Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]>>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled to yield tert-butyl (3S,5R)-1-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate. LCMS (m/z): 624.1/626.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[CH3:28][C:24]1[CH:23]=[C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(-c2ccc3ccc(N)nc3n2)c1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: O
Solvent: CC#N
Product: Cc1cccc(-c2ccc3ccc(NC(=O)c4cccc(Br)c4)nc3n2)c1
Temperature: 4 °C
Yield: 23.4 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.8 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(3-methylphenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (2.3 g) is dissolved in boiling acetonitrile (300 cc). After 4 hours of cooling at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×5 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-[7-(3-Methylphenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (1 g), m.p. 100° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.O.CN(C1C=CC=CN=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@H:13]([O:18][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 112.1 %

Procedure:
20 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyrate was dissolved in 100 ml of pyridine and 13.3 g of p-toluenesulfonyl chloride was added thereto while maintaining the reaction temperature at 10° to 20° C. Next, 0.03 g of dimethylaminopyridine (DMAP) was added thereto as a catalyst and the mixture was stirred at 20° to 25° C. for 5 hours. Then the reaction mixture was diluted with 500 ml of water and extracted with 150 ml portions of ethyl acetate twice. The extract was washed successively with 50 ml of 2 N hydrochloric acid and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated over anhydrous sodium sulfate and filtered. After distilling off the solvent, 32.5 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-p-toluenesulfonyloxy-4-phenylbutyrate was obtained as a pale yellow, oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(NCC)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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COc1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of 4-methoxy-phenyl-acetylene (10 g, 0.075 mol) and 4-iodo-anisole (17.65 g, 1.0 eq.) in diethylamine (150 mL) was added Pd(PPh3)2Cl2 (2.65 g, 0.05 eq.) and the reaction mixture was stirred for 30 min at 0° C. To the reaction mixture was then added Cul (1.43 g, 0.1 eq.) and the mixture was stirred at 6 h at 0˜25° C. The reaction mixture was then concentrated and partitioned between ethyl acetate/H2O (200/600 mL). The organic layer was separated, dried and purified on SiO2 (1˜5% ethyl acetate/hexane) to yield 1,2-di(4-methoxy-phenyl)-acetylene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27](B(O)O)=[CH:26][N:25]=1>>[CH3:22][O:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([NH:19][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][N:25]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Product: COc1ncc(-c2cccc(-n3cnc4cc(C(C)NC=O)ccc43)c2)c(OC)n1
Yield: 81 %

Procedure:
This was prepared analogously from N-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-formamide and 2,4-dimethoxypyrimidine-5-boronic acid in 81% yield. LC-ESI-HRMS of [M+H]+ shows 404.1729 Da. Calc. 404.172265 Da. dev. 1.6 ppm.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[N:7]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[N:2]1([O:1][C:13]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[O:14])[CH:6]=[CH:5][CH:4]=[N:3]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: On1cccn1
Product: O=C(On1cccn1)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxypyrazole and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, crystals).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][OH:9])=[NH:7])#[N:2].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=O>ClCCl>[Cl:20][CH2:21][C:22]1[O:9][N:8]=[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[C:1]#[N:2])[N:7]=1
Reactant: N#Cc1cccc(C(=N)NO)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(-c2noc(CCl)n2)c1

Procedure:
3-cyano-N-hydroxy-benzamidine (1.0 g, 6.2 mmol), triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl chloride (0.74 ml, 9.3 mmol) in dichloromethane (12 ml). Purification was performed by decolorizing with silica gel. 1H NMR (CDCl3), d (ppm): 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11]I.[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CI
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C)cc(C)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In 100 ml of DMSO were dissolved 10 g of 2,3,5-trimethylphenol and 10.4 ml of methyl iodide. Under ice-cooling, 5.6 g of 60% sodium hydride in oil was added, and the mixture was stirred at room temperature for 10 hours. After addition of water, the extraction with ether was carried out. The ether layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation leaves the oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N:18]([CH3:17])[CH3:28])[CH:20]=2)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1cccc(C(=O)N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)c1
Yield: 95 %

Procedure:
A mixture of 5-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.53 g, 2.3 mmol) (Eur. J. Med. Chem., 1987, 22, 33-43) and 3-(dimethylamino)benzoyl chloride (0.5 g, 2.3 mmol) (Chem. Pharm. Bull., 1980, 28, 2045-2051) in tetrahydrofuran was stirred and treated with triethylamine (0.64 mL, 2 eq). The mixture was stirred for 2 h, treated with aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4) to give the title compound (0.83 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:16])[N:3]=1.[N:17]1([CH2:23][CH2:24][OH:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[H-].[Na+].[ClH:28].C(O)C>O1CCCC1.C(O)C>[ClH:1].[ClH:28].[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=[C:4]([CH3:16])[N:5]=2)=[CH:9][CH:10]=1
Reactant: OCCN1CCCCC1
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(OCCN3CCCCC3)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.17 g of 4-chloro-6-(4-methoxyphenyl)-2-methylpyrimidine and 0.65 g of 2-piperidinoethanol were dissolved in 10 ml of dried tetrahydrofuran. After the addition of 60% sodium hydride 0.2 g, the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, and then was extracted with ethyl acetate. The extract was washed with water and was dried with anhydrous magnesium sulfate, and then this was evaporated in vacuo. The residue was purified with column chromatography with silica gel(Wako gel c-200 150 g, elution with chloroform and then chloroform: methanol=99:1), resulting 1.3 g of oily substance. This was dissolved in 10 ml of ethanol, 3 ml of 20% ethanol hydrochloride was added and evaporated in vacuo. Ether was added to the residue to crystallize. Whereby 1.32 g of crystals were obtained. These were recrystallized with isopropanol, resulting to obtain 0.83 g of crystals. Melting point is 165° to 167° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14](O)(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14]([Cl:3])(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Thionyl chloride (8.1 mL, 111.19 mmol) was added dropwise at 0° C. to a solution of 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonic acid (5.53 g, 22.24 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 3 h and then was poured onto crushed ice. Ethyl acetate (50 mL) was added to the mixture. The organic phase was separated, washed with brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The oily residue was purified on silica gel using hexane/ethyl acetate, 4:1 to give the target compound which was then recrystallized from pentane/diethyl ether to afford the title compound (2.30 g, 61% over 3 steps) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: Nc1cc(Cl)n2nccc2n1
Product: Nc1cc(-c2cccs2)n2nccc2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 7-chloropyrazolo[1,5-a]pyrimidin-5-amine (1E) and thiophen-2-ylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.82 (s, 2H), 6.24 (d, J=1.7 Hz, 1H), 6.52 (s, 1H), 7.21-7.25 (m, 1H), 7.66 (d, J=5.1 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H), 8.22 (d, J=3.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11].[ClH:13]>O1CCOCC1>[ClH:13].[CH2:10]([O:12][C:8](=[NH:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: N#CCc1ccccc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)Cc1ccccc1
Yield: 100 %

Procedure:
Combine benzyl cyanide (1.0 g, 8.50 mmol), ethanol (0.4 g, 8.50 mmol) and 4N hydrogen chloride in dioxane (8 mL) and stir the reaction mixture at ambient temperature for 17 h. Evaporate the solvent and triturate the residue with diethyl ether to obtain the desired intermediate as a white solid (1.7 g, 100%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]([CH3:31])[CH:21]=1>CN(C=O)C>[CH3:31][N:22]1[CH:21]=[C:20]([C:11]2[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:30]
Reactant: OC1CCOC1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCOC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 mL) was added NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) at 0° C. and then stirred at 0° C. for 0.5 hrs. 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (110.0 mg, 0.33 mmol) was added. The mixture was stirred at 0° C. for 0.5 h and then at r.t. for 3 hrs. It was then quenched with aqueous sat. NH4Cl (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure to afford a crude product which was purified by prep-HPLC to give the title compound (62.0 mg, 39.7%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J=7.6 Hz, 1H), 8.00 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.58-7.51 (m, 2H), 7.11-7.03 (m, 3H), 5.01-4.98 (m, 1H), 3.97 (dd, J1=10.4 Hz, J2=4.8 Hz, 1H), 3.76-3.70 (m, 2H), 3.67 (s, 3H), 3.61-3.42 (m, 1H), 3.11 (s, 3H), 2.18-1.88 (m, 2H). LCMS (M+H)+=400.0 (M+1)+
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(Cl)cc1Cl
Yield: 60.5 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2,4-dichloroaniline (2.43 g, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base, triturated with ethanol and recrystallised from ethyl acetate to give 3-butyryl-4-(2,4-dichlorophenylamino)-8-methylquinoline (2.26 g), m.p. 169°-170°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][NH:12][C:13](=[O:30])[C@H:14]1[O:22][CH:17](OC(=O)C)[C@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@@H:15]1[N:27]=[N+:28]=[N-:29].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C[Si](C)(C)N[Si](C)(C)C.ClC(Cl)C>[CH3:11][NH:12][C:13]([C@@H:14]1[C@@H:15]([N:27]=[N+:28]=[N-:29])[C@@H:16]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:22]1)=[O:30]
Reactant: CNC(=O)[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Reactant: Clc1ncnc2nc[nH]c12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1N=[N+]=[N-]
Temperature: 110 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
6-Chloropurine (20.4 g, 0.132 mol) was suspended in hexamethyl disilazane (165 mL) and heated at 110° C. After 2 h, the now homogeneous mixture was concentrated and the solid residue reconcentrated from toluene 2× and placed under high vac for 1 hour. The resulting solid was combined with 1,2-bis-O-acetyl-3-azido-3-deoxy-D-ribofuranuronic acid methyl amide (12.7 g, 0.044 mol) and dissolved in anhydrous dichloroethane (350 mL). Powdered 4A molecular sieves (15 g) were added and the mixture stirred for 15 minutes. TMSOTf (16.0 mL, 0.088 mol) was added and the reaction was then heated to 60° C. for two hours, cooled and quenched by the careful addition of saturated sodium bicarbonate solution (200 mL). Ethyl acetate (350 mL) was added and the mixture was filtered through sintered glass. The filtrate was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (15% then 20% acetone/dichloromethane) to afford the title compound (10.6 g) as an off-white foam. MS 381 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H); 8.2 (s, 1H); 7.6 (bs, 1H); 6.13 (d, 1H, J=7.0 Hz); 5.87 (dd, 1H, J=7.0, 5.6 Hz); 4.85 (dd, 1H, J=5.6, 3.0 Hz); 4.58 (d, 1H, J=3.0 Hz); 2.9 (d, 1H, J=4.9 Hz); 2.11 (s, 3H).
Reaction SMILES: C([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C(O)=O)#N.O.[CH3:17][N:18](C=O)C>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([CH3:3])[C:17]#[N:18])=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CC(C#N)C(=O)O)cc1
Solvent: O
Product: COc1ccc(C(C)C#N)cc1

Procedure:
A stirred solution of α-cyano-β(4-methoxyphenyl)propionic acid (127.3 g) in DMF (280 ml) is heated to 150° C. for 5 hours. The reaction mixture is cooled, poured into a liter of water and extracted with ether. The ether extract is washed, dried over Na2SO4, filtered and the filtrate evaporated in vacuo yielding a liquid which upon distillation yields the decarboxylated product as a clear liquid, B.P. 115° C. (1 mm).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:20][CH2:21][O:22][CH3:23])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: COCCBr
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 10 mg, 0.42 mmol) in DMF (3 mL) was added NaH (60%, 28 mg, 0.122 mmol). After stirring at room temperature for 15 minutes, 1-bromo-2-methoxyethane (25.4 mg, 0.183 mmol) was added and the reaction mixture was stirred at 80° C. for 60 minutes. The reaction was diluted with brine and extracted with EtOAc, the organic layers were dried with Na2SO4 and concentrated in vacuo to afford the title compound that was used in the next step without further purification (15 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O[C:15]1[CH:30]=[CH:29][C:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:17][CH:16]=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[CH2:22]([O:21][C:19]([C:18]1[CH:29]=[CH:30][C:15]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:16][CH:17]=1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol) in tetrahydrofuran (38.1 ml) was added benzyl 4-hydroxybenzoate (1.341 g, 5.87 mmol) and triphenylphpsphine polymer bound (4.45 g, 8.01 mmol). The reaction mixture was cooled to 0° C. and a solution of (E)-diisopropyl diazene-1,2-dicarboxylate (1.367 ml, 6.94 mmol) in tetrahydrofuran (5 mL) was added dropwise over 15 minutes. The reaction was allowed to stir at room temperature for 16 hours and the mixture was filtered. The solids were washed with dichloromethane, and the combined filtrates were concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:38]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNC(=O)c1cccc(Cl)c1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with 3-chlorobenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 594. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.82 (s, 1H) 7.7 (d, 1H) 7.55 (d, 2H) 7.2 (m, 2H), 7.3 (m, 2H), 6.9 (m, 2H), 6.8 (d, 2H), 6.71 (d, 1H), 6.5 (d, 2H), δ 4.2 (s, 2H), 3.49 (t, 2H), 3.2 (d, 2H), 3.5 (t, 2H), δ 2.6 (s, 3H), δ 1.4 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@:8]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C[C@]1(C(=O)OC(C)(C)C)CC(c2cccc(O)c2)=NO1
Yield: 49.1 %

Procedure:
A racemate of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (49.5 g) was fractionated by HPLC (column: CHIRALPAK AD (trade name), 50 mm ID×500 mm L, mobile phase: hexane/ethanol=850/150) to obtain the title compound (24.3 g) eluted at a larger retention time.