Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCNC[C@H]1C)=O)(C)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@H:26](COC)[N:25]([CH2:31][C:32]([OH:34])=[O:33])[CH2:24][C@H:23]1[CH3:35])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:31][C:32]([OH:34])=[O:33])[CH2:24][C@H:23]1[CH3:35])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Agent: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(CC(=O)O)CCN1C(=O)OC(C)(C)C

Procedure:
Prepared from (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester in an analogous manner to that described for (2R,5R)-4-carboxymethyl-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester in Preparations 13 and 14. 1H NMR (Me-d3-OD): 4.51-4.42 (1H, m), 4.10-3.99 (1H, m), 3.58 (1H, d), 3.53-3.39 (2H, m), 3.28 (1H, s), 2.99-2.82 (2H, m), 1.49 (9H, s), 1.36 (3H, d).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(Cl)(Cl)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[O:32])=[C:27]([Cl:40])[CH:26]=2)=[C:20]([CH2:41][O:42][CH2:43][CH2:44]O)[CH:19]=1>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:12][CH2:44][CH2:43][O:42][CH2:41][C:20]1[CH:19]=[C:18]([Br:17])[CH:23]=[CH:22][C:21]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:32])=[C:27]([Cl:40])[CH:26]=1)=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)OCCOCc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1)OCC

Procedure:
The reactions were performed under an argon atmosphere using oven dried glass ware. Diethylphosphonoacetic acid (0.053 mL, 0.33 mmol) was dissolved in dry toluene (2 mL) and thionylchloride (0.065 mL, 0.9 mmol) was added. The reaction mixture was refluxed for 2 h and then concentrated in vacuo. Compound 158 (0.14 g, 0.3 mmol) was dissolved in dry THF (1.5 mL). 4-N,N-dimethylaminopyridine (0.073 g, 0.6 mmol) was added followed by addition of the above acid chloride dissolved in THF(1.5 mL). The reaction mixture was heated at reflux temperature for 20 h. The reaction mixture was diluted with EtOAc and aqueous NaHCO3, and the organic phase was washed with H2O and brine, and the combined water phases were extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether 2:1 as the eluent to afford the title compound as a slightly coloured oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.[F:27][C:28]([F:35])([F:34])[CH2:29]S([O-])(=O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][N:24]([CH2:29][C:28]([F:35])([F:34])[F:27])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Reactant: O=S(=O)([O-])CC(F)(F)F
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(CC(F)(F)F)n4)nn23)no1

Procedure:
The title-compound was prepared from 3-(5-methylisoxazol-3-yl)-6-(1,2,4-triazol-3-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine and 2,2,2-trifluoroethylsulphonate following the procedure given for Example 47. The two regioisomers were separated by M.P.L.C. [Lobar Lichroprep Si60 (40-63 μm) (Art. 10402)], eluting with 2.5% methanol/dichloromethane, to give the title-product as the more polar isomer, 1H NMR (360 MHz, CDCl3) δ 8 2.58 (3H, s, CH3), 4.81 (2H, q, J=8.1 Hz, CH2), 5.75 (2H, s, CH2), 6.94 (1H, d, J=0.7 Hz, Ar—H), 7.80 (1H, t, J=7.2 Hz, Ar—H), 7.98 (1H, t, J=8.0 Hz, Ar—H), 8.26-8.28 (2H, m, Ar—H), 8.70 (1H, d, J=7.7 Hz, Ar—H); MS (ES+) m/e 431 [MH]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18]>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:13])[CH2:10][O:9][CH3:8]
Reactant: CNOC
Reactant: COCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64.1 %

Procedure:
Triethylamine (115 mL) was added to a solution of methoxyacetic acid (35.0 g, 389 mmol) in CH2Cl2 (1200 mL) at room temperature. N,O-dimethylhydroxylamine hydrochloride (45.5 g, 467 mmol) was added, and after stirring for 5 min, the suspension was cooled to 0° C. Ethyl diazocarboxylate (EDC) (81.7 g, 428 mmol) was then added and the reaction mixture was stirred overnight while allowing it to warm to room temperature. The mixture was poured into a separatory funnel and diluted with CH2Cl2 (500 mL). The organic layer was washed with 1 N HCl (2×300 mL), saturated aqueous NaHCO3 solution (2×300 mL), and brine (300 mL). The resulting solution was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by column chromatography on a short column of silica gel (5% methanol in CH2Cl2) to afford N,2-dimethoxy-N-methylacetamide (33.2 g, 64% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 2H), 3.67 (s, 3H), 3.45 (s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 69.7, 69.4, 61.4, 59.4; LRMS (ESI) m/e 134.1 [(M+H)+, calcd for C5H12NO3 134.1].
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]([CH3:15])=[C:6]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1>CC(O)=O.[Zn]>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]([CH3:15])=[C:6]([CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(=O)c1cc(Cl)c(OC)cc1C
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)C(O)c1cc(Cl)c(OC)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A solution of ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-oxoacetate (Intermediate 3-7; 6.12 g, 23.84 mmol) in warm AcOH (60 mL) was added to a stirred suspension of zinc dust (7.80 g, 119.21 mmol) in AcOH (20 mL) and the resulting suspension was stirred at ambient temperature for 16 hours. The reaction mixture was filtered, the filtrate diluted with EtOAc (200 mL), and washed with saturated brine (3×125 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-hydroxyacetate (5.70 g, 92%) as a pale yellow oil which solidified on standing, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][C:11](=O)[C:12](=O)[CH3:13]>C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:11]([C:12](=[N:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:13])[CH3:10]
Reactant: CC(=O)C(C)=O
Reactant: Cc1cccc(C)c1N
Solvent: CCO
Product: CC(=Nc1c(C)cccc1C)C(C)=Nc1c(C)cccc1C
Reaction time: 12 h
Yield: 77.5 %

Procedure:
A mixture of 37.2 ml (36.3 g, 0.3 moles) of 2,6-dimethylaniline, 13.1 ml (12.9 g, 0.15 moles) of 2,3-butanedione and 100 ml of ethanol is boiled for 12 hours. The solvent is evaporated under reduced pressure, 80 ml of water and 20 ml of acetic acid are added to the residue, and the resulting mixture is stirred for 6 hours at 0° to ±5° C. The mixture is allowed to stand overnight, thereafter the separated precipitate is filtered off, washed with water and dried. 34.0 g (77.5%) of crude 2,3-bis(2',6'-dimethylphenyl-imino)-butane are obtained; m.p.: 78°-86° C. After recrystallization from ethanol 25.1 g (57.2%) of the pure substance, melting at 88°-90° C., are obtained.
Reaction SMILES: [Br:1][C:2]1([Br:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:13]Br.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O>[Br:12][C:2]1([Br:1])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br

Procedure:
A solution of 3,3-dibromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (5.0 g, 13.4 mmol) in tert-BuOH (100 mL) and water (100 mL) was stirred at room temperature and bromine (5.5 g, 34.3 mmol) was added dropwise over 20 min. A saturated aqueous solution of sodium bicarbonate (approx. 15 mL) was added dropwise over 30 min to raise the pH of the solution to 6.5. The yellow solid formed was collected by filtration. The filtrate was condensed to approx. 100 mL and extracted with CHCl3 (2×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to leave a yellow solid. The solids were combined and dried under vacuum to give 3,3,5-tribromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one as a yellow solid, 6.25 g (98%). 1H NMR (CDCl3) δ 9.4 (br s, 1H), 8.28 (d, 1H, J=2 Hz), 7.95 (d, 1H, J=2 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 256A (0.065 g, 0.142 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.012 mL, 0.284 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.111 mL, 0.222 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H) 3.87 (s, 2 H) 6.03 (s, 1 H) 7.10 (m, 1 H) 7.21 (d, J=7.72 Hz, 2 H) 7.30 (t, J=7.17 Hz, 2 H) 7.42 (d, J=7.72 Hz, 2 H) 7.56 (t, J=8.64 Hz, 2 H) 7.70 (t, J=9.38 Hz, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.28 (m, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[CH3:50][C@@H:51]([O:55][C:56](=[O:61])[O:57][CH:58](Cl)[CH3:59])[CH2:52][CH2:53][CH3:54]>CN(C=O)C>[CH3:50][C@@H:51]([O:55][C:56](=[O:61])[O:57][CH:58]([O:16][C:14]1[N:13]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[N:12]=[C:11]([CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:4][CH:5]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[N:15]=1)[CH3:59])[CH2:52][CH2:53][CH3:54]
Reactant: CCC[C@@H](C)OC(=O)OC(C)Cl
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@@H](C)OC(=O)OC(C)Oc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 55 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 150 mg) and DMF (3 mL), potassium hydrogen carbonate (150 mg) and carbonic acid 1-chloroethyl ester (R)-1-methylbutyl ester (150 mg) were sequentially added, and the resulting mixture was stirred at 55° C. for 18 hours. The reaction mixture was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water) to obtain the captioned compound (130 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])[C:26](O)=[O:27])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:3]1[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])[C:31]([OH:32])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNC(=O)Nc1ncccc1N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ncccc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 86.9 %

Procedure:
A mixture of 1-(3-amino-2-pyridyl)-3-heptylurea (0.80 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.80 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.67 g) was stirred in dichloromethane (35 ml) at room temperature for 3 hrs. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to give N-[2-(3-heptylureido)-3-pyridyl]-3,5-di-t-butyl-4-hydroxybenzamide (1.34 g, 87%) as a non-crystallizable solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH2:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1)[CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:34][CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=2)([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: CCc1ccc(CCN)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(CC)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(4-ethyl-phenyl) ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H33NO5 [M+H]+: 428.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=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>[NH2:1][C:2]1[C:3]2[C:10]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](CO)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CO)C1

Procedure:
Following the general procedure for the Suzuki coupling, trans-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (139.2 mg, 0.4045 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (141 mg, 0.426 mmol), Na2CO3 (107 mg, 1.01 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-7)→2% MeOH in CH2Cl2 (8-22)→5% MeOH in CH2Cl2 (23-41)→7% MeOH in CH2Cl2 (42-51)], yielding the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.42-2.60 (m, 3H), 2.60-2.73 (m, 3H), 3.88 (d, J=6.4 Hz, 2H), 5.19 (brs, 2H), 5.44-5.53 (mc, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.7, 8.3 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 30.62 (+), 32.16 (2C1-), 46.70 (+), 65.12 (−), 101.04 (Cquart), 116.13 (Cquart), 118.88 (+), 120.64 (+), 125.82 (Cquart), 127.27 (+), 127.45 (2C, +), 128.17 (+), 128.21 (+), 128.71 (2C, +), 129.40 (+), 136.23 (Cquart), 136.49 (+), 139.23 (Cquart), 148.28 (Cquart), 150.47 (Cquart), 151.57 (+), 157.09 (Cquart) 157.97 (Cquart). MS (ES+): m/z 422.1 (51) [MH+], 338.2 (39) [MH+-cyclobutene-CH2OH]. HPLC: tR=2.4 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C>[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]([C:5]3[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: COC(=O)CNC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of methyl N-[4-(bromoacetyl)phenoxyacetyl]glycinate (0.85 g) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (0.81 g) in acetonitrile (30 ml). After stirring overnight the solvent was removed in vacuo and the residue partitioned between water/ethyl acetate. The organic phase was washed with water, then dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica, eluting with 0 to 7.5% v/v methanol/dichloromethane. Evaporation of the fractions gave the title compound, 130 mg, as a foam: NMR (d6DMSO) δ8.58 (1H, t), 8.16 (2H, d), 8.01 (2H, d), 7.08 (2H, d), 6.83 (2H, d), 5.75 (1H, s), 4.68 (2H, s), 3.92 (2H, d), 3.84 (2H, s), 3.65 (3H, s), 3.34 (4H, t+H2O), 2.65 (4H, t); m/e 427 (M+H)+ ; calculated for C22H26N4O5. 0.5CH2Cl2 : C, 57.6; H, 5.8; N, 11.9. found: C, 57.8; H, 5.7; N, 12.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:6]=[CH:5]2.[Cl:26][C:27]1[C:32]([O:33][CH2:34][CH3:35])=[CH:31][CH:30]=[C:29]([F:36])[C:28]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:26][C:27]1[C:32]([O:33][CH2:34][CH3:35])=[CH:31][CH:30]=[C:29]([F:36])[C:28]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(Br)ccc2n1
Reactant: CCOc1ccc(F)c(B(O)O)c1Cl
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-bromoquinazolin-2-yl)amino)cyclopentyl)carbamate (50 mg, 0.12 mmol), (2-chloro-3-ethoxy-6-fluorophenyl)boronic acid (40 mg, 0.18 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4 mg, 0.005 mmol) and potassium phosphate (78 mg, 0.37 mmol) in 1,4-dioxane/water (1.15 mL/0.15 mL) was degassed with nitrogen for 5 min and stirred at 100° C. for 30 min under microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated ammonium chloride solution and dried with sodium sulfate. The residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)-2-((6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (51 mg, 83%). MS (ES+) C26H30ClFN4O3 requires: 500, found: 501 [M+H]+.
Reaction SMILES: C(OC(N(C1C=CC=CC=1)CC(O)=O)=O)(C)(C)C.O1CCCCC1OCCCCCCCCCCN1CCNCC1.[NH2:42][CH:43]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:44]([N:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][O:64]2)[CH2:48][CH2:47]1)=O>>[NH2:42][CH:43]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[CH2:44][N:46]1[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][O:64]2)[CH2:50][CH2:51]1
Reactant: NC(C(=O)N1CCN(CCCCCCCCCCOC2CCCCO2)CC1)c1ccccc1
Agent: C(CCCCCN1CCNCC1)CCCCOC1CCCCO1
Agent: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Product: NC(CN1CCN(CCCCCCCCCCOC2CCCCO2)CC1)c1ccccc1
Yield: 75 %

Procedure:
A 583 mg (1.40 mmoles) quantity of 1-benzyl-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine was dissolved in 20 ml of ethanol, and 200 mg of 10% palladium-carbon was added thereto and the mixture was shaken at 3 atm. for 8 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated to dryness, giving 375 mg (yield: 82%) of N-[10-(2-tetrahydropyranyloxy)decyl]piperazine. Then, using N-t-butoxycarbonylphenylglycine and N-[10-(2-tetrahydropyranyloxy)decyl]piperazine, 1-(2-amino-2-phenylacetyl)-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine was prepared in the same manner as in Reference Example 1. The obtained product was treated by the same procedure as in Reference Example 3, giving 384 mg (yield: 75%) of 1-(2-amino-2-phenylethyl) -4-[10-(2tetrahydropyranyloxy)decyl]piperazine.