Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[F:27][C:28]1[C:33]([CH:34]=[O:35])=[CH:32][CH:31]=[C:30]([NH:36][C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[N:29]=1.O>O1CCCC1>[F:27][C:28]1[C:33]([CH:34]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)[OH:35])=[CH:32][CH:31]=[C:30]([NH:36][C:37]2[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[N:29]=1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: COc1ccc(Nc2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: 5 °C
Yield: 92.4 %

Procedure:
To a solution of 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1.02 g, 2.461 mmol) in 6.0 mL of tetrahydrofuran at −50° C. under nitrogen, isopropylmagnesium chloride (1.23 mL, 2.00 M in tetrahydrofuran, 2.46 mmol) is added slowly. The reaction is allowed to warm to 5° C. over 70 minutes, then cooled to −45° C., followed by addition of 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde (56, 0.165 g, 0.667 mmol) in 2.0 mL of tetrahydrofuran. The reaction is allowed to warm to room temperature over an hour, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (68, 330 mg). MS (ESI) [M+H+]+=536.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:2]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:9][CH2:8][N:7]([CH2:6][C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)[CH2:12][CH2:11]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: c1cc(CN2CCNCC2)cs1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(Cc2ccsc2)CC1

Procedure:
Reaction of N-(3-thienylmethyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2g) analogously to the procedure of Example 4 gave the title compound after crystallization from methanol/diethyl ether as the dihydrochloride salt; yield 3.35 g (91%), m.p. indistinct, decomposed at 245°-250° C.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][OH:14])[O:11][CH:12]=1)=[O:7])[CH3:4].CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1coc(CO)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1coc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-hydroxymethyl-oxazole-4-carboxylic acid ethyl ester (345 mg, 2.02 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.40 mL, 2.87 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.60 mmol). After stirring at 0° C. for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:2→1:1 EA-Hept) gave the title compound as a yellow solid. TLC: rf (1:1 EA-Hept)=0.23. LC-MS-conditions 01: tR=0.73 min; [M+H]+=249.94.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[C:4]([NH:22][C:23](=[O:25])[CH3:24])[CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[C:4]([NH:22][C:23](=[O:25])[CH3:24])[CH:3]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cc(Cl)nc2c1nnn2Cc1ccc2ncccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(-c2cnn(C)c2)nc2c1nnn2Cc1ccc2ncccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
To a mixture of N-(5-chloro-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)acetamide (80 mg, 0.227 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.24 mmol) and Na2CO3 (48 mg, 0.25 mmol) in dioxane (10 mL) and H2O (1 mL) under N2 was added Pd(dppf)Cl2 (20 mg, 0.02 mmol). The reaction mixture was stirred at 100° C. under N2 overnight. After cooled to room temperature, the reaction mixture was concentrated and purified by chromatography to afford the title compound (7 mg). MS: 400 (M+1)+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)[O:10]2)=[CH:5][CH:4]=1.C=O.S([O-])([O-])(=O)=O.[Mg+2].[C:29](O)(=O)C.C([BH3-])#N.[Na+]>>[OH:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:20])[C:8]([CH3:19])=[C:9]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH3:29])[O:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: Cc1c([C@H]2CCCN2)oc2c(C)c(O)ccc2c1=O
Agent: C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Product: Cc1c([C@H]2CCCN2C)oc2c(C)c(O)ccc2c1=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
A mixture composed of 7-hydroxy-3,8-dimethyl-2-[(2R)-pyrrolidin-2-yl]-4H-chromen-4-one hydrochloride (78 mg, 0.30 mmol) obtained in Example 2-3, 90% paraformaldehyde (50 mg, 1.50 mmol), magnesium sulfate (60 mg), and acetic acid (17 μL, 0.30 mmol) was stirred at 50° C. for 5 minutes. Then, sodium cyanoborohydride (43 mg, 0.66 mmol) was added thereto, and the mixture was stirred at 50° C. for 3 hours. Insoluble matter in the reaction solution was filtered off and then washed with methanol. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase HPLC to obtain 23 mg of the title compound (yield: 27%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1.[C:25]([OH:30])(=O)[C:26]([CH3:28])=[CH2:27]>>[CH3:27][C:26](=[CH2:28])[C:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:25](=[O:30])[C:26]([CH3:28])=[CH2:27])[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:25](=[O:30])[C:26]([CH3:28])=[CH2:27])=[CH:15][CH:16]=3)[CH:8]=2)=[CH:23][CH:22]=1)=[O:30]
Reactant: C=C(C)C(=O)O
Reactant: OCCCc1cc(-c2ccc(O)cc2)cc(-c2ccc(O)cc2)c1
Product: C=C(C)C(=O)OCCCc1cc(-c2ccc(OC(=O)C(=C)C)cc2)cc(-c2ccc(OC(=O)C(=C)C)cc2)c1

Procedure:
In analogy to step 2 of example 1, 5′-(3-hydroxy-propyl)-[1,1′;3′,1″]terphenyl-4,4″-diol and methacrylic acid are reacted to give 2-methyl-acrylic acid-3-[4,4″-bis-(2-methyl-acryloyloxy)-[1,1′;3′,1″]terphenyl-5′-yl]-propyl ester as colourless, viscous oil.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([O:16][CH2:32][CH2:33][CH3:34])=[O:15])=[O:11]
Reactant: CCCBr
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCOC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.6 %

Procedure:
To a solution of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid (100 mg) in N,N-dimethylformamide (2 ml) were added triethylamine (50 mg) and propyl bromide (100 mg) and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed succesively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 30 mg of propyl 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionate as a colorless viscous oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CCCC1
Reactant: NCc1ccccc1
Product: O=C1CCCC(NCc2ccccc2)C1

Procedure:
2-Cyclohexenone is reacted with benzylamine to give 3-benzylaminocyclohexanone. Hydrogenolysis of the benzylamino group then gives 3-aminocyclohexanone. Reaction with hexadecanoyl chloride affords 3-hexadecanamidocyclohexanone, which is then reduced with sodium borohydride to produce a cis/trans mixture of 3-hexadecanamidocyclohexanol. Separation by column chromatography then gives the pure isomers. Reaction with bromoethylphosphodichloridate, then with trimethylamine will produce 3-hexadecanamido-cyclohexylphosphocholine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([CH3:10])=[C:4]([Cl:11])[CH:3]=1.Cl[CH2:13][C:14](Cl)=[O:15].C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:4]1[C:5]([CH3:10])=[C:6]([Cl:9])[C:7]2[O:8][CH2:13][C:14](=[O:15])[NH:1][C:2]=2[CH:3]=1
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2

Procedure:
6-Amino-2.4 dichloro-3-metylphenol (1.9 g, 10 mmol), 2-chloroacetyl chloride (1.2 g, 11 mmol) and K2CO3 (3.0 g, 22 mmol) were mixed according to GP1 to give the title compound as a crude (80MF2225) (2.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][C:22]([C:24]([F:25])([F:27])[F:26])=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2sc(C(F)(F)F)cc21
Product: CC1c2cc(C(F)(F)F)sc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-2-trifluoromethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([O:22][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1O)C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl N-(3,4-difluoro-2-hydroxyphenyl)aminomethylenemalonate (80 mg) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 ml) was added benzyl bromide (30 μl). The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyloxy-3,4-difluorophenyl)aminomethylenemalonate (90 mg), mp 87° C.; MS m/z 405 (M+).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH3:5].[O:6]=[CH:7][C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:14][C:13]1[CH:15]=[CH:16][C:8]([CH:7]=[O:6])=[CH:9][C:10]=1[O:11][CH3:12])[C:3]#[C:4][CH3:5]
Reactant: CC#CCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc(C=O)cc1OC
Yield: 95.2 %

Procedure:
1-Bromobut-2-yne (0.36 mL, 4.0 mmol) was added to a suspension of vanillin (0.55 g, 3.6 mmol) and potassium carbonate (1.79 g, 10.9 mmol) in acetone (10 mL) and treated according to Procedure 3. 4-(But-2-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 95%) was obtained as a pale yellow crystalline solid; mp 90-92° C.; δH (400 MHz, CDCl3) 1.84 (t, J=2.2 Hz, 3H, CH3), 3.93 (s, 3H, OCH3), 4.81 (q, J=2.2 Hz, 2H, OCH2), 7.12 (d, J5,6=8.4 Hz, 1H, H5), 7.42 (d, J2,6=2.0 Hz, 1H, H2), 7.45 (dd, J5,6=8.4, J2,6=2.0 Hz, 1H, H6), 9.86 (s, 1H, CHO); δC (100 MHz, CDCl3) 4.0, 56.2, 57.5, 73.2, 85.2, 109.4, 112.4, 126.7, 130.7, 150.1, 152.7, 191.2; vmax 991, 1259, 1504, 1586, 1679, 2226, 2302, 2833, 2921 cm−1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)=C=O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]([NH:36][C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:35])[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
1-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-3-p-tolylurea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (66 mg, 0.22 mmol) and 1-isocyanato-4-methylbenzene (29.4 mg, 0.22 mmol) according to General Procedure G to give 30 mg (31.4%) of white solid. Anal. Calcd. for C26H33N5O m/z 431.3, found: 432.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (m, 2H), 7.39 (d, J=8.9 Hz, 2H), 7.25 (m, 2H), 7.03 (d, J=8.3 Hz, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.02 (s, 1H), 3.81 (m, 2H), 2.22 (s, 3H), 1.91 (m, 3H), 1.64 (m, 4H), 1.48 (m, 2H), 1.2 (m, 5H), 1.19 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:15]1([CH2:14][C@H:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:35](=[O:36])[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccn1)Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (100 mg, 0.288 mmol) and 2-pyridylacetic acid HCl (67 mg, 0.386 mmol) in DMF (3 mL) was added EDCI HCl (111 mg, 0.576 mmol, 2 equiv). The yellow solution turned orange overnight. Some of the DMF was removed under reduced pressure. The residue was dissolved in H2O and 1 M NaOH was added until the solution was basic (pH 10). The mixture was extracted thoroughly with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a bright yellow oil. Purification by chromatography (7% MeOH/CH2Cl2) afforded the title compound as a pale yellow foam (107 mg, 0.229 mmol, 80%). The structure was confirmed by NMR and mass spectrometry. MS m/z 467 (M++H).
Reaction SMILES: CO[CH:3](CSC(=O)NCCCCCCCCCCCCCCCCCC)[CH2:4]N.[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:36][CH2:37][CH:38]([O:57][CH3:58])[CH2:39][S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])(=[O:35])=[O:34]>>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:36][CH2:37][C:38]1([CH2:39][S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:4][CH2:3][CH2:58][O:57]1)(=[O:34])=[O:35]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)SCC(CN)OC
Product: CCCCCCCCCCCCCCCCSCC1(CNS(=O)(=O)CCCCl)CCCO1

Procedure:
2-Aminomethyl-2-hexadecylthiomethyltetrahydrofuran IV b1 is allowed to react and worked by the same procedure as described in (4). m.p. 44.5° to 45.5° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to benzylamine via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 476 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC#N>[N+:12]([C:3]1[C:2]([O:1][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(OC2CCOCC2)c1[N+](=O)[O-]
Yield: 136.7 %

Procedure:
Methyl 3-hydroxy-2-nitrobenzoate (95 g, 0.52 mol), tetrahydro-2H-pyran-4-yl methanesulfonate (234 g, 1.3 mol) and K2CO3 (358 g, 2.6 mol) was suspend in MeCN (2 L). The mixture was heated at reflux for 20 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered; the filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether: ethyl acetate=10:1, 5:1, 2:1) to give the title compound (200 g 100%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[O:8][N:9]=2.O>C(O)(=O)C.[Fe]>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: Oc1ccc(-c2onc3ccc(Cl)cc23)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 83.7 g (0.34 mole) of 5-chloro-3-(4-hydroxyphenyl)-2,1-benzisoxazole in 1500 ml of glacial acetic acid was added 45 g of iron filings. The mixture was stirred and heated on the steam bath for 20 min. Every 30 min. an additional 20 g of iron filings and 100 ml of water was added for 2.5 hr. After 30 min. more, the reaction mixture was filtered while hot. The collected precipitate was heated with acetic acid and filtered. The combined filtrates were diluted with ice water to precipitate 39.8 g (47%) of product, mp 170°-175°. Recrystallization from methanol-water gave yellow rods, mp 173°-178°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[Br:44][C:45]1[S:49][C:48]([NH2:50])=[N:47][CH:46]=1.C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[Br:44][C:45]1[S:49][C:48]([NH:50][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:47][CH:46]=1
Reactant: Nc1ncc(Br)s1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)Nc2ncc(Br)s2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (4 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 5-bromo-thiazol-2-ylamine (377 mg, 1.45 mmol) and was stirred at 25° C. for 30 min. The reaction was then treated with N,N-diisopropylethylamine (0.22 mL, 1.26 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (30 mL) and ethyl acetate (30 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl)-amide (33 mg, 13%) as a yellow solid: mp 240-242° C.; (ES)+-HRMS m/e calcd for C15H13BrClN3OS (M+H)+ 397.9724, found 397.9730.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH:26]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([CH2:16][CH2:17][C@@H:18]([NH2:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a solution of tert-butyl(R)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbutan-2-ylcarbamate (0.089 g, 0.20 mmol) in 5 mL of DCM was added 1 mL of TFA. After 30 minutes, the solvent was removed by rotary evaporation. The residue was taken up in 2 N NH3/MeOH to free base the amine. Concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 10% MeOH/DCM) afforded (2R)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbutan-2-amine (0.015 g, 22% yield) as a brown solid. MS m/z: 344 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.58-8.55 (m, 1H), 8.48 (s, 1H), 8.35-8.25 (m, 2H), 8.12 (d, J=6.2 Hz, 1H), 7.40-7.27 (m, 5H), 6.79 (s, 1H), 3.61-3.50 (m, 2H), 3.19-2.94 (m, 3H), 2.16-2.03 (m, 2H).