Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[C:13](OC(=O)C)(=[O:15])C>C(O)=O>[CH:13]([NH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4])=[O:15]
Reactant: CC(N)(C(=O)O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(NC=O)(C(=O)O)c1ccccc1

Procedure:
(RS)-2-amino-2-phenylpropanoic acid (20 g, 0.12 mol) in 88% formic acid (220 mL) was reacted with acetic anhydride (100 mL) at such rate as to keep the internal temperature at 60-65° C. After the final addition, the reaction was stirred until the internal temperature dropped to 35° C., and then concentrated. The solid residue was dried by azeotroping with toluene. The solid residue was dissolved in hot ethanol (70 mL), treated with active charcoal (0.5 g), and filtered. Hot water (210 mL) was added with stirring to the hot filtrate. The mixture was cooled in the refrigerator for 3 days. The resulting crystals was collected by filtration, washed with cold EtOH/water (1:3), and dried at 60° C. for 4 hours to give the title compound as colorless crystal. (17.8 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[C:32]([NH:35][NH2:36])(=O)[CH3:33].O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]3[O:30][C:32]([CH3:33])=[N:35][N:36]=3)=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: CC(=O)NN
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
To a 30 mL vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (100 mg, 0.230 mmol) and acetohydrazide (85 mg, 1.151 mmol) were dissolved in POCl3 (2 mL, 21.46 mmol) and the mixture was heated to 100° C. for 18 h. The reaction mixture was cooled to room temperature poured into ice. The solution was quenched with sat. sodium bicarb and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide the crude material. The crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole (83 mg, 0.176 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=2.38 (s, 3 H), 2.57 (s, 3 H), 3.90 (s, 3 H), 6.81-6.98 (m, 4 H), 6.98-7.08 (m, 2 H), 7.28-7.42 (m, 2 H), 7.44-7.58 (m, 4 H), LC/MS (m/z, MH+): 473.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:13][C:14]1[C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCc2sccc2C(O)C1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Product: CN1CCc2sccc2C(Oc2cccc(Cl)c2C(F)(F)F)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-6-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH:9](O)[C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([F:15])=[C:13]2[C:8]([CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (63.0 g, 154 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (30.2 g, 50%) as a yellow oil: LC/MS m/e calcd for C19H19BrFNO2 (M+H)+: 393.27, observed: 392.0 & 394.0. A mixture of 2-(3-bromo-phenyl)-8-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (6.0 g, 15.3 mmol), morpholine (13.3 mL, 153 mmol), copper(I) iodide (874 mg, 4.6 mmol), N,N-dimethylglycine hydrochloride (1.3 g, 9.2 mmol) and potassium carbonate (8.5 g, 61.2 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (4.8 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27FN2O3 (M+H)+: 399.48, observed: 399.1.
Reaction SMILES: [O:1]=[C:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9].Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C1C=CC=CC=1>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][CH2:32][C@H:33]([C:35](=[O:37])[NH2:36])[NH:34][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Reactant: CCCCCC(=O)CCCCCC(=O)N[C@@H](C)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(=O)CCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
N-(7-oxododecanoyl)-L-alanine (590 mg, 2.07 mmoles) and D-isoglutamine benzyl ester hydrochloride (565 mg, 2.07 mmoles) were dissolved in N,N-dimethylformamide (7 ml). The solution was cooled to 0° C. and diphenylphosphoryl azide (578 mg, 2.1 mmoles) and triethylamine (424 mg, 4.2 mmoles) were added thereto. The reaction mixture was stirred for 1 hour on an ice bath and for another 48 hours at room temperature. To the resulting suspension there were added benzene (5 ml) and ethyl acetate (25 ml) and it was washed successively with citric acid (0.52M; 3×5 ml), water (3×5 ml), saturated NaCl solution (3×5 ml), saturated NaHCO3 solution (3×5 ml), water (3×5 ml) and saturated NaCl solution (3×5 ml). The organic phase was dried with MgSO4 and filtered, the filtrate was evaporated and the compound was precipitated from n-hexane/diethyl ether.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(O)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:19]=[CH:18][C:17]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][CH:5]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:22][CH:21]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C(=C2CCNCC2)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 4 h
Yield: 94.5 %

Procedure:
A solution of 10.0 grams (0.025 mole) of 4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine (known compound) in 50 mL of trifluoroacetic acid was heated to 70° C. where it stirred for four hours. After this time, excess trifluoroacetic acid was removed by distillation. The residue remaining from the distillation was added drop wise to ice water. Upon completion of addition, the mixture was neutralized with an aqueous solution saturated with potassium carbonate. The mixture was then extracted with methylene chloride, and the extract was washed with an aqueous solution saturated with sodium chloride. The extract was concentrated under reduced pressure to a residue, and the residue was crystallized in hexane, yielding in two crops, 9.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:12])[CH:5]=[C:6]([CH2:9][O:10][CH3:11])O[CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:12])[CH:5]=[C:6]([CH2:9][O:10][CH3:11])[S:22][CH:8]=1
Reactant: COCc1cc(=O)c(OC)co1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COCc1cc(=O)c(OC)cs1
Yield: 190.1 %

Procedure:
5-Methoxy-2-(methoxymethyl)-4-pyranone (3.24 g, 19 mmol) (K. Heyns and G. vogelsang, Chem. Ber. 1954, 87, 1377) in toluene (60 ml) was heated at 80° C. with Lawessons reagent (4.23 g, 10 mmol) for 2h. After cooling the reaction mixture was chromatographed on silica gel 60 eluting with toluene/ethyl acetate mixtures to give the title compound (3.54 g, 100%); νmax (CH2Cl2) 3050, 2950, 2830, 1625, and 1560 cm-1 ; δH (CDCl3) 3.4 (3H, s), 3.8 (3H, s), 4.2 (2H, s), 7.3 (1H, s), 7.4 (1H, s); M+ 186.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].C(OCC)C.S(=O)(O)[O-].[Na+].[C-:31]#[N:32].[Na+]>O.C(Cl)(Cl)Cl>[OH:20][CH:19]([C:18]1[C:6]2[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]=2[CH:15]=[CH:16][CH:17]=1)[C:31]#[N:32]
Reactant: [C-]#N
Reactant: O=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CC(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2.7 g. (0.010 mole) of 2-nitro-3-phenylbenzofuran-7-aldehyde and 20 ml. of diethyl ether is treated with 1.6 g. (0.015 mole) of sodium bisulfite in 10 ml. of water. After 30 minutes, 30 ml. of chloroform is added and then, 30 minutes later, 1.5 g. (0.030 mole) of sodium cyanide in 5 ml. of water is added. One-half hour after that 0.7 g. of sodium bisulfite is added, then, after another 30 minutes, the mixture is cooled at 0° C. for about 16 hours. The organic layer is separated, washed with aqueous sodium bisulfite solution, then with water, and dried over magnesium sulfate. Evaporation of the solution provides a solid which is recrystallized from a chloroform-heptane mixture to provide yellow crystals of α-hydroxy-2-nitro-3-phenylbenzofuran-7-acetonitrile, m.p. 137°-139° C.
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1)[CH3:10].N#N.[Li]CCCC.[I:29]I>C1COCC1>[CH2:9]([O:11][C:12](=[O:21])[NH:13][C:14]1[C:19]([I:29])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1)[CH3:10]
Reactant: II
Reactant: CCOC(=O)Nc1cccc(F)n1
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc(F)ccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
28.6 ml (0.18 mol) TMEDA was added to a solution of compound 56 (13.41 g, 72.9 mmol) dissolved in 300 ml anhydrous THF. The mixture was cooled to −78° C. (under N2). To the stirred reaction mixture was added 76 ml (2.5 M n-BuLi) and the mixture was stirred for 2 hours at −78° C. After the addition of I2 (48 g, 0.17 mol), the mixture was stirred for 1 hour at −78° C. The reaction mixture was subsequently quenched with a saturated Na2S2O3 solution and allowed to warm to ambient temperature. Ethyl acetate was added to the mixture and the organic layer was washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE (1/3) to 1/1) and afforded (6-fluoro-3-iodo-pyridin-2yl)-carbamic acid ethyl ester (57) (amorphous, 15.86 g, 70%). 1H-NMR (400 MHz, CDCl3): δ 8.07 (bt, J=8 Hz, 1H), 7.24-7.14 (bs, 1H), 6.49 (dd, J=8 Hz, 3 Hz, 1H), 4.29 (q, J=8 Hz, 2H), 1.35 (t, J=8 Hz, 3H). (TLC diethyl ether/PE 1/1 Rf 0.27).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:49]([CH2:47][CH3:48])[C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCNc1ccc(C)cc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC)c2ccc(C)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-ethyl-p-toluidine (VWR) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][C:9]=2[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.ClCCl>O1CCCC1>[NH2:1][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:11][C:9]=2[CH:10]=1
Reactant: N#Cc1ccc(-c2ccc3oc(CCN=[N+]=[N-])cc3c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc3oc(CCN)cc3c2)cc1
Reaction time: 72 h

Procedure:
The product from Example 162A was dissolved in 3 mL of tetrahydrofuran, and treated with triphenylphosphine (262 mg, 1 mmol) was added, along with 0.5 mL water. After 3 days, the reaction was poured into dichloromethane and washed with aqueous ammonia. The organic layer was purified by flash chromatography, eluting with 10-20% methanol/dichloromethane, (0.1% NH3) to give the title compound as a white powder. mp 118-120° C.; MS (DCI) m/z 263.0 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 3.00 (m, 2H), 3.08 (m, 2H), 6.64 (s, 1H), 7.56 (m, 2H), 7.82 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCCC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (50 mg, 0.165 mmol) and valeric acid (36 mg, 0.247 mmol) in DMF (5 ml) were added N-methyl morpholine (51 mg, 0.5 mmol) and HBTU (94 mg, 0.247 mmol), and the reaction mixture was stirred for 16 h at 25° C. The reaction mixture was poured into water and extracted with ethyl acetate (3×20 ml). The combined ethyl acetate part was dried over Na2SO4 and evaporated to furnish the crude material (60 mg). The crude was purified by prep. HPLC and the desired product (30 mg, 47%) was obtained as sticky white solid. MS (LC/MS): 387.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:45][C:46]1[CH:62]=[CH:61][C:49]([O:50][CH2:51][CH2:52][NH:53]C(=O)OC(C)(C)C)=[C:48]([C:63]2[N:67]([CH3:68])[N:66]=[CH:65][CH:64]=2)[CH:47]=1.[C:69]([OH:75])([C:71]([F:74])([F:73])[F:72])=[O:70]>C(Cl)Cl>[F:72][C:71]([F:74])([F:73])[C:69]([OH:75])=[O:70].[NH2:53][CH2:52][CH2:51][O:50][C:49]1[CH:61]=[CH:62][C:46]([NH:45][C:4](=[O:6])[C:3]2[C:7]([F:13])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:47][C:48]=1[C:63]1[N:67]([CH3:68])[N:66]=[CH:65][CH:64]=1
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
2,6-difluoro-4-methoxybenzoic acid (22.6 mg, 120 μmol) was weighed into a microwave vial and CH2Cl2 (1 mL) was added followed by HATU (34.3 mg, 90.3 μmol) and Et3N (20 μl, 144 μmol). After stirring 10 minutes, tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (20 mg, 60 μmol) was added to the solution. The reaction mixture was heated at 60° C. for one hour. Then, TFA (1 mL) was added and heated for one hour at 90° C. in order to remove the Boc-protecting group from the amine. The solvent was evaporated. The resulting oil was dissolved in DMSO (1 mL) and purified by Prep LC/MS to give N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamide trifluoroacetate (8.2 mg, 0.02 mmol, 34%) as a white solid. LCMS m/z (%)=403 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16 (s, 2 H), 3.70 (s, 3 H), 3.84 (s, 3 H), 4.17 (t, J=5.56 Hz, 2 H), 6.36 (d, J=1.77 Hz, 1 H), 6.89 (d, J=9.85 Hz, 1 H), 7.24 (d, J=9.09 Hz, 1 H), 7.49 (d, J=1.77 Hz, 1 H), 7.63 (d, J=2.78 Hz, 1 H), 7.77 (dd, J=9.09, 2.53 Hz, 1 H), 7.89 (br. s., 3 H), 10.69 (s, 1 H), 13.46 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.I[C:13]1[C:21]2[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([C:13]2[C:21]3[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Reactant: COc1ncccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 170 °C

Procedure:
A mixture of (2-methoxypyridin-3-yl)boronic acid (36 mg, 0.23 mmol), 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.16 mmol), sodium carbonate (83 mg, 0.78 mmol) and SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 111 mg, 0.031 mmol) in dioxane (1.30 mL) and water (0.26 mL) was heated to 170° C. under the microwave irradiation for 15 minutes. The reaction mixture was concentrated, redissolved in DMSO, filtered and the resulting solution was reconcentrated. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% formic acid modifier afforded 5-(2-methoxypyridin-3-yl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C18H15N4O [M+H]+: 303, found 303. 1H NMR (600 MHz, DMSO-D6) δ 12.40 (s, 1H), 8.82 (s, 1H); 7.97 (dd, 1H, J=1.1, 4.3 Hz); 7.65 (s, 1H); 7.64 (dd, 1H, J=1.1, 5.6 Hz); 7.28 (d, 2H, J=6.6 Hz), 7.24 (t, 1H, J=6.1 Hz); 7.08 (dd, 2H, J=6.1, 6.6 Hz); 6.94 (dd, 1H, J=4.3, 5.6 Hz); 3.05 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16]OCC)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9].O>C(O)C>[F:5][C:6]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:7]=1[C:8]([C:10](=[CH:16][NH:3][N:2]([CH3:4])[CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9]
Reactant: CN(C)N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNN(C)C)C(=O)c1cc(F)c(F)c(F)c1F

Procedure:
3.1 g of 1,1-dimethylhydrazine are added dropwise to a solution of16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate in 60 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 60 ml of H2O are added, the mixture is cooled with ice and the precipitate is filtered off with suction and washed with water/ethanol (1:1). 12.9 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2,2-dimethylhydrazino)-acrylate of melting point 81° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][OH:41])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: OCCOCCCl
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCOCCO)c2ccc(C#CCO)cc2c1=O
Temperature: 100 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide (0.37 gm) from Preparation No. 5 in DMF (10 mL) is treated with potassium carbonate (2.75 gm), potassium iodide (1.66 gm) and 2-(2-chloroethoxy)ethanol (1.0 mL). The mixture is tightly capped and heated to 100° C. for 48 hrs. The reaction mixture is allowed to cool to room temperature, poured into water and extracted with dichloromethane. The layers are separated and the aqueous layer is re-extracted with dichloromethane containing a small amount of methanol and finally again with dichloromethane. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 15% methanol in dichloromethane and then by recrystallization from methanol to afford 82 mg of the title compound as a light yellow solid.