Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:24]C(=O)C)([CH2:22][OH:23])[CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:5]1.O[Li].O>CO.C1COCC1.O.C(OCC)(=O)C>[NH2:24][C:3]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:5]1)([CH2:22][OH:23])[CH2:2][OH:1]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(CO)(CO)NC(C)=O)C2
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CCC(C(N)(CO)CO)C2
Yield: 75 %

Procedure:
A solution of compound 7 (53 mg, 0.14 mmol) and LiOH.H2O (45 mg, 1.1 mmol) in MeOH (3 ml), THF (1.5 ml) and water (3 ml) was stirred at 50° C. for 5 hours and diluted with ethyl acetate (20 ml). The solution was washed with brine (2×10 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 50% MeOH in CH2Cl2) to provide 35 mg of compound VPC104061(75%).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][N:3]([CH2:9][CH2:10][C:11]([C:13]#[N:14])=[CH2:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[C:13]([CH:11]1[CH2:12][O:2][N:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9][CH2:10]1)#[N:14]
Reactant: C=C(C#N)CCN(OC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(C#N)CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of (3-cyano-3-butene-1-yl)(ethoxycarbonyl)azanyl 1,1-dimethylethyl carbonate (i.e. the product of Step G) and trifluoroacetic acid (3 mL) in dichloromethane (40 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to a tan oil. The oil was combined with potassium carbonate (3.6 g, 0.026 mol) in N,N-dimethylformamide (30 mL) and stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure to near dryness. Methanol and dichloromethane were added and the precipitated solids were removed by filtration. The resulting solid was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel chromatography to provide the title compound as a pale-tan oil (0.645 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:1].[ClH:43].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28]([CH3:31])[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc3n2C)C1
Yield: 64 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (50 mg, 0.12 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39 mg, 64%) as a white solid: mp 278-282° C.; 1H NMR (300 MHz, CD3OD) δ 8.60 (d, J=2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.61 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 7.06 (dd, J=8.4, 1.7 Hz, 1H), 6.34 (dd, J=7.6, 2.6 Hz, 1H), 6.12 (d, J=2.6 Hz, 1H), 5.27 (s, 2H), 4.75 (d, J=14.2 Hz, 1H), 4.38 (d, J=14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s, 3H), 3.63 (m, 1H), 3.31 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 435 [M+H]+; HPLC (Method B) 98.9% (AUC), tR=12.1 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:17][C:18]([F:21])([F:20])[F:19])C>C1(C)C=CC=CC=1>[Cl:15][C:13]1[C:12]([Cl:16])=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][OH:3])[C:7]([CH2:17][C:18]([F:19])([F:20])[F:21])=[N:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Solvent: Cc1ccccc1
Product: OCCn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
To [5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzimidazol-1-yl]-acetic acid ethyl ester (915 mg) in toluene (20 mL) at −78° C. was added DiBAI-H (3.43 mls of 1.5 M in toluene). The resulting mixture was stirred for 1 hour. The reaction mixture was quenched with Rochelle's salt (aq), extracted with EtOAc, and dried over Na2SO4. The extracts were concentrated to a toluene solution and ethanol (10 mL) was added. To the resulting solution was added NaBH4 (533 mg). The resulting mixture was stirred for 5 hour. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (15%-60% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.[F:36][C:37]1[CH:38]=[C:39]2[C:43](=[C:44](/[C:46](/[NH:49]O)=[N:47]/[H])[CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:47]=[C:46]([C:44]3[CH:45]=[C:37]([F:36])[CH:38]=[C:39]4[C:43]=3[NH:42][CH:41]=[C:40]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc(F)cc2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
HOBT (216 mg) and EDCI (273 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (151 mg) in THF (4 mL). The reaction mixture was stirred at RT for 1 hour. Ethyl 3-{5-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D136) (268 mg) in THF (4 mL) was added. Then stirring continued overnight. TBAF (1.18 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D137) (287 mg) as a pale yellow solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH2:12][Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCC=C(COCc1ccccc1)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Crude 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol (1.42 g, 3.16 mmol) in 10 ml of CH2Cl2 was added to 0.71 g thionyl chloride (6 mmol) and 2 drops of DMF in 10 ml of CH2Cl2, and the solution was stirred for 0.5 h and evaporated in vacuum. Toluene was added and the mixture was evaporated in vacuum to yield crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH3:10])[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[In]>C(O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](Nc1cccc(Br)n1)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](Nc1cccc(Br)n1)c1cccc(N)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a solution of 6-bromo-N-[(1S)-1-(3-nitrophenyl)ethyl]pyridin-2-amine (100 mg, 0.31 mmol) in ethanol (5 mL) was added a solution of ammonium chloride (166 mg, 3.1 mmol) in water (2.5 mL), then indium powder (142 mg, mesh 100, 1.24 mmol). The mixture was heated at reflux for 4.5 hours, was allowed to cool to room temperature and was filtered through Celite. The filter cake was washed with water and ethanol and the combined filtrates were extracted with dichloromethane (2×30 mL) and the extracts washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give N-[(1S)-1-(3-aminophenyl)ethyl]-6-bromopyridin-2-amine (70 mg, 77%) as a dark yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCC(O)CC2)cn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCC(O)CC4)cn3)ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.50 g, 6.76 mmol) and 6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (1.96 g, 10.13 mmol) were combined in toluene (10.0 ml) under nitrogen. The reaction mixture was heated to reflux and stirred for 4 h. The reaction mixture was cooled to RT and filtered. The solids were washed with additional toluene (75 mL total) and dried in vacuo to produce a yellow powder (566 mg, 1.13 mmol). MS (APCI+) 499, 501 (M+2, 100); 1H NMR δ(400 MHz, DMSO-d6) 10.06 (s, 1H), 8.96 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 5.93-5.89 (m, 1H), 4.71 (s, 1H), 3.65-3.60 (m, 1H), 3.53-3.51 (m, 2H), 2.88-2.83 (m, 2H), 2.57 (s, 3H), 2.18 (br, 2H), 1.90-1.81 (m, 5H), 1.59-1.48 (m, 3H); Anal. Calc'd for C23H27Br1N6O2, 0.45H2O: C, 54.43; H, 5.54; N, 16.56. Found: C, 54.04; H, 5.23; N, 16.33.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH2:25][O:21][C:20](=[O:22])[C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h and then cooled to 0° C. DBU (46.6 g, 0.03 mol) was then added and the reaction mixture was stirred for 2 h at 0° C. and quenched with HCl (1 N). The aqueous layer was basified with a NaHCO3 solution and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (600 mg, 15%) as a solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: Brc1cccc2c1C=CC2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A mixture of compound 4 (40 g, 205 mmol, 1 equiv), (biphenyl-2-yl)boronic acid (81.2 g, 410 mmol, 2 equiv), powdered potassium carbonate (85 g, 615 mmol, 3 equiv), and bis(triphenylphosphine)palladium(II)dichloride (7.2 g, 10.3 mmol, 0.05 equiv), 1,4-dioxane (300 mL) and water (150 mL) was heated overnight at 80° C. The reaction was poured into 500 mL of water and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with saturated brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified over silica gel (400 g) eluting with heptanes to give compound (5) (50 g, 91% yield) as a light-yellow oil that slowly turned to an off-white solid on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](C)=[N:7][C:6]=2[CH:11]=1.[OH-].[Na+]>C(O)CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:8])=[C:6]([CH:11]=1)[NH2:7]
Reactant: Cc1nc2cc(F)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: CSc1ccc(F)cc1N

Procedure:
5-Fluoro-2-methylbenzothiazole was heated with ethylene glycol and 10N sodium hydroxide solution and the resulting thiol methylated using procedures similar to those described in Example 5, to give 5-fluoro-2-(methylthio)aniline.
Reaction SMILES: O[C@@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:27]([OH:30])(=[S:29])[CH3:28].Cl>O1CCCC1>[C:27]([S:29][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1)(=[O:30])[CH3:28]
Reactant: CC(O)=S
Reactant: CCOC(=O)C1=CCOC[C@@H]1O
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCOC[C@H]1SC(C)=O
Temperature: -45 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, to a solution (500 mL) of ethyl (3R)-3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (23.5 g) in tetrahydrofuran was added dropwise N,N-diisopropylethylamine (35.7 mL) at −70° C. Then, methanesulfonyl chloride (13.7 mL) was added dropwise, and the mixture was stirred at −45° C. for 2 hr. The mixture was again cooled to −70° C., N,N-diisopropylethylamine (14.6 mL) and thioacetic acid (35.7 mL) were respectively added, and the mixture was stirred at −45° C. for 2 hr. The reaction mixture was treated with 1N hydrochloric acid (300 mL) and extracted with diisopropyl ether (300 mL×2). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and water (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=6:1→4:1) to give the title compound (19.5 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]([O:17]CC)=[O:16])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:6]2.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]([C:20]([OH:22])=[O:21])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2nc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2cc(C(=O)O)c(C(=O)O)nc2cc1OC
Yield: 101 %

Procedure:
A suspension of 26.7 g (80 mmol) of 6,7-dimethoxy-2,3-quinolinedicarboxylic acid, diethyl ester, prepared as described by S. B. Kadin and C. H. Lamphere, J. Org. Chem., 49, 4999 (1984), in 10% sodium hydroxide solution (containing 16 g (400 mmol) of sodium hydroxide) was refluxed for 5 hours. After the filtration of the hot solution, 300 ml of water and subsequently 3N hydrochloric acid were added until the pH reached 1.0. The solids were filtered off by suction, washed thoroughly with water, and dried in vacuo to give 22.4 g of the desired product having a melting point of 264°-266° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=2)[C:12]#[N:13])[CH2:4][CH2:3]1>N.[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[CH:10]=[C:11]([CH2:12][NH2:13])[CH:14]=[CH:15][N:16]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Oc2cc(C#N)ccn2)CC1
Agent: [Ni]
Agent: N
Product: CN1CCC(Oc2cc(CN)ccn2)CC1
Yield: 95 %

Procedure:
2-[(1-Methylpiperidin-4-yl)oxy]isonicotinonitrile (0.250 g, 1.51 mmol, from step a above) was dissolved in 10 mL of ammonia saturated MeOH and 0.200 g Raney Nickel was added. The mixture was hydrogenated at 5 atm overnight. The mixture was filtered and evaporated to give 0.242 g (95%) of crude product which was used in the following step. 1H NMR (300 MHz, CD3OD) δ 8.01 (d, 1H), 6.89 (d, 1H), 6.76 (bs, 1H), 5.00 (m, 1H), 3.77 (bs, 2H), 2.73 (m, 2H), 2.37 (m, 2H), 2.30 (s, 3H), 2.03 (m, 2H), 1.81 (m, 2H).
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[OH-].[NH4+].[I:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:30](O)=[O:31]>CN(C=O)C>[I:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:30]([NH2:3])=[O:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(N)=O)cc1I
Reaction time: 8 h
Yield: 87 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.49 g, 28.6 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (3.90 g, 28.9 mmol) and 32% aqueous ammonium hydroxide solution (1.10 mL, 28.7 mmol) were sequentially added to a stirred solution of 3-iodo-4-methylbenzoic acid (5.00 g, 19.1 mmol) in N,N′-dimethylformamide (15 mL) at room temperature. After stirring overnight, the mixture was concentrated in vacuo and water and dichloromethane were added to the mixture. The organic layer was washed with 2N aqueous sodium hydroxide solution, brine, dried (MgSO4) and evaporated to give the title compound (4.34 g, 70%) as a yellow solid.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>C(#N)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccccc1
Solvent: CC#N
Product: ClCc1coc(-c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
A mixture of benzamide (0.8 g, 6.60 mmol) and 1,3-dichloropropan-2-one (1.00 g, 7.92 mmol) was heated at 130° C. stirring under nitrogen atmosphere for 1 hour (UPLC/MS complete conversion). The obtained brown solution was cooled to room temperature, and the brown solid was suspended in acetonitrile (25 ml) and heated to reflux. The white insoluble solid was eliminated by filtration, and the solution was allowed to cool to room temperature. The formed precipitate was collected by filtration and washed with acetonitrile (8 ml), dissolved in EtOAc (20 ml) and washed with aq. NaHCO3 (15 ml). The organic phase was dried (Na2SO4), filtered and evaporated to obtain 4-(chloromethyl)-2-phenyloxazole (315 mg, 24.7% yield).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: CCCCCCCCNCC(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCCCCCN(CC(=O)OC)C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
Methyl 2-(octylamino)acetate (31.6 mg, 0.157 mmol) and n-octanoic acid (30.0 μL, 0.188 mmol) were dissolved in 1 mL of well-dried DCM under argon condition and EDC (90.3 mg, 0.471 mmol), HOBt (63.6 mg, 0.471 mmol) and DIPEA (135 μL, 0.785 mmol) were added. The reaction mixture was then stirred for 12 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 5 mL of water and the reaction mixture was extracted with DCM (4 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 44.7 mg (0.136 mmol, 87%) of the desired compound.
Reaction SMILES: [CH2:1]([C:3]1([C:9]#[N:10])[CH2:7][CH2:6][NH:5][C:4]1=[O:8])[CH3:2].[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:11][C:12]1[N:17]=[C:16]([N:5]2[CH2:6][CH2:7][C:3]([CH2:1][CH3:2])([C:9]#[N:10])[C:4]2=[O:8])[CH:15]=[CH:14][N:13]=1
Reactant: CCC1(C#N)CCNC1=O
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 3-ethyl-2-oxopyrrolidine-3-carbonitrile (40 mg) obtained in Step H of Example 1, 2,4-dichloropyrimidine (86 mg), cesium carbonate (190 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg) in tetrahydrofuran (1 mL) was added tris(dibenzylideneacetone)dipalladium(0) (5 mg), and the mixture was stirred overnight at 100° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (46 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of t-butyl piperazine-1-carboxylate (1.96 g, 10.54 mmol, 2.00 equiv), 1-bromo-3-chlorobenzene (1 g, 5.26 mmol, 1.00 equiv), BINAP (330 mg, 0.53 mmol, 0.10 equiv), Pd2(dba)3 (243.8 mg, 0.27 mmol, 0.05 equiv), NaOt-Bu (1.59 g, 16.56 mmol, 3.00 equiv), and toluene (17 mL) was placed in a 100-mL round bottom flask, stirred overnight at 100° C. in an oil bath, and concentrated under vacuum. Purification via silica gel column (PE/EA (50:1)) yielded 1.3 g (83%) of t-butyl 4-(3-chlorophenyl)piperazine-1-carboxylate as a yellow solid.