18].N1CC[O:22]CC1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:22][CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[NH2:18]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: C1COCCN1
Product: COc1cc(CCN2CCOCC2)ccc1N

Procedure:
2-Methoxy-4-(2-morpholin-4-yl-ethyl)-phenylamine was prepared in a similar manner as 2-Methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine of Example 488 replacing 1-Methyl-piperazine with morpholine. LC/MS (E/I+) 237.07 (M+H).
Reaction SMILES: [K].[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24][CH2:25]Cl)(=[O:23])[CH3:22]>CN(C)C=O>[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([O:20][CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:19])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCl
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethyl acetate in dimethylformamide to provide acetoxymethyl 3-phenyl-7-benzofuranacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[NH:12][C:11]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:37][OH:38]>C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[NH:20])[NH:37][OH:38])[CH:17]=2)[NH:12][C:11]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C#N)cc3c2CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=N)NO)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 32.3 %

Procedure:
A solution of {2-[5-cyano-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (300 mg in 5 mL ethanol) was added to a suspension of 725 mg potassium carbonate and 273 mg hydroxylamine hydrochloride in 7 mL ethanol and the whole heated to reflux on an oil bath. After 21 hours, the mixture was cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo then partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8) to give the title compound (105 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:16])[C:8](=[O:9])[C:7]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:6]=2[O:5]1.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:6]2[O:5][C:4]([CH3:16])([CH3:3])[C:8](=[O:9])[C:7]=2[C:10]=1[CH3:15]
Reactant: Cc1cc(C)c2c(c1)OC(C)(C)C2=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc2c(c(C)c1Br)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Bromine (8.7 mL, 169 mmol) was added to a mixture of acetonitrile (200 mL) containing 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (30.7 g, 161 mmol) synthesized in Reference Example 118 and sodium acetate (14.5 g, 177 mmol), and the mixture was stirred at room temperature for 2 hours. After that, the reaction solution was poured into 5% sodium sulfite aqueous solution, and extraction was performed using ethyl acetate. The extract was washed with water and saturated saline, and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 50:1-9/1), and crystallization was performed using methanol to give 26.2 g of the title compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10](O)[C:9]=2[C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[NH:10][C:9]=2[C:18]([F:21])([F:19])[F:20])=[CH:6][CH:7]=1
Reactant: On1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)c1C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)c(C(F)(F)F)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Zinc dust (20 g, 0.3 mol) is added to a solution of 3-(p-chlorophenyl)-2,5-bis(trifluoromethyl)-1-hydroxypyrrole (7.5 g, 0.023 mol) and acetic acid (50 mL). The reaction mixture is refluxed for 1/2 hour, cooled to room temperature, filtered to remove solids, diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a pale red liquid (6.8 g). A portion of the red liquid (1.6 g) is chromatographed using silica gel and eluted with methylene chloride to give the title product as a colorless liquid (1.1 g). Identified by IR and NMR spectral analyses.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:65]([NH2:70])[C:66]([CH3:69])([CH3:68])[CH3:67]>CN(C)C=O>[CH3:67][C:66]([CH3:69])([CH3:68])[CH2:65][NH:70][C:30](=[O:32])[CH2:29][N:27]1[CH:28]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC(C)(C)CN
Reactant: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (0.60 g, 0.128 mmol) in dimethylformamide (1 ml) was added EDCl (50 mg, 0.256 mmol), diisopropylethylamine (112 μl, 0.640 mmol), HOBT (35 mg, 0.256 mmol) and finally neopentylamine (30 μl, 0.256 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.51 min, MI: 517 [M+1]; 1H NMR (300 MHz, DMSO) 9.40 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 7.61 (d, 2H), 7.54 (d, 1H), 7.40 (dd, 2H), 6.92 (d, 2H), 4.98 (s, 2H), 4.02 (t, 2H), 2.93 (d, 2H), 2.87 (t, 2H), 2.63 (s, 4H), 1.69 (s, 4H), 0.83 (m, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.O>CN(C=O)C>[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: OCCC1CCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4CCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
In DMF (3ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200mg), and to the mixture was added 2-(2-hydroxyethyl)piperidine (214mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[2-(2-hydroxyethyl)piperidinomethyl]phenyl]-3-(4-methyl-phenyl)cinnamamide (Compound 69) (202mg) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([OH:15])C>[OH-].[Na+]>[CH3:13][O:15][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[C:3]2[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2c(C(=O)O)c[nH]c12
Yield: 47 %

Procedure:
Preparation of 5 was based on a procedure for the synthesis of indole-3-carboxylic acid reported by R. K. Mackie et al. [supra]. To a 200-mL round bottom flask, 2.369 g of 4 (9.75 mmol) was added. Compound 4 was dissolved in 19 mL of absolute ethanol and 53 mL of 5N aqueous sodium hydroxide, refluxed overnight, and allowed to cool. The ethanol was removed by rotary evaporation, and the resulting solution was extracted with two 25-mL portions of diethyl ether. The aqueous solution was acidified with concentrated hydrochloric acid, and the peach-colored precipitate was collected. Recrystallization from hot aqueous ethanol (50:50 ethanol:water) yielded 0.883 g (47%) of 5 as cream-colored crystals: 1H NMR (acetone-d6) δ 3.95 (s, 3H, OCH3), 6.76 (d, 1H, J=7.3 Hz), 7.10 (app. t, 1H, J=8 Hz), 7.71 (d, 1H, J=8.5 Hz), 7.95 (m, 1H), 11.0 (br s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCC1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Product: Nc1ncnn2c(-c3cccc(CNC4CCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 17 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclobutanone as starting materials, 39 mg (17%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (m, 2 H), 2.10 (m, 1 H), 2.00 (m, 2 H), 1.70-1.40 (m, 4 H); ES-MS m/z 500.2 [M+H]+, HPLC RT (min) 2.46.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][N:13]=1)#[N:11].[NH:20]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:21]([C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:10]([C:12]1[N:13]=[CH:14][C:15]([CH2:18][NH:19][C:33](=[O:34])[C@@H:32]2[CH2:36][CH2:37][CH2:38][N:31]2[C:29](=[O:30])[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:20][C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(CN)cn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)nc1
Reaction time: 2 h

Procedure:
8.12 g of diisopropylethylamine, and subsequently 11 ml (15 mmol) of propanephosphonic anhydride (50% strength solution in ethyl acetate), were added dropwise to a solution of 2.11 g (12.5 mmol) of 2-cyano-5-(aminomethyl)pyridine and 4.5 g (12.5 mmol) of Boc-D-Phe-Pro-OH in 70 ml of CH2Cl2 at -5° C. The mixture was then stirred for 2 h, allowing the temperature to rise from -5° to 20° C. The organic phase was washed with water, 5% strength sodium bicarbonate and 5% strength citric acid solutions, dried over Na2SO4 and evaporated to dryness, a pale yellowish crystalline residue was obtained, melting point 167-170° C., which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:14][CH:15]([NH:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:16].C(N=C=NCCCN(C)C)C>>[CH3:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[C:10]=1[O:11][CH3:12])[C:5]([N:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([NH:17][CH:15]([CH3:16])[CH3:14])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1)=[O:7]
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Product: COc1c(C)cc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1C

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 3,5-dimethyl-4-methoxybenzoic acid (0.075 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.101 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.096 g), the title compound is obtained, mp 89°-93°.