Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[C:18]1[C:27]([O:28][CH3:29])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.[Sn].BrBr>C1(C)C=CC=CC=1.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.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.[Pd]>[CH3:14][O:13][C:12]1[C:3]([C:18]2[C:27]([O:28][CH3:29])=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc2ccccc2nc1Br
Reactant: COc1cc2ccccc2nc1[Sn](C)(C)C
Agent: [Pd]
Agent: BrBr
Agent: [Sn]
Solvent: Cc1ccccc1
Product: COc1cc2ccccc2nc1-c1nc2ccccc2cc1OC

Procedure:
Toluene is distilled over LiAlH4 and made absolute in this manner directly before reaction. Under argon inert gas, 0.79 (2.46 mmol) of the 2-trimethylstannyl-3-methoxyquinoline described above is taken up in 5 ml of absolute toluene. 0.61 g (2.51 mmol) of 2-bromo-3-methoxyquinoline is then added to this solution. The reaction solution has a yellow color. To [sic] 20 mg (0.017 mmol) of tetrakis(triphenylphosphine) palladium(O) are then added to the reaction solution, and the reaction is monitored by thin-layer chromatography (silica gel/Et2O). The reaction solution is heated to boiling. After a reaction time of 20 hours, the tin compound and the bromine compound can still be detected. At the same time, a new band having an RF value of 0.25 and yellow fluorescence, which can be assigned to the desired product, can be detected. After a reaction time of 50 hours, another 0.010 g (0.008 mmol) of catalyst is added. After a total reaction time of 75 hours, the reaction is finally stopped. The educt can no longer be detected in the thin-layer chromatogram. The dark brown reaction solution obtained is filtered. A brownish precipitate remains and a reddish brown solution is obtained. This solution is evaporated on a rotary evaporator and taken up in diethyl ether. The reaction mixture is separated on a silica gel column using diethyl ether as the eluent. Five charges are obtained, of which the first is triphenylphosphine, the second a decomposition product of the organotin compound having a blue fluorescence, the third is 2-bromo-3-methoxyquinoline, the fourth is a small amount of a non-identified by-product and the fifth is 3,3'-dimethoxy-2,2'-biquinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.CO[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:38]
Reactant: COc1cccc(S(=O)(=O)Nc2cccc(C(=O)Nc3ccc(C(=O)O)cc3)c2)c1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(OC)c3)c2)cc1

Procedure:
4-[3-(3-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=425.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-methoxy-benzenesulfonyl chloride and yielded 4-[3-(3-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[Si:18]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CCCCN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCCCN1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a DMF (3 ml) solution of 2-piperidinemethanol (1.00 g, 8.7 mmol) and imidazole (1.48 g, 21.7 mmol) was added tert-butyldimethylchlorosilane (1.57 g, 10.4 mmol) at room temperature. After stirring for 30 min., a reaction solution was poured onto water followed by extraction with diethyl ether (about 30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford 1.61 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[F:24][C:25]([F:30])([F:29])[C@@H:26]([NH2:28])[CH3:27].O>C(O)(C)C.CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:28][C@@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]
Reactant: C[C@H](N)C(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Product: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 110 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
In scheme 1, step d, a solution of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 in an aprotic solvent, preferably 1-methyl-2-pyrrolidinone (NMP) in a ratio of 1–10 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5, preferably 1–5 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5, most preferably 1 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is added (S)-2,2,2-trifluoro-1-methyl-ethylamine 6 in a mole ratio of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 to (S)-2,2,2-trifluoro-1-methyl-ethylamine 6 is 1:2–1:3 (mole/mole) preferably 1:2.5 (mole/mole) with stirring for over 24–48 h, preferably about 24 hours in a temperature range of about 90–125° C., more preferably at about 110° C. for about 24 hours. In an optional embodiment of the invention, the reaction is sealed to prevent loss of (S)-2,2,2-trifluoro-1-methyl-ethylamine 6. The reaction mixture is diluted with isopropyl alcohol (IPA), IPA to NMP (V/V) of about 1:1–1:5 preferable at about 1:3, then water is added with stirring at about 10–20° C. in a ratio of NMP to water (v/v) of about 1:1–1:5 (v/v), preferably at about 1:3 (v/v) with about 30 minutes of additional stirring and collecting, without the need of chromatography, the solid product, washing with water and drying to give 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine 7. In a preferred embodiment of the invention, 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-pyrimidine in 1-methyl-2-pyrrolidinone (NMP) is treated with (S)-2,2,2-trifluoro-1-methyl-ethylamine at about 110° C. for about 24 h and the reaction mixture diluted with IPA, then water 1:3 (v/v) is added slowly forming a precipitated product. The precipitated product is filtered, washed with water, and dried to give a solid product in 92% yield, having a 96% HPLC purity and an enantiomeric excess of >99%. The product 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine 7 is collected without the need for chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[NH:34][N:33]=[N:32][N:23]=3)[CH:17]=2)[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C#N)c2)C[C@H]1C(=O)N1CCSC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C[C@H]1C(=O)N1CCSC1

Procedure:
To a solution of Example 30A (300 mg, 0.67 mmol) in anhydrous DMF (4 mL) was added sodium azide (522 mg, 8.04 mmol) followed by ammonium chloride (428.8 mg, 8.04 mmol). The mixture was flushed with nitrogen, then exposed to microwave irradiation (20 W, 175° C.) for 15 minutes. The mixture was concentrated under reduced pressure to afford a brown oil. The brown oil was purified by RP-HPLC to provide the titled compound. MS (ESI) m/e 488 (M+H)+, 486 (M−H)−; 1H NMR (300 MHz, CD3OD) δ ppm 1.39 (s, 6 H) 1.47 (s, 3 H) 1.68 (m, 1 H) 1.94 (m, 1 H) 2.59 (m, 2 H) 3.02 (m, 1 H) 3.14 (m, 1 H) 3.23 (m, 1 H) 3.48 (m, 2 H) 3.79 (m, 2 H) 4.56 (m, 2 H) 4.72 (m, 1 H) 7.55 (t, 1 H) 7.82 (d, 1 H) 8.18 (dd, 1 H) 8.44 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH2:21])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH:21][C:32](=[O:34])[CH3:33])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CCC(N)C2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To 2-(6-amino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester (4.7 g; 14.6 mmol), dissolved in CH2Cl2 (25 mL), is added DIEA (3.3 mL; 18.9 mmol) and the reaction mixture is cooled to 0° C. Acetyl chloride (1.25 mL; 17.5 mmol) is added dropwise at a rate to maintain the temperature between 0-5° C. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated under reduced pressure. The crude oil was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 1.7 g (32%) of 2-(6-acetylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[N:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>O1CCOCC1>[CH:16]1([NH:19][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]=[C:4]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:3]=2)[CH2:18][CH2:17]1
Reactant: Clc1nc(NC2CC2)nc(NC2CC2)n1
Reactant: NC1CC1
Solvent: C1COCCO1
Product: C1CC1Nc1nc(NC2CC2)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 20 g of 2-chloro-4,6-bis-cyclopropylamino-s-triazine, 10.1 g of cyclopropylamine and 80 ml of dioxan is heated at 140° C. in an autoclave for 22 hours. The reaction mixture is concentrated in vacuo to half its volume and 300 ml of water are added. The mixture is extracted with ethyl acetate, the product phase is dried over sodium sulfate and the solvents are removed in vacuo. The residue is recrystallised from dioxan/petroleum ether; melting point 75°-77° C.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:10]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[O:9][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: N#Cc1ccc(C(N)=O)s1
Product: N#Cc1ccc(-c2nc(CCl)co2)s1
Yield: 22 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-cyano-2-thiophenecarboxamide was reacted with 1,3-dichloroacetone to obtain 4-chloromethyl-2-(5-cyano-2-thienyl)oxazole. The yield was 22%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 146-147° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][CH2:3][C:2]1=[O:13].[CH3:14][N:15]([CH3:18])[CH:16]=O>C(OCC)C>[CH3:14][N:15]([CH:18]=[C:3]1[CH2:4][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:1][C:2]1=[O:13])[CH3:16]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)c2ccccc2N1
Solvent: CCOCC
Product: CN(C)C=C1CC(=O)c2ccccc2NC1=O
Temperature: 90 °C
Yield: 79 %

Procedure:
A mixture of 0.250 g (1.43 mmol) of 3,4-dihydro-1H-1benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,N-dimethylformamide, dimethylacetal is heated at 90° C. for 1.5 hour. The mixture is cooled, diluted with diethylether and filtered. The solid is washed well with diethylether and dried to give 0.26 g of tan crystals, m.p. 203°-205° C.
Reaction SMILES: [CH:1]([C:4]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1>C(OC(=O)C)(=O)C>[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]/[C:13](=[C:8]2/[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][C:7]/2=[O:9])/[CH:12]=1
Reactant: [O-][n+]1ccc(Cl)c2ccccc21
Reactant: CC(C)C1=NNC(=O)C1
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1

Procedure:
Methyl isobutyrylacetate (0.5 g, 3.47 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL) and treated with hydrazine (0.13 mL, 4.16 mmol). After 24 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-isopropyl-1H-pyrazol-5(4H)-one. Then, the 3-isopropyl-1H-pyrazol-5(4H)-one (0.169 g, 1.34 mmol) and 4-chloroquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid was filtered off and washed with a minimum amount of ether to yield Example 18. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 3.98 (bs, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].C([O-])(=O)C.[Na+].[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:31]([O:33][C:34](=O)[C:29]=12)=[O:32])([O-:27])=[O:26]>C(O)(=O)C.C(Cl)Cl>[N+:25]([C:28]1[CH:38]=[CH:37][CH:36]=[C:30]2[C:29]=1[C:34](=[O:33])[N:5]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8])[C:31]2=[O:32])([O-:27])=[O:26]
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 87.4 %

Procedure:
A mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (8.0 g, 28.5 mmol), sodium acetate (2.6 g, 31 mmol) and 3-nitrophthalic anhydride (5.5 g, 28.5 mmol) in glacial acetic acid (60 mL) was heated to reflux for 5 hours. The mixture was concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2, and washed with water and brine, and dried over MgSO4. Solvent was removed and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 9.5 g (84%) of 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile; mp 155-157° C.; 1H NMR (DMSO-d6) δ 8.31 (d, J=7.8 Hz, 1H), 8.20 (d, =7.2 Hz, 1H), 8.09 (t, J=7.8 Hz, 1H), 7.06-6.91 (m, 3H), 5.59 (t, J=8.0 Hz, 1H), 4.04-3.96 (q, J=7 Hz, 2H), 3.74 (s, 3H), 3.66 (d, J=8 Hz, 2H), 1.31 (t, J=7 Hz, 3H); 13C NMR (DMSO-d6) δ 165.46, 162.69, 149.07, 147.78, 144.45, 136.63, 132.81, 128.81, 128.52, 127.24, 122.39, 119.77, 118.08, 112.46, 111.68, 63.80, 55.48, 50.36, 20.30, 14.60. Analy. Calculated For C20H17N3O6: C, 60.75; H, 4.34; N, 10.63. Found: C, 60.95; H, 4.37; N, 10.50.
Reaction SMILES: COC([C@@H]1CC2C(=CC(O)=CC=2)CN1C(OC(C)(C)C)=O)=O.C(C1C=CC(B(O)O)=CC=1)(C)(C)C.C[O:37][C:38]([C@@H:40]1[CH2:49][C:48]2[C:43](=[CH:44][C:45]([O:50][C:51]3[CH:56]=[CH:55][C:54]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:53][CH:52]=3)=[CH:46][CH:47]=2)[CH2:42][N:41]1C(OC(C)(C)C)=O)=[O:39]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:57]([C:54]1[CH:55]=[CH:56][C:51]([O:50][C:45]2[CH:44]=[C:43]3[C:48]([CH:49]=[C:40]([C:38]([OH:39])=[O:37])[N:41]=[CH:42]3)=[CH:47][CH:46]=2)=[CH:52][CH:53]=1)([CH3:60])([CH3:58])[CH3:59]
Reactant: COC(=O)[C@@H]1Cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2CN1C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)ncc3c2)cc1

Procedure:
The above phenol (1.20 g, 3.91 mmol) was reacted with 4-(tert-butyl)phenylboronic acid (1.6 eq., 6.26 mmol, 1.11 g ), copper(II) acetate (1.0 eq. 3.91 mmol, 710 mg) as desribed in general procedure G. Flash column chromatography on silica (ethyl acetate/hexanes) provided 750 mg of the desired product, (3S)-7-(4-tert-butylphenoxy)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(CCc1ccc([N+](=O)[O-])cc1)C2
Reaction time: 15 h
Yield: 23 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (6.4 g), 1,2,3,4-tetrahydro-6-methoxyisoquinoline (4.6 g; Daniel J. Sall and Gary L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216) and potassium carbonate (9.7 g) in DMF (150 ml) was stirred at 50° for 15 h. The mixture was evaporated to dryness and the residue was extracted with dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was then purified by column chromatography eluting with dichloromethane/methanol (98:2) to give the title compound (2 g) as an oil which solidified on standing.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:44]=[CH:45][C:46]([C:49](OC)=[O:50])=[N:47][CH:48]=2)[CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1.O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][O:24][C:14]2[CH:13]=[C:12]([NH:11][C:49]([C:46]3[CH:45]=[CH:44][C:43]([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)=[CH:48][N:47]=3)=[O:50])[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
NaHMDS (1M solution in THF, 0.45 ml, 0.451 mmol, 1.5 eq) was added dropwise to a stirred suspension of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (105 mg, 0.301 mmol, 1 eq) and methyl 5-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (85 mg, 0.361 mmol, 1.2 eq) in dry THF (2.5 ml) under nitrogen. The solution was stirred at room temperature for 1 h. The solution was neutralised with satd. aq. NH4Cl and diluted with water (5 ml). The aqueous phase was extracted with ethyl acetate (3×8 ml) and the combined organic extracts were dried over MgSO4, filtered and evaporated. The reaction was repeated as above on a 0.338 mmol scale. The crude extracts were combined with those above and purified on by silica column chromatography, eluting with 0-6% MeOH in DCM, to afford the title compound as a pale brown solid (92 mg, 35% yield); 1H NMR (399.902 MHz, DMSO) δ 2.25 (s, 3H), 2.45-2.50 (m, 4H), 3.37-3.43 (m, 4H), 3.75 (s, 6H), 5.08 (s, 2H), 5.88 (bs, 1H), 6.45 (t, 1H), 6.60 (d, 2H), 7.45-7.49 (m, 1H), 7.94 (d, 1H), 8.35 (d, 1H), 10.89 (bs, 1H), 11.36 (bs, 1H) MS: m/z 453 (MH+)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.CC#N.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1COCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cnc2[nH]ccc2c1)Oc1ccccc1
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-5-ylamine (0.50 g, 3.7 mmol, see Synthesis, 2005, No. 15, 2503-2506) in THF (4 mL) and CH3CN (6 mL) was added pyridine (0.36 mL, 4.4 mmol) followed by phenyl chloroformate (0.49 mL, 3.8 mmol) slowly. The reaction was stirred overnight. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (0-100% EtOAc/hexane) provided the desired product as a white solid (0.213 g, 23%). MS M+1: 254.15.
Reaction SMILES: C([O:4][CH:5]([C@@H:12]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7])(=O)C.[OH-].[Na+]>CO>[CH:14]1([CH2:13][C@H:12]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:5]([OH:4])[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)=[O:7])[CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)OC(C(=O)NC1CC1)[C@H](CC1CCC1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of (3S)-3-(tert-butoxycarbonylamino)-4-cyclobutyl-1-(cyclopropylamino)-1-oxobutan-2-yl acetate (3.8 g, 10.7 mmol) in methanol (50 mL) was added sodium hydroxide aqueous solution (1N, 15 mL) at room temperature. After 2 hours, methanol was removed under reduced pressure, and the concentrate was extracted with ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from 100 mL of ethyl acetate and hexane(v/v=3/1) to give tert-butyl (2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (2.9 g) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[N:12]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][NH:17][C:16]1=[O:28])=[N+:13]=[N-:14].C(OCC)(=O)C>CN(C)C=O.O>[N:12]([C@@H:15]1[CH2:21][CH2:20][C@@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:16]1=[O:28])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=N[C@@H]1CC[C@@H](c2ccccc2)CNC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N=[N+]=[N-])C1=O
Reaction time: 1.5 h

Procedure:
0.9 ml of t-butyl bromoacetate followed by 219 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, under a stream of nitrogen, to a solution of 1.05 g of 3(S*)-azido-6(R*)-phenylperhydroazepin-2-one (Isomer A) [prepared as described in Example 1(f)] in 10 ml of dimethylformamide, whilst ice-cooling. The mixture was stirred for 1.5 hours, and then ethyl acetate and water were added. The ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent, to give 1.54 g of the title compound as crystals, melting at 119°-121° C.