Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([CH3:22])[CH3:21]>CS(C)=O.O1CCCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@@:13]12[CH2:21][C:20]1([CH3:4])[CH3:22]
Reactant: CC(C)=C1C(=O)Nc2ccc(F)cc21
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(C)C[C@]12C(=O)Nc1ccc(F)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A solution of NaH (60%) (0.6 g, 15 mmol) and trimethylsulfoxonium iodide (3.3 g, 15 mmol) in dimethyl sulfoxide (30 mL) was stirred for 30 minutes at 25° C. Then a solution of 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 13.6 mmol) in dry tetrahydrofuran (30 mL) was added dropwise over 20 minutes. After being stirred for 1 hour at 25° C. and 1 hour at 50° C., the reaction solution was poured into ice-cold water and extracted with ether (3×100 mL), washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ether to afford the title compound as white solid (2.39 g, 85%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OCC=C)=O)[C@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.N1CCOCC1>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.C1COCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=1
Reactant: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of rac-cis-allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carboxylate (1.18 g, 3.32 mmol), Pd(PPh3)4 (0.384 g, 0.003 mmol) and THF (20 mL) was added morpholine (3.0 mL, 33.2 mmol). The mixture was degassed for 5 min and stirred at rt. The reaction was monitored for disappearance of starting material by analytical reverse-phase HPLC. After ˜1 h, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated and the resulting crude residue was purified by silica gel chromatography (0˜100% DCM/EtOAc) to afford the title compound ESI-MS (m/z): 472, [M+1]+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]1([C:17](=[O:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl>CN(C=O)C.O>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:18][C:17](=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
Diethyl oxalate (7.23 g, 49.47 mmol) was added to a stirred solution of 1-phenyl-ethanone (5.0 g, 41.6 mmol) in DMF (40 mL) at room temperature. The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in oil, 2.0 g, 83.3 mmol) was added. The resulting mixture was maintained at 0° C. for 30 minutes, stirred for a further hour at room temperature and then slowly heated to 50° C. and stirred for a further 30 minutes. Chilled water was then added, the mixture was acidified with 2.4 N HCl and the resulting precipitate was filtered to afford 2,4-dioxo-4-phenyl-butyric acid ethyl ester in 42.6% yield. LC-MS purity: 85.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([CH2:13][O:14]C)=[C:6]2[C:16]([O:18][CH3:19])=[O:17].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COCc1c(C(=O)OC)c2cc(OC)ccc2n1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C=O)n(C)c2ccc(OC)cc12
Yield: 72 %

Procedure:
5.0 g (19.0 mmol) of 5-methoxy-3-methoxycarbonyl-2-methoxymethyl -1-methylindole obtained in Example 2 or 4 was dissolved in 200 ml of anhydrous toluene, followed by the addition of 4.94 g (20.9 mmol) of DDQ and subsequent 2 hours of heating under reflux. After cooling the reaction mixture and removing impurities by filtration, the organic layer was washed with water and saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by a silica gel column chromatography (eluent: hexaneethyl acetate, 3:1) to obtain 3.38 g of the title compound with a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1.O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([NH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1)=[O:18]
Reactant: Cn1ccc2c(=O)[nH]c(N)nc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1ccc2c(=O)[nH]c(NC(=O)C(C)(C)C)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a suspension of 2-amino-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (4.82 g, 29.4 mmol) in pyridine (45 ml) was added pivaloyl chloride (11.6 ml, 94.0 mmol) at 0° C., and the mixture was stirred at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×1). The organic layer was washed with water (×1) and brine (×1), dried over sodium sulfate and concentrated in vacuo. The residual solids were suspended in methanol (45 ml), and concentrated aqueous ammonia (10 ml) was added at 0° C. The suspension was stirred at the same temperature for 30 minutes, before addition of water. After stirring at 0° C. for 2 hours, the resulting crystals were collected by filtration and washed with water to give 5.46 g (75%) of the title compound.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11](=[O:29])[C:10]=1[C:8]#[N:7]
Reactant: O=C(NC1CCCCC1)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Yield: 76 %

Procedure:
A solution of Compound 7 (0.7 g, 1.77 mmol) in 20 mL neat phosphorus oxychloride was heated at 90° C. for 2 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 420 mg (76%) of white solids. M.P. 231° C. 1H NMR (DMSO-d6): δ 5.54 (s, 2H), 7.13 (m, 2H), 7.34 (m, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.80 (t, J=8.4 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H). EIMS m/z 335 (M+23). Anal. (C17H10ClFN2O) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(C(=O)O)cc1
Reaction time: 5 h
Yield: 5.7 %

Procedure:
Methyl 4-(3-t-butoxycarbonylaminoprop-1-ynyl)benzoate (1.09 g, 38 mmol, reference example 81) is dissolved in MeOH (15 mL) and to this solution added NaOH (0.15 g, 38 mmol) dissolved in water (5 mL). This mixture is heated to reflux. After 5 hours, the solvent is removed in vacuo and CH2Cl2 and 1N HCl added to the residue. The organic layer is washed with 1N HCl, water and brine, then dried over magnesium sulfate. The solvent is removed in vacuo to give a white solid (0.60 g, 57% yield): 1H NMR (300 MHz, CD3OD) d 7.86 (d, 2H), 7.39 (d, 2H), 3.98 (s, 2H), 1.38 (s, 9H).
Reaction SMILES: [OH-].[NH4+:2].[C:3]([P:7](=[O:16])([O:12]CC=C)[O:8][CH2:9][CH:10]=[CH2:11])(OC)=[O:4]>>[C:3]([P:7](=[O:16])([O-:12])[O:8][CH2:9][CH:10]=[CH2:11])(=[O:4])[NH2:2].[NH4+:2]
Reactant: C=CCOP(=O)(OCC=C)C(=O)OC
Agent: [NH4+]
Agent: [OH-]
Product: C=CCOP(=O)([O-])C(N)=O
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
A solution of 48.5 parts of 29% aqueous ammonium hydroxide is stirred and cooled with an external ice bath to 15° C. To the cooled solution 22 parts of diallyl carbomethoxyphosphonate is slowly added over a ten-minute period. The mixture turns cloudy, but clears up after about 15 minutes. During this time, the mixture is allowed to warm spontaneously to about 30° C. and stirring is continued for two hours. The clear solution is stripped under reduced pressure (15 mm of Hg) at a water-bath temperature or 70° C. The residue is a white crystalline solid which is recrystallized from absolute ethyl alcohol, giving 12.3 parts of ammonium allyl carbamoylphosphonate, m.p. 160-162.5° C. Nonaqueous titration either as an acid or a base gives a molcular weight of 182±1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1ccc(N)c(C)c1
Product: Cc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)c(C)c1
Yield: 43.5 %

Procedure:
Using the procedure of example 1, 2,4-dimethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 33 (37 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.18 (s, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 7.12 (d, J=5.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0 Hz, 4.8 Hz, 1H), 2.38 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([OH:58])=O)=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.Cl.[CH3:76][N:77]1[C@H:82]([CH3:83])[CH2:81][NH:80][CH2:79][C@@H:78]1[CH3:84].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:80]4[CH2:81][C@H:82]([CH3:83])[N:77]([CH3:76])[C@H:78]([CH3:84])[CH2:79]4)=[O:58])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: C[C@@H]1CNC[C@H](C)N1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C[C@@H](C)N(C)[C@@H](C)C3)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 28.9 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), (2S,6R)-1,2,6-trimethylpiperazine dihydrochloride (46 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/CH3CN gradient, and concentrated to give the titled compound (31 mg, 0.033 mmol, 29% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: C([O:8][C:9]1[CH:41]=[CH:40][C:12]2[C:13]3[N:14]([CH2:25][C:26]4[CH:39]=[CH:38][C:29]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[CH:28][CH:27]=4)[C:15]4[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=4[C:21]=3[O:22][C:11]=2[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[CH2:36]([N:33]([CH2:34][CH3:35])[CH2:32][CH2:31][O:30][C:29]1[CH:38]=[CH:39][C:26]([CH2:25][N:14]2[C:15]3[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=3[C:21]3[O:22][C:11]4[CH:10]=[C:9]([OH:8])[CH:41]=[CH:40][C:12]=4[C:13]2=3)=[CH:27][CH:28]=1)[CH3:37]
Reactant: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4cc(OCc5ccccc5)ccc4c32)cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(Cn2c3ccc(OC)cc3c3oc4cc(O)ccc4c32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {2-[4-(7-benzyloxy-3-methoxy-benzo[4,5]furo[3,2-b]indol-10-ylmethyl)-phenoxy]-ethyl}-diethyl-amine (102 mg, 0.186 mmol) and 10% Pd/C (˜100 mg) in EtOH (10 mL) was stirred under a H2 balloon at 25° C. overnight. The solution was filtered, concentrated and purified to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([OH:33])(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH3:1][CH2:2][C@:3]12[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:24][CH2:25][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[C:26]([O-:33])(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CCCCCC(=O)[O-]

Procedure:
As in the preceding example, from 3.36 g of apovincamine and 1.17 g of caproic acid, there are obtained 4.1 of a semi-solid product, having low melting point, insoluble in water and alcohol, and with an apovincamine content of 71%
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([NH:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24](OC)[O:25]C)[N:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1)#[N:2].O.Cl>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([NH:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=[O:25])[N:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:4]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C#N)c(C#N)cn1)CCC2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3ccc(C=O)nc32)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(4,5-dicyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2F, 15 mg, 0.040 mmol) was dissolved in THF (0.6 ml) and water (0.6 ml) and treated at room temperature with conc. HCl (0.10 ml). The reaction mixture was stirred at room temperature for 1.5 h, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with MeOH, the solid was filtered and dried overnight at 40° C. under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC[O:13][C:14]([CH3:16])=[O:15].[CH:17]1([C:22](=[O:35])[CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([CH2:33][CH3:34])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(OC)(C)C>[CH:17]1([C:22]([OH:35])([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH2:33][CH3:34])[N:28]=[C:29]([CH2:31][CH3:32])[CH:30]=2)[CH2:16][C:14]([OH:13])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(C)=O
Reactant: CCc1cc(CCC(=O)C2CCCC2)cc(CC)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CCc1cc(CCC(O)(CC(=O)O)C2CCCC2)cc(CC)n1
Temperature: -34 °C
Reaction time: 0.5 h

Procedure:
A clean 2-L, 3-neck flask was charged with LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) and purged with nitrogen. The flask was cooled to −34° C. An addition funnel was then charged with EtOAc (35 mL, 0.3583 mol) and this reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel could be maintained. After complete EtOAc addition another addition funnel was charged with the 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution (crude MTBE soln from prior reaction, theor. 73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 mL). The 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature could be maintained. Five minutes after complete addition, a reaction aliquot was removed and analyzed by HPLC, showing less than 1% 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one. Ten minutes after complete ketone addition, the bath was switched to 0° C. Once the internal temperature had warmed to −10° C., 1M NaOH (510 mL) was added. After complete NaOH soln addition, the reaction was heated to 50° C. After 21 hours the reaction solution was cooled below 30° C. and an aliquot of both layers was removed and analyzed for completion. The mixture was added to a separatory funnel with MTBE (350 mL) and the phases were mixed well and separated. An aliquot of the organic phase was analyzed by HPLC, verifying no significant product, and this layer was discarded. The aqueous phase was added to a flask with CH2Cl2 (350 mL). Concentrated aqueous HCl (about 100 mL) was slowly added to the aqueous phase until the pH=5. The mixture was added back to a separatory funnel and mixed well. The phases were separated and the aqueous layer was extracted a second time with CH2Cl2 (150 mL). The organic layers were combined and charged to a clean flask set up for distillation. The solution was distilled down to 370 mL then displaced with THF by addition of solvent portions followed by continued distillation down to 370 mL after each addition. When the distillation head temp. held steady at 65° C. for 30 min an aliquot was removed and analyzed by 1H NMR, showing a 12.5:1 ratio of THF:CH2Cl2. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH:26]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][C:3]([C:23]#[N:24])=[C:2]2[NH:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[CH:37][CH:36]=1
Reactant: Nc1ccc(Oc2cccnc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1OCC1CCN(C)CC1
Yield: 70.6 %

Procedure:
Following the procedure used to prepare Reference Example 22, a mixture of 4-chloro-6- methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile (200 mg, 0.58 mmol) and 4-(pyridin-3-yloxy)phenylamine (161.5 mg, 0.87 mmol) (Cacciola, J.; Fevig, J. M.; Stouten, P. F. W.; Alexander, R. S.; Knabb, R. M.; Wexler, R. W. Bioorg. Med. Chem. Let. 2000, 10, 1253) provides 203 mg of 6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-{[4-(pyridin-3-yloxy)phenyl]amino}quinoline-3-carbonitrile, mp 182-184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].II.[C:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[NH4+]>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:21]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (8 g, 41.4 mmol) in dry tetrahydrofuran (100 ml), under nitrogen, was added magnesium turnings (0.99 g, 41.4 mmol) and one crystal of iodine. The mixture was refluxed for 1 h, cooled to ambient temperature and a solution of 1-N-boc-3-pyrrolidone (7.66 g, 41.4 mmol) in dry tetrahydrofuran (40 ml) was added drop wise. The resulting mixture was refluxed 1 h, cooled to ambient temperature, aqueous saturated ammonium chloride solution (50 ml) was added and the mixture was extracted with ethylacetate (3×50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (3.8 g, 30%). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 243 (30), 198 (39), 127 (36), 57 (bp).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:19]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
1.89 g (45.2 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 10.0 g (41.1 mmol) of 4-(benzyloxycarbonylamino)phenol [prepared as described in step (a) above] in 100 ml of dimethylformamide, and the mixture was stirred for 5 minutes. 5.01 ml (45.2 mmol) of ethyl bromoacetate were then added to the resulting mixture, after which the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting organic solution was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 10:1 to 6:1 by volume as the eluent, to give 11.7 g of the title compound as colorless crystals, melting at 85°-86° C.