Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([NH:7][C:8](=[O:17])[O:9][CH2:10]C1C=CC=CC=1)([CH3:6])CO.[H-].[Na+].CC(O)=O>C1COCC1>[F:1][CH2:2][C:3]1([CH3:6])[CH2:10][O:9][C:8](=[O:17])[NH:7]1
Reactant: CC(CO)(CF)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(CF)COC(=O)N1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of benzyl 1-fluoro-3-hydroxy-2-methylpropan-2-ylcarbamate (562 mg, 2.3 mmol) in THF (29 ml) was cooled to 0° C. and 60% NaH in mineral oil (117 mg, 2.9 mmol) was added. The reaction was warmed to RT over 3 h, and then heated to 50° C. for 16 h. AcOH (200 ul) was added to quench the reaction, and the solution was concentrated in vacuo. The residue was purified by flash chromatography (1% to 12% MeOH in DCM) to afford the title compound as a clear oil (251 mg, 82%). 1H NMR (CDCl3, 400 MHz) δ 1.40 (d, J=2.0 Hz, 3H), 4.08 (dd, J=2.0, 8.8 Hz, 1H), 4.24 (dd, J=9.6, 20.4 Hz, 1H), 4.32-4.40 (m, 2H), 6.61 (s, 1H). 19F NMR (CDCl3, 376 MHz) δ −225.4 (t, J=47 Hz). 13C NMR (CDCl3, 100 MHz) δ 21.7 (d, J=3 Hz), 67.4 (d, J=20 Hz), 72.3 (d, J=4.2 Hz), 86 (d, J=178 Hz), 159.3 (s).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.O>S(=O)(=O)(O)O.C1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 85.3 %

Procedure:
A mixture of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate (13g, 0.05 mole), 3-methyl-1-butanol (4.4g, 0.05 mole) and concentrated sulphuric acid (4 drops) in benzene (50 ml) was heated at reflux under a Dean and Stark trap until 0.9 ml water (0.05 mole) had been eliminated. The reaction mixture was cooled, washed with dilute aqueous sodium hydroxide solution and with water (twice) and dried over sodium sulphate. The benzene was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(3-methylbutoxy)-5-benzofuranyl methanesulphonate as a yellow oil (14 g, 86% yield) which slowly solidified (melting point 35°-38° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=[O:24])[CH:19]=2)[C:14]1=[O:26].O.O.[Sn](Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:44])[CH:5]=[C:6]([Cl:43])[C:7]=1[CH2:8][C@@H:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:36])[F:37])=[C:30]([O:38][CH2:39][CH:40]2[CH2:41][CH2:42]2)[CH:29]=1)[O:10][C:11](=[O:27])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:23][OH:24])[CH:19]=2)[C:14]1=[O:26]
Reactant: O=C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN1C(=O)c2ccc(NO)cc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (60 mg, 0.092 mmol) was dissolved in THF (5 ml), and added with tin(II) chloride dihydrate (25.0 mg, 0.111 mmol). The reaction was stirred at RT for 18 hours. THF was evaporated under vacuum at RT, and the residue quenched by addition of K2CO3/H2O (15% w/w; 50 ml) and extracted with EtOAc (50 ml). The organic phase was extracted with K2CO3/H2O (15% w/w) (×3), dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound (35.0 mg, 0.055 mmol, 60% yield). 1H NMR (400 MHz, acetone) ppm 8.80 (bs, 1H), 8.32 (bs, 1H), 8.18 (s, 2H), 7.70 (d, J=8.38 Hz, 1H), 7.36 (d, J=1.76 Hz, 1H), 7.28 (dd, J=8.16, 1.98 Hz, 1H), 7.15-7.23 (m, 2H), 7.03 (dd, J=8.38, 1.76 Hz, 1H), 6.93 (t, 1H, CHF2), 6.13 (dd, J=9.48, 4.63 Hz, 1H), 4.39 (s, 2H), 4.00 (dd, J=7.06, 3.09 Hz, 2H), 3.51 (dd, J=14.33, 9.48 Hz, 1H), 3.31 (dd, J=14.11, 4.41 Hz, 1H), 1.24-1.36 (m, 1H), 0.53-0.71 (m, 2H), 0.31-0.49 (m, 2H). MS/ESI+ [MH]+=637.9
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.CCCCCCC>CN(C=O)C>[Si:18]([O:8][CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CC(O)CC1CC
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CC1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (10.0 g, 53.7 mmol) in DMF (18 mL) was added TBDMS-Cl (9.72 g, 64.5 mmol) and imidazole (9.15 g, 134 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. Heptane (50 mL) was added to the reaction and the layers were separated. The bottom layer was extracted with heptane (2×30 mL). The combined organic extracts were washed with water (2×30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concd to give ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (15.87 g, 52.8 mmol, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (m, 3H), 2.79 (m, 1H), 2.09 (m, 1H), 1.99 (m, 3H), 1.50-1.24 (m, 6H), 0.89 (m, 12H), 0.05 (s, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+].C(O)C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:30]3[CH:31]=[CH:32][C:33]4[N:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:22]5[C:27]([C:28]=4[CH:29]=3)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: Brc1ccc(Nc2ccccc2)cc1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(Nc2ccc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)cc2)cc1
Temperature: 100 °C

Procedure:
In a 500-mL three-neck flask, 6.5 g (26 mmol) of 4-bromodiphenylamine, 7.5 g (26 mmol) of 9-phenyl-9H-carbazol-3-boronic acid, and 400 mg (1.3 mmol) of tri(o-tolyl)phosphine were added, and the atmosphere in the flask was substituted by nitrogen. Then, 100 mL of toluene, 50 mL of ethanol, and 14 mL of aqueous solution of potassium carbonate (2.0 mol/L) were added to this mixture. The mixture was degassed while stirring under reduced pressure, which is followed by the addition of 67 mg (0.3 mmol) of palladium(II) acetate. This mixture was refluxed at 100° C. for 10 hours. After the reflux, the organic layer was separated from the aqueous layer, the aqueous layer was extracted with toluene, and the extract and the organic layer were combined and washed with brine. The organic layer was dried with magnesium sulfate, subjected to gravity filtration. The resulting filtrate was concentrated to give a pale brown oily product. The oily product was purified by silica gel column chromatography (the developing solvent containing a 4:6 ratio of hexane to toluene), and a white solid obtained after the purification was recrystallized with a mixed solvent of dichloromethane and hexane to give a white solid which was the desired substance. The yield was 4.9 g and 45%. The synthetic scheme of PCBA is shown in the scheme (C-4).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[CH:14]([N:19]([CH3:21])[CH3:20])[NH:13][C:12]2=[O:22])=[C:4]([F:23])[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:23])=[C:5]([N:11]2[C:16](=[O:17])[N:15]([CH3:18])[CH:14]([N:19]([CH3:20])[CH3:21])[NH:13][C:12]2=[O:22])[CH:6]=1
Reactant: CN(C)C1NC(=O)N(c2cc([N+](=O)[O-])c(Cl)cc2F)C(=O)N1C
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)C1NC(=O)N(c2cc(N)c(Cl)cc2F)C(=O)N1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of iron powder (5.3 g) in 5% aqueous acetic acid (30 mL) was added dropwise a solution of the title compound of step B (2.8 g, 8.1 mmol) in a mixture of concentrated acetic acid (25 mL) and ethyl acetate (25 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes, diluted with excess ethyl acetate, filtered through Celite®, and washed with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and water. The organic layers were then dried over magnesium sulfate and concentrated under reduced pressure. The title compound of Step C was isolated by flash chromatography as a foam (1.59 g). 1H NMR (CDCl3) δ 7.15 (d, 1H), 6.65 (d, 1H), 3.95 (br s, 2H), 3.4 (s, 3H), 3.1 (s, 6H).
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8]>COC(O)C>[N+:14]([C:13]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[N:4]=[CH:1][NH:3][C:7]2=[O:8])([O-:16])=[O:15]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: NC=O
Agent: COC(C)O
Product: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Yield: 14.3 %

Procedure:
Formamide (17.1 g, 380 mmol) was added to a solution of 2-amino-3-nitrobenzoic acid (2.0 g, 11 mmol) in methoxy ethanol (5 ml) and the reaction was heated at 200 C in a sealed tube for 17 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with sat. aq. NaHCO3 solution and the aqueous phase was extracted with EtOAc (100 ml, ×2). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (300 mg, 14%).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)C=CC=CC=1.[C:25]([O:29][C:30](=[O:37])[NH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:37])[NH:31][C@@H:32]1[CH2:36][CH2:35][N:34]([C:8](=[O:24])[NH:9][CH:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:15]2)[CH2:33]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)CC1
Temperature: 100 °C

Procedure:
(4-tert-Butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester (1 eq.) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1 eq.) are dissolved in NMP and heated at 100° C. for 1 hour.
Reaction SMILES: O1CCCC1.C([Li])CCC.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:54]=[CH:55][C:56]=1[O:57][CH2:58][C:59]1[N:60]=[C:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[O:62][C:63]=1[CH3:64])[CH2:29][N:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45](Cl)=[O:46])[C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2.O>O1CCCC1>[CH3:64][C:63]1[O:62][C:61]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[N:60][C:59]=1[CH2:58][O:57][C:56]1[CH:55]=[CH:54][C:28]([CH2:29][N:30]2[C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([O:43][CH:44]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:45]([N:19]4[C@@H:18]([CH2:11][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:22][O:21][C:20]4=[O:23])=[O:46])[C:37]=3[C:36]3[C:31]2=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:27][C:26]=1[O:25][CH3:24]
Reactant: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)Cl)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccccc4)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
9.1 mL of 2.44M n-butyllithium tetrahydrofuran solution was added thereto dropwise to tetrahydrofuran (30 mL) solution of 3.92 g of (S)-4-benzyl-2-oxazolidinone at −50° C. The mixture was stirred at −50° C. for 1 hour. Thereafter, the solution of the previously prepared (±)-{9-[3-methoxy-4-(5-methyl-2-phenyl-oxazole-4-ylmethoxy)-benzyl]-9H-carbazole-4-yloxy}phenylacetyl chloride in tetrahydrofuran (30 mL) was added thereto dropwise at −50° C. After the dropwise addition thereto, the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the prepared diastereomer mixture was purified by medium-pressure silica gel chromatography (ethyl acetate:n-hexane=5:1), and two types of the subject compound, 1.52 g of compound A (first fraction) and 1.2 g compound B (second fraction), were respectively prepared as pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(C3CCCC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=266.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromocyclopentane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:26])([CH3:25])[C:19]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:29]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH3:28])[C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH3:25])([CH3:26])[C:19]=3[CH:27]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C
Product: Cc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethyl-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][S:25][CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][S:25][CH2:24][S:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)CSCSC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)CSCSC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (154 mg, 0.95 mmol) with compound 526 (250 mg, 0.73 mmol) in THF (4 mL) in the presence of LiHMDS (2.2 mL, 2.2 mmol) afforded compound 132 as a white solid material after purification by column chromatography (45-55% EtOAc in light petroleum). LC-MS: RT=4.39 min.; m/z 472.15, 474.14 (M+H)+. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.9), 6.88 (1H, d, J 8.9), 4.64 (2H, s), 4.43 (2H, s), 4.24 (2H, s), 3.85 (3H, s), 3.84 (2H, s), 2.91 (4H, s).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2].[C-:31]#[N:32].[K+]>CS(C)=O>[C:1]([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C#N)n2Cc2ccccc2)n(C)c1=O
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 89.7 %

Procedure:
To a solution of (R)-1-(5-acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (9.55 g, 20.0 mmol) in anhydrous dimethylsulfoxide was added potassium cyanide (1.43 g, 22.0 mmol). After stirring at 70-80° C. for 4.5 hours, the mixture was cooled to room temperature, quenched with water (500 ml) and extracted with ethyl acetate (4x 150 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (45 ml), dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-1-(5-acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (7.60 g, 90% yield) as a beige powder.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][N:12]([CH3:14])[NH2:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:14])[NH:13][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: Cc1ccccc1N=C=O
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: Cc1ccccc1NC(=O)NN(C)C
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
o-Tolyl isocyanate (10.0 g) was dissolved in 75 mL toluene under N2. The solution was cooled to 5° C. and to this was slowly added a solution in toluene of 1,1-dimethylhydrazine (5.7 mL). After addition, the ice-bath was removed and the resulting slurry allowed to stir an additional 10 minutes. The solid was filtered off rinsing successively with hexane, a small amount of 20% diethylether/hexane, then hexanes again. This afforded 11.1 g (77%) of the title compound of Step A. 1 H NMR (CDCl3) δ8.1 (bs,1H), 7.94 (d,1H), 7.21-7.15 (m,3H), 6.99 (t,1H), 5.23 (bs,1H), 2.63 (s,6H) 2.27 (s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@H:4](O)[CH3:5].C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:25]([C@H:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])[CH3:5])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)c1ccccc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@H](N=[N+]=[N-])c1ccccc1Br
Temperature: 50 °C
Yield: 84.3 %

Procedure:
To a solution of (R)-(+)-2-bromo-α-methylbenzyl alcohol (402 mg, 2.0 mmol) and diphenylphosphoryl azide (0.692 ml, 3.2 mmol) in THF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.466 ml, 3.2 mmol). The mixture was heated at 50° C. for overnight, partitioned with H2O and AcOEt, and then adjusted to pH 7 by adding 1M HCl. The organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography [eluting with n-hexane/AcOEt=95/5] to give the title compound (381 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][C:8]2=[O:27])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:38].Cl>ClCCl>[CH2:40]([O:39][C:37]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[C:12]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[CH2:10][CH2:9][C:8]2=[O:27])=[CH:28][CH:29]=1)=[O:38])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCOC(=O)Cl
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOC(=O)Nc1ccc(CN2C(=O)CCc3c(CC4SC(=O)NC4=O)ccc(OC)c32)cc1
Reaction time: 1 h
Yield: 489.3 %

Procedure:
0.6 g of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione was suspended in dichloromethane (6 ml), and 4 ml of pyridine was added with ice cooling to form a solution. 0.26 g of amyl chloroformate was added to this solution, followed by stirring for 1 hour. 1 N hydrochloric acid was added to the reaction liquid, and extracted with ethyl acetate. The extract was washed twice with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), and recrystallized from diisopropyl ether, giving 3.75 g (97% yield) of 5-[1-(4-pentyloxycarbonylaminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:8][C:7]2=[O:21])=[CH:2]1.Cl>O1CCOCC1>[NH2:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[C:7](=[O:21])[CH:8]=1
Reactant: CC(C)(C)OC(=O)NCc1ccn(-c2ccoc2)c(=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccn(-c2ccoc2)c(=O)c1

Procedure:
tert-Butyl (1-furan-3-yl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-carbamate (0.18 g, 0.62 mmol) is treated with 4N hydrogen chloride in dioxane in order to remove the Boc protecting group. The hydrochloride salt of 4-aminomethyl-1-furan-3-yl-1H-pyridin-2-one, obtained after concentration of the reaction mixture, is dissolved in N,N-dimethylformamide (4 mL) and is coupled to (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.20 g, 0.62 mmol) in the presence of triethylamine (400 μL). After three hours, the reaction mixture is concentrated under reduced pressure, and the residue is triturated with acetonitrile to provide (4Z)-4-[({[1-(3-furyl)-2-oxo-1,2-dihydropyridin-4-yl]methyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione as a brown powder (0.12 g, 40%).
Reaction SMILES: [CH:1]([C@H:4]1[C:20](=[O:21])[O:19][C@H:18]([CH:22]=[CH2:23])[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:28])([CH3:27])[C:6](=[O:29])[NH:5]1)([CH3:3])[CH3:2].[Br:30][CH2:31][CH2:32]C=C>ClCCCl>[Br:30][CH2:31][CH2:32]/[CH:23]=[CH:22]/[C@@H:18]1[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:27])([CH3:28])[C:6](=[O:29])[NH:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:20](=[O:21])[O:19]1
Reactant: C=C[C@@H]1CC(=O)NCc2nc(cs2)C(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)O1
Reactant: C=CCCBr
Solvent: ClCCCl
Product: CC(C)[C@@H]1NC(=O)C(C)(C)NC(=O)c2csc(n2)CNC(=O)C[C@@H](/C=C/CCBr)OC1=O
Temperature: 85 °C

Procedure:
To a mixture of (7S,10S)-7-isopropyl-4,4-dimethyl-10-vinyl-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-diene-2,5,8,12-tetraone (20 mg, 0.047 mmole) in 2 mL 1,2-dichloroethane was added 4-bromo-1-butene (25.6 mg, 0.19 mmole) and Zhan-1 catalyst (3.2 mg, 0.0047 mmole). The mixture was briefly degassed and then heated in a sealed tube at 85° C. overnight. The crude product was concentrated and passed through a silica gel plug to get a mixture of the desired product and recovered starting material (2:1 ratio). It was further purified by reversed phase chromatography, eluted with 0˜80% water/CH3CN to get the desired product (8 mg, 32% yield).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[NH3:11].O>>[CH2:9]([C:5]1[CH:4]=[C:3]([CH2:2][NH2:11])[N:7]([CH3:8])[N:6]=1)[CH3:10]
Reactant: CCc1cc(CBr)n(C)n1
Reactant: N
Solvent: O
Product: CCc1cc(CN)n(C)n1

Procedure:
A solution of compound 5 (660 mg, 3.27 mmol) in NH3.H2O (5 mL) was stirred at 90° C. for 3 h. The solvent was evaporated to give the crude product as a white solid which was used in the next step without further purification.