Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH:19]=O.[BH4-].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH2:19][NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(N)cc1OC
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Commercially available 3,4-dimethoxy-phenyl-amine (1.74 g, 11.3 mmoles) and 3,5-dichloro-pyridine-4-carbaldehyde (2.0 g, 11.3 mmoles) were dissolved in toluene (40 mL) under nitrogen atmosphere. Molecular sieves (4A, 1 g) were added, and the mixture was heated to reflux. Reaction monitoring was performed by TLC analysis (petroleum ether/AcOEt 7/3): formation of the imine intermediate was completed after 3 hours. Molecular sieves were removed by filtration and the solvent was evaporated. The residue was dissolved in ethanol (99%, 40 mL). The solution was cooled to 0° C. and NaBH4 (559 mg, 14.7 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours, then water was added (50 mL), and the mixture was extracted AcOEt (3×60 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3). The title compound was obtained as a yellow solid (3.04 g).
Reaction SMILES: O[C:2]([C:14]1[C:15]([NH:20][C:21](=[O:26])[C:22](C)(C)C)=[N:16][CH:17]=[CH:18][CH:19]=1)([CH:11]([CH3:13])[CH3:12])CC(OC(C)(C)C)=O>Cl>[CH:11]([C:2]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:20][C:21](=[O:26])[CH:22]=1)([CH3:12])[CH3:13]
Reactant: CC(C)C(O)(CC(=O)OC(C)(C)C)c1cccnc1NC(=O)C(C)(C)C
Agent: Cl
Product: CC(C)c1cc(=O)[nH]c2ncccc12
Yield: 40.9 %

Procedure:
A solution of tert-butyl 3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate (3.78 g, 10.4 mmol) in 12.0 mL 3N HCl were reacted as outlined in Scheme 1 to give the desired 4-isopropyl-1,8-naphthyridin-2(1H)-one (800 mg, 41%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.34 (d, J=7.03 Hz, 6 H) 3.34 (quin, J=6.81 Hz, 1 H) 6.66 (s, 1 H) 7.23 (dd, J=12.31, 4.10 Hz, 2 H) 8.09 (dd, J=8.06, 1.61 Hz, 1 H) 8.71 (dd, J=4.69, 1.47 Hz, 1 H) 11.98 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].FC(F)(F)C([O-])=O.C[NH+]1CCCC(C([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C(=O)C)=O)C1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[NH3+][C@H](C1[NH2+]C(C2C=CC=CC=2)=CN=1)CCCCCC(=O)C.CCN(CC)CC.[CH3:87][O:88][C:89]1[CH:94]=[CH:93][C:92]([S:95](Cl)(=[O:97])=[O:96])=[CH:91][CH:90]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:87][O:88][C:89]1[CH:90]=[CH:91][C:92]([S:95]([NH:24][C@H:25]([C:34]2[NH2+:35][C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:37][N:38]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:3](=[O:5])[CH3:2])(=[O:97])=[O:96])=[CH:93][CH:94]=1
Reactant: CC(=O)CCCCC[C@H](NC(=O)C1CCC[NH+](C)C1)C1=NC=C(c2ccccc2)[NH2+]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)CCCCC[C@H]([NH3+])C1=NC=C(c2ccccc2)[NH2+]1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCCCC(C)=O)C2=NC=C(c3ccccc3)[NH2+]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1, A3 and Et3N (1.1 eq.) in DCM was added 4-methoxybenzene sulfonyl chloride (1.1 eq.). The reaction mixture was stirred at RT for 3 hr and the mixture was washed with sat. aq. NaHCO3. The organic phase was concentrated under reduced pressure and the crude residue was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound B1 as a colourless oil. 1H NMR (300 MHz, CD3CN) δ: 8.87 (1H, d, J=9.3 Hz), 7.60-7.52 (4H, m), 7.51-7.40 (3H, m), 7.31 (1H, s), 6.79-6.63 (2H, m), 4.78-4.65 (1H, m), 3.51 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.04 (3H, s), 1.89-1.78 (2H, m), 1.51-1.32 (3H, m), 1.31-1.14 (3H, m). MS (ES) C24H29N3O4S requires: 455, found: 456 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:14](Cl)(Cl)[Cl:15]>[Cl-].[Zn+2].[Cl-]>[Cl:15][P:14]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13]1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: ClP(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2ccccc21

Procedure:
reacting o-phenylphenol with phosphorus trichloride in the presence of zinc chloride catalyst to form a 6-chloro-6H-dibenz[c,e] [1,2]oxaphosphorin of the following formula (II);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:15]C)[C:9]([O:13]C)=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1.Cl.N[CH2:25]C1C2C(=C(OC)C(OC)=CC=2)CC(C2C=CC=CC=2)C=1>>[OH:15][C:8]1[C:9]([OH:13])=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:4]=[C:3]2[CH2:2][NH:1][CH3:25]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Agent: Cl
Product: CNCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O

Procedure:
1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, the product of Step 2 of Example 2, was N-methylated as described in Example 111 and deprotected as described in Step 4 of Example 2 to give the title compound as its hydrochloride salt, m.p. 131°-133° C.; DCI MS: 282 (M+H)+. Analysis calculated for C18H20ClNO2 : C, 68.03; H, 6.34; N, 441. Found: C, 67.64: H, 6.54; N, 4.31.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]2[O:9][C:8](=[O:10])[CH:7]=[C:6]2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1
Yield: 75.3 %

Procedure:
At 60° C., 600 mg (2.48 mmol) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (V-1a), 354 mg (2.48 mmol) of 1-(6-chloropyridin-3-yl)methanamine and 0.43 ml (2.48 mmol) of N-ethyl-N-isopropylpropan-2-amine in 10 ml of acetonitrile are stirred for 21 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (98:2 to 90:10) gives 650 mg (73% of theory) of 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([OH:22])=O)=[CH:12][CH:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>CN(C)C=O>[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH:18]([OH:23])[CH2:19][C:20]([N:56]2[CH2:57][CH2:58][S:54][CH2:55]2)=[O:22])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(O)CCc1ccc(-c2ccccc2)cc1
Reactant: C1CSCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(O)CCc1ccc(-c2ccccc2)cc1)N1CCSC1
Reaction time: 0.08 h
Yield: 47.2 %

Procedure:
Diisopropylethylamine (32 μL, 0.19 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1, 25 mg, 93 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.19 mmol) in dimethylformamide (1 mL) at room temperature under nitrogen. After stirring for 5 minutes, thiazolidine (11 μL, 0.14 mmol) was added then stirring was continued for a further 2 hours. The volatiles were removed by evaporation under reduced pressure and the residue partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated and the organic phase evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:1 ethyl acetate: 40–60 petroleum ether) to give the title compound (15 mg, 47%) as a white solid. LC/MS: 3.22 min; z/e 342, calcd (M+1) 342.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].O>O1CCCC1>[F:11][C:8]([F:9])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(F)(F)F)Oc1ccccc1
Reaction time: 4.5 h

Procedure:
2-Aminobenzotrifluoride (5 mL) and pyridine (6.44 mL) were dissolved in tetrahydrofuran (100 mL), and phenyl chloroformate (5.5 mL) was added dropwise under ice-cooling. After dropwise addition of the reagent, the mixture was brought back to room temperature and stirred for 4.5 hours. Water was added to the reaction solution and the mixture was concentrated under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was washed with 2 N hydrochloric acid and brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (12.1 g). The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[C:19]1[N:23]([C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:3])=[O:2].Br[C:35]1[C:36]([CH3:46])=[N:37][C:38]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:43]([O:42][C:38]1[N:37]=[C:36]([CH3:46])[C:35]([C:8]2[CH:7]=[CH:6][C:5]([C:19]3[N:23]([C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[N:22]=[CH:21][C:20]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:40]([CH3:41])[CH:39]=1)([CH3:45])[CH3:44]
Reactant: Cc1cc(OC(C)C)nc(C)c1Br
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OC(C)C)nc2C)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(2) (70 mg) was dissolved in a mixed solution of 1,4-dioxane (1 mL) and water (0.2 mL), and 3-bromo-6-isopropyloxy-2,4-dimethylpyridine (41.1 mg), Pd(PPh3)4 (17.7 mg) and cesium carbonate (150 mg) were added. The reaction mixture was stirred at 110° C. overnight. After returning the reaction mixture to room temperature, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10 to 50% to 100%) to give the title compound (66.5 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:23]([O:25]C)=[O:24])[C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Li+].[Br-].Cl>CC#N.O>[CH2:14]([O:13][C:11](=[O:12])[C:10]([CH3:22])([CH3:21])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-benzyl 1-methyl N-(tert-butoxycarbonyl)-3,3-dimethyl-L-aspartate (Preparation 45, 2 g, 5.47 mmol) in MeCN (30 mL) and water (0.6 mL) was added triethylamine (2.3 mL, 16.41 mmol) followed by LiBr (4.75 g, 54.73 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction was acidified with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step (1.5 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:13])=[O:12].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])(=[O:13])=[O:12]
Reactant: O=S(=O)(CCCCO)c1ccc2ccccc2c1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=CCCCS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of the product of step c (524 mg, 1.98 mmol) and triethylamine (0.829 ml, 5.96 mmol) in DMSO (10 ml) was added a solution of sulfur trioxide-pyridine (948 mg, 5.96 mmol) in DMSO (10 ml) and the reaction mixture stirred at ambient temperature for 15 minutes. The reaction mixture was poured into ice-water (150 ml) and then extracted thrice with ethyl acetate (60 ml). The combined organic phases were washed with aqueous citric acid (70 ml) and brine (70 ml), then dried over anhydrous sodium sulfate. The filtrate was evaporated at reduced pressure and the residue purified by flash column chromatography (2:1 ethyl acetate:hexane) to afford the title compound (457 mg, 88%). 1H NMR 9.75 (1H, s), 8.50 (1H, s), 8.05-7.65 (6H, m), 3.26-3.22 (2H, m), 2.71 (2H, t, 6.9), 2.15-2.04 (2H, m).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([CH:19]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:21]
Reactant: CCCCC(Br)C(=O)OC
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC(Oc1ccccc1C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
15.2 g of methyl salicylate and 18.0 g of potassium carbonate were introduced into 125 ml of acetonitrile in a 250 ml flask under an argon atmosphere and, at room temperature, 20.9 g of methyl 2-bromohexanoate were added. The colourless suspension was heated under reflux with stirring for 16 hours, and the progress of the reaction was checked by thin-layer chromatography. After cooling to room temperature, the suspension was filtered and the residue was washed with acetone. Concentration of the filtrate in vacuo resulted in 27.8 g (99% of theory) of methyl 2-(1-methoxycarbonylpentoxy)benzoate as yellow oil.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])=[O:18])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Br
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC(F)F)c(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 30 mg quantity of 3-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 229 was dissolved in 0.5 ml of dimethylformamide. An 18 mg quantity of 2-bromopropane and 30 mg of potassium carbonate were added thereto, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. Drying was performed with anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 23 mg of white powdery 3-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one.
Reaction SMILES: O.[C:2]1([CH:8]([CH3:11])[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:12].[H][H]>C(O)C>[ClH:12].[C:2]1([CH:8]([CH3:11])[CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(C#N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(CN)c1ccccc1
Temperature: 57 °C
Yield: 76.2 %

Procedure:
To an autoclave hydrogenation apparatus under nitrogen was charged water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-phenylpropionitrile (636 g, 4.85 moles) and finally concentrated (12M) hydrochloric acid (613 g, 5.6 mole). The mixture was stirred rapidly and pressurized to 89.7-92.7 psi (618.46-639.15 kPa) with hydrogen. The mixture was then heated to 50-64° C. for 3 hours. 1H NMR analysis of an aliquot showed less than 5% starting material. The reaction mixture was depressurized and filtered to afford two lots of filtrate that were concentrated under reduced pressure to ˜400 mL each. To each lot was added methyl tert-butyl ether (MTBE) (2.2 L each) and the precipitate solids were allowed to stir overnight. Each lot was filtered and the collected solids were each washed with fresh MTBE (100 mL) and dried overnight. The lots were combined to afford 2-phenyl-1-propylamine HCl (634.4 g, 76.2%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH3:28])[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(N(C)c3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenylamino)pyrimidine (1.0 g) in N,N-dimethylformamide (15 ml) were added potassium tert-butoxide (0.37 g) and methyl iodide (0.34 ml), and the mixture was stirred at ambient temperature for 1.5 hours. Then the mixture was poured into ice-water (200 ml) and stirred for an hour. The precipitates were collected, washed with water, dried in the air, and recrystallized from ethanol to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-[N-methyl-N-(2,4,6-trimethylphenyl)amino]pyrimidine (0.58 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu+2].[I-].[I-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: Brc1ccccn1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+2]
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
In a dry reaction tube containing in suspension iodide copper (38 mg, 0.2 mmol), and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine (632 mg, 4 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) in triethylamine (2.2 mL). Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80° C. for 20 h. Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography (prepacked 15 g silicagel column, from DCM 100% to DCM/MeOH: 98/2 as eluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-1-ol (Yield: 74%) as brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[CH3:25][N:22]1[C:23]2[CH:24]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:17]=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)cn1
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Yield: 58.1 %

Procedure:
4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (220 mg, 58%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.1, 2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.37 (d, J=1.4 Hz, 1H), 7.30 (1H, partially under solvent), 7.08 (d, J=8.7 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.50 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (br s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.64 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CCOC(C)=O>[Cl:20][C:19]([Cl:22])([Cl:21])[CH2:18][O:17][C:15](=[O:16])[NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.5 g, 3.26 mmol) in EtOAc (10 mL) was treated with aqueous NaOH (1M, 5.87 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol), and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (10 mL) and water (2×10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as a pale orange gum (0.915 g, 86%). LCMS (Method 3): Rt 3.88 min, m/z 328/330 [MH+].