Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC([C@@H](N)CO)=CC=1.[C:11]([O:15][C:16](=[O:40])[N:17]([CH2:27][CH2:28][C:29](=[O:39])[NH:30]OCC1C=CC=CC=1)[C@H:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19]O)([CH3:14])([CH3:13])[CH3:12].C(OC(N1CCC(=O)N(OCC2C=CC=CC=2)C[C@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:15][C:16]([N:17]1[CH2:27][CH2:28][C:29](=[O:39])[NH:30][CH2:19][C@H:18]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:40])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NOCc1ccccc1)[C@@H](CO)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(=O)N(OCc2ccccc2)C[C@H]1c1ccccc1
Agent: N[C@@H](CO)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(=O)NC[C@H]1c1ccccc1

Procedure:
The title compound, m/e=416.4, was produced in analogy with intermediate 16, steps A to D. Thus, D-phenylglycinol was elaborated to (2-benzyloxycarbamoyl-ethyl)-((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester in step A, then cyclized in step B, leading to (R)-4-benzyloxy-5-oxo-2-phenyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester. Hydrogenation in step C gave (R)-5-oxo-2-phenyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester, which was alkylated with 1-(3-chloropropyl)piperidine in step D.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH2:29][CH3:30]>C1COCC1>[CH2:29]([N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a suspension of NaH (11 mg of 60% in mineral oil, hexane-washed, 0.28 mmol) in 2 mL of THF at ambient temperature was added (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 1, Part H (40 mg, 0.11 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodoethane (0.039 mL, 0.63 mmol) and the reaction was allowed to stir at 45° C. in a sealed vial for 18 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 2:1 hexane/EtOAc) to afford 30 mg (71%) of the title compound. LRMS (ESI): 407.22 (M+H+Na)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:2][CH2:3]1
Reactant: Nc1ccccc1OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1OCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of 2-(cyclopropylmethoxy)aniline (1.03 g, 6.31 mmol) in pyridine (20 ml) was cooled to 0° C., and methanesulfonyl chloride (0.541 ml, 6.94 mmol) was added. The mixture was warmed to RT and stirred for 2 hours. The solvent was removed, and the crude was portioned between EtOAc and HCl 1N. The organic phase was washed with brine and dried over Na2SO4. The solvent was removed and the crude was purified by filtration on silica gel cartridge (petroleum ether:EtOAc=80:20) affording N-(2-(cyclopropylmethoxy)phenyl)methanesulfonamide (1.456 g, 6.03 mmol, 96% yield, MS/ESI+ 263.9 [MNa]+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2(O)[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[S:19][CH2:18][CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].O>ClCCCl.[I-].[Zn+2].[I-]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[S:19][CH2:18][CH:17]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 68 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
To a solution of 4-[3-(t-butyldimethylsilyloxymethyl)phenyl]-7-methoxy-3 (4-methoxyphenyl)thiochroman-4-ol (619 mg, 1.184 mmol) in 1,2-dichloroethane (70 ml) were added zinc iodide (567 mg, 1.776 mmol) and sodium cyanoborohydride (558 mg, 8.88 mmol) and stirred at 68° C. for 2.5 hours. When the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate: The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed on silica gel (n-hexane:ethyl acetate=8:2) to give 365 mg (yield: 61%, 3RS,4RS/3RS,4SR=6:1) of the title compound as a white solid. In this reaction, 260 mg (42%) of the unreacted starting compound was recovered.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3]1.[CH:13](OC)=[O:14].CC([O-])(C)C.[K+]>C1COCC1>[CH:13]([CH:8]([CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: COC(=O)CCc1cnn(C)c1
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate (18.7 g, 111 mmol) and methyl formate (14.02 g, 233 mmol) in dry THF (20 ml) was added dropwise over 2 h to a stirred, ice-cooled suspension of t-BuOK (31.2 g, 278 mmol) in dry THF (160 ml) under argon. The mixture was then allowed to warm to room temperature and stirred for 16 h. The solvents were removed in vacuo, and the residue was dissolved in water (50 ml). The solution was extracted with ethyl acetate (30 ml×2), and the aqueous phase was neutralized with 1M HCl to pH˜5. The solid was collected. The filtrate was extracted with ethyl acetate (40 ml×2), dried over Na2SO4, filtered and concentrated in vacuo. The solids were combined to give the title compound as a white solid (9.1 g, 39.8% yield). LCMS: rt=1.05 min, [M+H+]=197
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=[C:22]([NH2:29])[C:21]=2[N:20]=[C:19]1[CH3:30]>>[NH2:29][C:22]1[C:21]2[N:20]=[C:19]([CH3:30])[N:18]([CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:26]=2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the method of Examples 54–68, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 397.2343.
Reaction SMILES: C(N)(OC(C)(C)C)=O.Cl.C(OC([NH:17][CH2:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3[S:32][CH:33]=[CH:34][C:26]2=3)=[O:24])=[CH:21][C:20]=1[Cl:37])=O)(C)(C)C>Cl.O1CCOCC1>[ClH:37].[NH2:17][CH2:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3[S:32][CH:33]=[CH:34][C:26]2=3)=[O:24])=[CH:21][C:20]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)N2CCCCc3sccc32)cc1Cl
Agent: CC(C)(C)OC(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(C(=O)N2CCCCc3sccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The BOC amine from 11A was dissolved in 4N HCl/dioxan (30 ml). The mixture was stirred at room temperature for 40 min then concentrated in vacuo to leave a tan solid; yield 0.41 g (63%, for 2 steps).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][NH:27][CH:28]=O)=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=2)[N:4]=1)[CH3:2].C[Si](C)(C)O[Si](C)(C)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:48]>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[S:48][CH:28]=[N:27][N:26]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC=O)ccn34)c12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5nncs5)ccn34)c12
Temperature: 110 °C
Yield: 4.2 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-formylhydrazinecarbonyl)imidazo[1,2-a]pyridine-3-carboxamide (36 mg, 0.073 mmol) in toluene/dioxane (1 mL/1 mL) was added hexamethyldisiloxane (71 mg, 0.44 mmol) and P2S5 (81 mg, 0.36 mmol). The reaction mixture was sealed and heated in a microwave reactor to 110° C. for 3 hours. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (1.5 mg). MS (ES+APCI) m/z=495 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:15]=1[CH2:16]Br>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:16][C:15]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:14]=3[F:13])[C:4]=2[CH:3]=1
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: O=C1CNc2ncc(I)cc2N1
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.0 g) was reacted with 2,4,5 trifluorobenzyl bromide as in General Procedure 1 to give the title compound as a pale yellow solid (55% yield). M.p. 227-228° C., LCMS: m/z=420.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.26 (s, 2H), 4.89 (bs, 1H), 5.06 (s, 2H), 6.91-7.00 (m, 2H), 7.16 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)CCC>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([NH:20][C:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=2)[CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1nccc(Nc2cccc(OCc3ccccc3)c2)n1
Temperature: 50 °C
Reaction time: 17 h
Yield: 40.7 %

Procedure:
A mixture of 2,6-dichloropyrimidine (2.00 g, 13.4 mmol), 3-benzyloxyaniline (2.07 g, 13.4 mmol) and triethylamine (2.72 g, 26.8 mmol) in 1-butanol (20 mL) was stirred at 50° C. for 17 h. The reaction mixture was concentrated to remove most of the 1-butanol, the crude product was preabsorbed onto silica gel using chloroform and purified by flash chromatography (95:5 chloroform/methanol) to afford N4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (1.70 g, 40%) as colorless oil: 1H NMR (300 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 7.48-7.24 (m, 7H), 7.12 (d, J=9.0 Hz, 1H), 6.78 (m, 2H), 5.11 (s, 2H); ESI MS m/z 312 [C17H14ClN3O+H]+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][CH2:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CCCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 38.5 %

Procedure:
Using cyclohexyl{3-propyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.65 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.38 g, 39%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH2:11][NH:10][CH2:9]1.[Na]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:10]1[CH2:9][CH:8]=[C:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11]1
Reactant: O=C(O)C1=CCNCC1
Reactant: Clc1ncccn1
Agent: [Na]
Solvent: O
Product: O=C(O)C1=CCN(c2ncccn2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloropyrimidine (0.570 g, 4.98 mmol), and isoguvacine, sodium salt (1.2 g, 8.2 mmol) in water (7 mL) was heated to 90° C. and stirred for 4 hour. Additional isoguvacine, sodium salt (0.52 g, 3.3 mmol) was then added and stirred overnight. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was acidified with conc HCl (pH˜3) and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid a white solid (0.564 g, 2.75 mmol, 55%): 1H NMR (300 MHz, CD3OD) δ 8.43 (d, J=4.8 Hz, 2H), 7.02 (sept, J=1.7 Hz, 1H), 6.74 (t, J=4.8 Hz, 1H), 4.39 (q, J=3.0 Hz, 2H), 3.97 (t, J=5.8 Hz, 2H), 2.49 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]([C:21]1[CH:38]=[CH:37][CH:36]=[CH:35][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1)=[O:20].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:10]([N:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:32](=[O:34])[CH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:22]2[CH:35]=[CH:36][CH:37]=[CH:38][C:21]=2[C:19]([O:18][CH3:17])=[O:20])=[CH:30][CH:29]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCNCCc1ccccc1
Reactant: COC(=O)c1ccccc1OCc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccccc1)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
N-(2-Phenylethyl)heptan-1-amine (0.110 g, 0.500 mmol) was dissolved in DMF (10 ml), (4-{[2-(methoxycarbonyl)phenoxy]methyl}phenyl)acetic acid (0.150 g, 0.500 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.176 g, 0.549 mmol) and N-ethyl-N,N-diisopropylamine (0.136 g, 1.049 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.229 g of methyl 2-[(4-{2-[heptyl(2-phenylethyl)amino]-2-oxoethyl}benzyl)oxy]benzoate (yield 91.4%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([N:57]2[C:65]3[CH2:64][CH2:63][CH2:62][NH:61][C:60]=3[CH:59]=[N:58]2)=[CH:53][CH:52]=1>O.C(OCC)(=O)C.CN(C)C=O>[F:50][C:51]1[CH:52]=[CH:53][C:54]([N:57]2[C:65]3[CH2:64][CH2:63][CH2:62][N:61]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:13]([F:16])([F:15])[F:14])=[N:5]4)[CH2:11][CH3:12])[C:60]=3[CH:59]=[N:58]2)=[CH:55][CH:56]=1
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)cc1C
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)cc1C
Reaction time: 0.02 h
Yield: 91.6 %

Procedure:
Dimethylformamide (0.7 mL) was added to a mixture containing 2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]butyric acid (50.5 mg, 0.214 mmol) and HATU (84.1 mg, 0.221 mmol). Diisopropylethylamine (92 μL, 0.53 mmol) was added at room temperature and the reaction mixture was stirred for 1 minute. 1-(4-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (44.1 mg, 0.203 mmol) was then added all at once and the reaction mixture was stirred at room temperature overnight. Ethyl acetate and water were added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 17-33% ethyl acetate in hexanes) to afford the desired product as a white solid (80.9 mg, 0.186 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (ddd, J=8.8, 5.2, 2.0 Hz, 2H), 7.15 (ddd, J=8.4, 8.4, 2.0 Hz, 2H), 6.30 (s, 1H), 5.32 (dd, J=8.4, 6.8 Hz, 1H), 3.78 (ddd, J=12, 7.2, 2.8 Hz, 1H), 3.47 (ddd, J=12, 8.8, 3.2 Hz, 1H), 2.69-2.81 (m, 2H), 2.31 (s, 3H), 2.18-2.38 (m, 2H), 1.88-1.97 (m, 1H), 1.74-1.83 (m, 1H), 0.98 (t, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C21H21N5OF4 [M+H]+ 436, found 436.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>CN(C=O)C>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:32]
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinoline (0.1 g, 0.24 mmol) in DMF was treated with N,N-diethylamine (excess) and KI (catalytic). The reaction was heated to 60° C. in a sealed tube and stirred overnight. The reaction was quenched with water and extracted with CH2Cl2. The organic was dried and the solvent removed. The crude was purified by silica gel column to afford the desired product. MS ES+ m/e 452 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:18]([C:20]2[CH:21]=[N:22][C:23](Cl)=[N:24][CH:25]=2)=[O:19])[CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])#[N:28]>>[CH:15]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:20]2[CH:25]=[N:24][C:23]([C:32]3[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[C:30]([F:38])[CH:31]=3)=[N:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1F
Product: N#Cc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1F

Procedure:
The title compound is prepared from 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester and 4-cyano-3-fluorophenylboronic acid following a procedure analogous to that described in Intermediate 6. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=366 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]=1[N+:23]([O-:25])=[O:24]>CN(C)C=O>[N+:23]([C:14]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:21]=[CH:22][C:13]=1[O:12][CH2:10][CH2:9][CH2:8][Br:7])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1c(O)ccc2c1CCCC2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(OCCCBr)ccc2c1CCCC2
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
N,N-dimethylformamide (180 ml), potassium carbonate (37.8 g, 0.273 mol), and 1,3-dibromopropane (93 ml, 0.916 mol) were added to 2-hydroxy-5,6,7,8-tetrahydro-1-nitronaphthalene (17.6 g, 0.091 mol) and the mixture was stirred at 70° C. for 4 hours. The precipitated salts were removed by filtration, and then the solvent was evaporated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 500 g, eluent: ethyl acetate/hexane=1/20) to give 5,6,7,8-tetrahydro-1-nitro-2-(3-bromopropoxy)naphthalene (19.4 g).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH:7]([CH3:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:9].C1COCC1.O>CO>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[CH:7]([CH3:23])[C:6]([OH:24])=[O:5])=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
LiOH.H2O (73 mg, 1.7 mmol) was added to a solution of N-biphenyl-4-yl-2-methyl-malonamic acid methyl ester (330 mg, 1.16 mmol) in a mixture of methanol (1.75 mL), THF (10 mL) and H2O (1 mL). The resulting mixture was stirred for 2 hours at ambient temperature then concentrated. The residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 260 mg (83%) of N-biphenyl-4-yl-2-methyl-malonamic acid.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO.C(N(CC)CC)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]2[CH2:12][C:5]3[C:4](=[CH:9][CH:8]=[C:7]([O:10][CH3:11])[CH:6]=3)[C:3]2=[O:14])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccc(OC)cc1CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)CN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (1.28 g, 4.94 mmol, 1.0 equiv) in methanol (9 mL) and triethylamine (0.83 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.04 g, 5.19 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice/diluted HCl, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaHCO3 and water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (3:7) yielding 0.84 g (49%) of the title compound as white crystals. MS (ISP): 347.3 [M+H]+.