Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[CH3:20][S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>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.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloro-6-fluoroquinazolin-4-yl)morpholine (0.15 g, 0.0004 mol—Preparation 2), 3-methylsulfonylphenylboronic acid (0.078 g, 0.00039 mol), sodium carbonate (0.114 g, 0.0011 mol), DMF (6 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.015 g, 0.000022 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane) to yield the desired product (0.12 g, 66%). 1H NMR (300 MHz, CDCl3): δ 8.23 (d, J=1.8 Hz, 1H), 8.06-7.90 (m, 3H), 7.68 (t, J=7.8 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 3.92 (s, 8H), 3.12 (s, 3H): LC-MS (ESI): Calculated mass: 421.0; Observed mass [M+H]+: 422.1 (RT=1.45 min).
Reaction SMILES: [S].[C:2]([SH:6])([CH3:5])([CH3:4])[CH3:3]>C(N(CC)CC)C>[CH3:3][C:2]([S:6][C:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: CC(C)(C)S
Agent: [S]
Solvent: CCN(CC)CC
Product: CC(C)(C)SC(C)(C)C
Temperature: 40 °C
Yield: 144.1 %

Procedure:
Into a flask was placed 106.6 g of sulfur (3.33 mol) and 200.0 g (250 mL, 2.22 mol) of tert-butyl mercaptan. To the stirring mixture under a nitrogen atmosphere was cautiously added few drops of triethylamine. Vigorous gas evolution occurred and the temperature rose to 35° C. When the vigorous reaction subsided, the reaction mixture was heated to 40° C. for 1 hour. Additional triethylamine was added to a total of 2.22 g, (0.022 mol, 3.06 mL). The sulfur dissolved. The material was heated at 85° C. for 1 hour and cooled to room temperature. The product was washed with three 100 mL portions of 10% sodium hydroxide solution and two 100 mL portions of water. The product was dried by heating at 100° C. under a high vacuum using a rotary evaporator. The product was filtered to yield 234.0 g (87.4%) of a light yellow mobile oil with a trace of mercaptan odor.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Clc1ccnc(Cl)n1
Product: FC(F)(F)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Yield: 39.8 %

Procedure:
2,4-Dichloropyrimidine (317 mg, 2.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-(2-chloropyrimidin-4-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (167 mg) as a white solid: δH (400 MHz, DMSO) 7.91 (1H, d, J 7), 8.25 (1H, d, J 5), 8.83 (1H, d, J 5), 9.17 (1H, s), 10.22 (1H, d, J 7); m/z (ES+) 300, 302 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][CH2:33][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=3)[CH:36]=[CH:35]2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:29]2)=[CH:38][CH:39]=1
Reactant: Fc1ccc2ccn(CCC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(CCn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.43 g, 0.79 mmol), 1-(2-azetidin-3-yl-ethyl)-6-fluoro-1H-indole (0.25 g, 0.95 mmol) and triethylamine (0.2 mL, 1.4 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.3 g of the (S)-enantiomer of the title compound as a brown oil. The hydrochloride salt was prepared in ethyl acetate and collected as a yellow solid: m.p. 115° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH:40]([CH3:42])[CH3:41])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH:40]([CH3:42])[CH3:41])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Reactant: CC(C)OS(C)(=O)=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 40a), from 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester and isopropyl methanesulfonate. Light-yellow foam. MS (m/z): 513.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:35][CH3:36]>>[CH2:35]([N:22]([CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:36]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc5ccccc5c4)cc3)c2)o1
Reactant: CCI
Product: CCN(Cc1ccc2ccccc2c1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-2-ylmethyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.94-7.36,(14H, m), 4.89-4.70,(2H, m), 3.46-3.25,(2H, m), 2.55,(3H, s), 2.33-2.28,(3H, m), 1.16-1.09,(3H, b). LCMS; retention time 3.77 min, MH+ 462.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[C:10]([N+:20]([O-:22])=[O:21])=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:13]=2)[CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C([N+](CCCC)(CCCC)CCCC)CCC>C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.[Cl-].[Cl-].[Pd+2].[Pd+2].CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:3][C:4]=1[C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[N:11][N:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:13]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(Cl)ccc1O
Agent: [Pd+2]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(O)c(-c3cn(C4CCCCO4)nc3[N+](=O)[O-])c2)c1
Temperature: 130 °C
Yield: 42.1 %

Procedure:
4-Chloro-2-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenol (500 mg, 1.544 mmol), 3-cyanophenylboronic acid (453 mg, 3.09 mmol), di-mu-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino)methyl]phenyl]palladium (II) dimer (63 mg, 0.0772 mmol), tri-tert-butylphosphonium tetrafluoroborate (45 mg, 0.154 mmol), potassium carbonate (426 mg, 3.09 mmol) and tetrabutyl ammonium hydroxyde solution (1M in MeOH, 0.31 mL, 0.31 mmol) were combined in a microwave vial. DMF (7.5 mL) was added and the vial was sealed. The mixture was heated at 130° C. for 1 hour under microwave irradiation and then partitioned between ethyl acetate (25 mL) and water (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (10% to 80% EtOAc in heptane over 20 CV) to give the title compound (254 mg, 41%) as brown oil
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:27][CH2:28][CH3:29])[C:6]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=4[CH3:24])[C:11]3=[N:10][C:9]=2[CH2:25]C)=O)[CH2:3][CH2:2]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]([CH2:6][C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=4[CH3:24])[C:11]3=[N:10][C:9]=2[CH3:25])[CH2:27][CH2:28][CH3:29])[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)C(=O)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCN(Cc1c(C)nc2n1CCN2c1c(C)cc(C)cc1C)CC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A solution of Red-A1 (3.3 M in toluene, 0.70 mL, 2.33 mmol) was added dropwise to a solution of 2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (0.177 g, 0.46 mmol) in toluene (3 mL) at 0° C. After stirring at room temperature for 24 h, the reaction mixture was cooled to 0° C. and I N sodium hydroxide (10 mL) was added dropwise. The above mixture was extracted with dichloromethane (40 mL), and the organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvents were removed in vacuo to afford the title compound as a light yellow oil which solidified upon cooling (109 mg, 65% yield). The purity of the product was determined to be 91% by LC/MS. 1H NMR (CDC13, 300 MHz) δ 6.85 (s, 2H), 4.09-3.96 (m, 4H), 3.45 (s, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.29 (d, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.04 (s, 3H), 1.46 (quintet, J=7.3 Hz, 2H), 1.28-1.25 (m, 1H), 0.87 (t, J=7.2 Hz, 3H), 0.49-0.46 (m, 2H), 0.09-0.06 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 155.4, 137.1, 136.9, 136.0, 135.0, 129.7, 117.7, 58.5, 55.5, 53.8, 48.0, 42.4, 20.9, 20.3, 18.2, 13.3, 12.0, 8.9, 4.0. Mass spec.: 367.24 (MH+).
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.C1COCC1.[Na].[CH3:31][SH:32]>C(OCC)(=O)C>[CH3:31][S:32][CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC=CC(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to THF (5 ml), sodium salt of methyl mercaptan (0.075 g) was added thereto and stirred for four hours at room temperature. Ethyl acetate (50 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated of sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-methylthio-N-phenylacrylimidate (0.20 g) as yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]1=O)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1.CO>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]1=[S:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cccc(OC)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCn1cccc(OC)c1=S
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 1-butyl-3-methoxy-2-pyridone (2-034-02) (6.4 g) in toluene (150 mL) was added Lawesson's reagent (16.8 g), and the reaction mixture was heated under reflux. After the reaction mixture was stirred for 3 h, to the reaction mixture was added methanol (100 mL), and the reaction mixture was stirred for 30 min. After the solvent was evaporated under reduced pressure, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1-butyl-3-methoxypyridine-2-thione (2-034-03) (5.6 g, 80%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5](I)=[CH:4][N:3]=1.[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:36])[C@@H:25]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:20]=[CH:21][CH:22]=1)#[CH:16].O.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([C:16]#[C:15][C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:36])[C@@H:25]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:26])[CH:20]=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reactant: Clc1ncc(I)c(N2CCOCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](C(=O)Nc1cccc(C#Cc2cnc(Cl)nc2N2CCOCC2)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 4-(2-chloro-5-iodopyrimidin-4-yl)morpholine (H11, 300 mg), (S)-tert-butyl (1-((3-ethynylphenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (G1, 558 mg), bis(triphenylphosphine)palladium(II) dichloride (32 mg) and copper(I) iodide (9 mg) in N,N-dimethylformamide (5 mL), triethylamine (640 μL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 85 to 70% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-((2-chloro-4-morpholinopyrimidin-5-yl)ethynyl)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (L5, 437 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:15](=O)[C:16]([F:19])([F:18])[F:17])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]([C:16]([F:19])([F:18])[F:17])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:7][C:6]=2[CH:14]=1
Reactant: CCOC(=O)COc1cc(C)ccc1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1oc2cc(C)ccc2c1C(F)(F)F
Temperature: 90 °C
Reaction time: 48 h
Yield: 34.3 %

Procedure:
The mixture of ethyl 2-(5-methyl-2-(2,2,2-trifluoroacetyl)phenoxy)acetate (7.3 g, 25.2 mmol) and pre-oven dried K2CO3 (5.21 g, 37.7 mmol) in 25 mL of CH3CN in sealed tube was heated and stirred at 90° C. for two days. After cooling to room temperature, the reaction was filtered, and the solid was washed with anhydrous CH3CN. The combined filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-2% Ethyl Acetate/98% Heptane, to give ethyl 6-methyl-3-(trifluoromethyl)benzofuran-2-carboxylate (2.35 g). LCMS retention time=1.52 minutes (LC method 1); MS (m+1)=273.3. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.45 (t, J=7.1 Hz, 3H), 2.53 (s, 3H), 4.50 (q, J=7.2 Hz, 2H), 7.24 (dd, J=8.3, 0.9 Hz, 1H), 7.43 (d, J=0.6 Hz, 1H), 7.69-7.77 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1COCC1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCOC(C)=O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]2[N:6]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COCCOCCl
Reactant: COc1cc2[nH]cnc2cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCn1cnc2cc(Cl)c(OC)cc21
Reaction time: 18 h
Yield: 65.4 %

Procedure:
To a mixture of 5-chloro-6-methoxy-1H-benzoimidazole (0.320 g, 1.75 mmol) and THF (10 mL), was added DIPEA (0.850 mL, 4.9 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (0.310 g, 2.45 mmol) at 23° C. After stirring for 18 h. EtOAc (50 mL) was added. The organic layer was washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure to afford (0.31 g) of crude material which was used without further purification in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16]C(OCC2C=CC=CC=2)=O)[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of (S)-2-(3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (2.48 g, 6.43 mmol) in a mixture of MeOH (15 mL) and EtOAc (15 mL) was added 10% Pd/C (250 mg). The mixture was degassed and stirred at room temperature for 90 minutes under an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through a short pad of silica which was then flushed with MeOH. The combined filtrates were evaporated under reduced pressure to afford the title compound as a white solid (1.62 g, 100%); 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, t), 1.44 (9H, s), 1.91 (1H, m), 2.21 (1H, m), 4.24 (2H, br s), 5.50 (1H, dd), 6.11 (1H, t), 6.53 (1H, d), 6.77 (1H, d)
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].[CH2:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[CH2:33]([N:40]1[CH2:45][CH2:44][C:43](=[CH:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a suspension of 4-cyanobutyltriphenylphosphonium bromide (21.80 g) in tetrahydrofuran (100 ml) was added potassium tert-butoxide (5.76 g) in tetrahydrofuran (50 ml) over 30 minutes at 0° C. After 1 hour, a solution of 1-benzyl-4-piperidone (8.84 g) was added to the mixture over 30 minutes at 0° C. The mixture was stirred at ambient temperature for 1 hour, poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on alumina eluting with chloroform/hexane (1:1) and the fractions containing the object compound were combined and evaporated to afford 1-benzyl-4-(4-cyanobutylidene)piperidine (9.8 g) as an oil.
Reaction SMILES: COC([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=O.[C:32]([O:36][C:37]([O:39]C([O-])=O)=O)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([NH:5][CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][OH:8])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)NC(=O)OC(C)(C)C
Yield: 93.4 %

Procedure:
2-tert-Butoxycarbonylamino-3-octadecylcarbamoyloxypropanol V e2 is prepared by the same manner as described in (41) by using tert-butyldicarbonate instead of methyl chloroformate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:27])[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: NCCN1CCCCC1
Reactant: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)O)c4)c3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)NCCN5CCCCC5)c4)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-pyridine-2-carboxylic acid (0.07 g, 0.17 mmol) was dissolved in DMF (2.5 mL), followed by sequential addition of 1-(2-aminoethyl)piperidine (0.02 g, 0.17 mmol), 1-hydroxybenzotriazole (0.05 g, 0.38 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol), and N-methylmorpholine (0.04 g, 0.38 mmol). The mixture was stirred at room temperature for 12 h, and the solvent was removed in vacuo. The crude residue was dissolved in CH2Cl2 (10 mL), and washed with H2O (3 mL). The solvent was removed in vacuo, and the crude product was purified by preparative HPLC. The isolated product was washed with aq. Na2CO3 to give 0.07 g (78%) of the title compound. 1H-NMR (CD3OD) δ 8.51 (d, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.50-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.26 (dd, 1H), 7.10 (dd, 1H), 6.81-6.77 (dd, 1H), 4.03 (s, 3H), 3.60 (t, 2H), 2.78-2.71 (m, 6H), 1.69-1.51 (m, 6H); MS LC-MS (M+H)+=514.3, RT=2.62 min.