Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:6][CH:7]([O:10][C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.[C:16](OC)(=[O:20])[C:17]([CH3:19])=[CH2:18].O>[OH-].[Li+].COC1C=CC(O)=CC=1.CO>[C:16]([O:9][CH2:8][CH:7]([O:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[O:10][C:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: OCC(OC1=CCCC1)OC1=CCCC1
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)OCC(OC1=CCCC1)OC1=CCCC1
Yield: 84.7 %

Procedure:
In a 3000-liter reactor equipped with a stirrer, a thermometer, an air introducing pipe, a distillation column and a reflux condenser, 776 kg (4 kmoles) of dicyclopentenyloxyethyl alcohol, and 1200 kg (12 kmoles) of methyl methacrylate were placed and mixed well with stirring. The water content of the resulting mixture was 800 ppm. The water content was measured by using a Karl Fischer type digital microamount water content measuring device (mfd. by Mitsubishi Chemical Industries Ltd.). Subsequently, 3 kg of anhydrous lithium hydroxide as a catalyst and 390 g of hydroquinone monomethyl ether as a polymerization inhibitor were added to the reactor, and the reaction was carried out while introducing dried air at a rate of 4 m3/ hr and refluxing the methyl methacrylate through the distillation column. While removing methanol by-produced by the reaction from the distillation column, the reaction was continued until almost no methanol was distilled (about 8 hours), followed by removal of unreacted methyl methacrylate under reduced pressure. After cooling, the reaction solution was filtered under pressure (5 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 943 kg of dicyclopentenyloxyethyl methacrylate. The filtering time was 2.5 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:27]([NH2:34])[C@H:26]1[OH:35]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:34][C@@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@@H:26]2[OH:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (1R,2S)-(+)-cis-1-amino-2-indanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.O=S(Cl)[Cl:13]>>[Cl:13][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:10])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CO)c(C)n1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(CCl)c(C)n1

Procedure:
The solution of compound (2,6-dimethylpyridin-3-yl)methanol (0.76 g, 5.6 mmol) in SOCl2 (5 mL) was stirred at room temperature for 1 hour and then concentrated to give the crude product 3 which was used for next step directly without further purification. LCMS (ESI) m/z=156.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]2[CH2:21][CH2:22][CH2:23][C:15]=12.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:20][C:19]2[N:14]=[C:15]3[CH2:23][CH2:22][CH2:21][C:16]3=[CH:17][CH:18]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Nc1ccc2c(n1)CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A heavy walled resealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (1.5 g, 6.79 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine (1.09 g, 8.14 mmol), acetonitrile (10 mL) and Hunig's base (877 mg, 1.19 mL, 6.79 mmol). The mixture was heated at 80° C. with stirring for 3d, after cooling to room temperature, the solvents were distilled off and the crude residue obtained was purified by chromatography (80 g column, 50 μM from Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 26%) as a light brown solid. 1H NMR (CHLOROFORM-d) δ: 10.51 (s, 1H), 8.94 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.92 (t, J=7.7 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 1.87-2.24 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); LC-MS 319.0 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H](OCC4C=CC=CC=4)C)[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.[C:51]([O:55]C(=O)N)(C)(C)[CH3:52]>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[CH2:52][CH2:51][OH:55])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)(C)OC(N)=O
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CCO)[C@@H](O)[C@H]4O)c3n2)C1

Procedure:
The title compound is prepared analogously to (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting {(R)-1-[9-[(1R,2S,3R,4S)-4-(3-tert-butoxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate ZG3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-(R)-2-Benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[CH:18]([OH:20])[CH3:19]>CN(C=O)C.CCCCCC.CCOC(C)=O>[F:16][C:17]([CH:18]([O:20][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:19])([F:25])[C:21]([F:24])([F:23])[F:22]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)C(F)(F)F
Temperature: 130 °C
Yield: 97.7 %

Procedure:
Add potassium carbonate (27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M+).
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(=O)=[O:19].CC(C)=O.O=[O+][O-].O=O>ClCCl.CO>[N:16]1[C:17]2[C:8](=[O:19])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Reactant: O=C=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (18.2 g, 137 mmol), benzaldehyde (17.67 g, 166.0 mmol), and acetic anhydride (24.5 mL, 254 mmol) was heated under a nitrogen environment at 165° C. for 16 hours. The reaction mixture was cooled to room temperature. Crushed ice was added, and the mixture was slowly basified with NaOH (solid then 2 N NaOH) to pH around 7. The aqueous layer was extracted with hexane/ethyl acetate (1:1 solution) 3 times. The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum to give 8-benzylidene-5,6,7,8-tetrahydro-quinoline (Intermediate 1) as a brown solid. A solution of Intermediate 1 in dichoromethane (100 mL) and methanol (500 mL) was cooled to −78° C. (dry ice/acetone bath), and charged with ozone/oxygen (3 psi, 1.5 ampere). The dark brown solution turned yellow after several hours. When Intermediate 1 was consumed (TLC), ozone/oxygen flow was stopped. The reaction mixture was purged with nitrogen for 10 minutes. Methyl sulfide (6 mL) was added, and the mixture was stirred for 30 minutes at room temperature. The solvents were removed under vacuum. The residue was dissolved in 1 N HCl (500 mL), and washed with diethyl ether (4×150 mL). The aqueous layer was basified to pH˜7 with NaOH (s), and extracted with ethyl acetate (2×200 mL). The pooled ethyl acetate layers were dried over magnesium sulfate. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 90% EtOAc:hexane to give a clean product. The aqueous layer was extracted with chloroform/isopropanol (3:1) several times. The pooled chloroform/isopropanol layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum to give 6,7-dihydro-5H-quinolin-8-one (Intermediate 2), 17.89 g (122.0 mmol, 89% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[C:12]1(=O)OC(C)CO1.FC(F)(F)C(O)=O.[CH3:26][CH:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42](O)([CH:44]=C)[CH3:43])[CH3:38])[CH3:33])[CH3:28]>O.CCCCCCC>[CH2:1]([C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([OH:7])[C:8]=1[CH3:12])/[CH:26]=[C:27](/[CH2:29][CH2:30][CH2:31][C@@H:32]([CH2:34][CH2:35][CH2:36][C@@H:37]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:38])[CH3:33])\[CH3:28]
Reactant: CC1COC(=O)O1
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: C/C(=C\Cc1c(C)c(O)c(C)c(C)c1O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of trimethylhydroquinone (15.5 g, 100 mmol), propylene carbonate (100 ml) and heptane (100 ml) was heated to 140° C. (bath temperature) in a three-necked reaction flask equipped with a water separator, a reflux condenser and argon gasification means. Trifluoroacetic acid (0.5 ml, 6.52 mmol) was then added dropwise using a syringe to the biphasic reaction mixture at reflux temperature, followed by isophytol (35.99 ml, 100 mmol) to the resulting solution over a period of 30 minutes at 140° C. (internal temperature 100° C.). After stirring for a further 10 minutes at 140° C., water and heptane were distilled off from the reaction mixture. The produced phytyltrimethylhydroquinone was extracted with three 50 ml portions of heptane from the carbonate phase, and the combined heptane phase was cooled down to room temperature. The resulting yellowish suspension was filtered through a P4 frit (requiring 2-3 days) and washed with 100 ml of cold propylene carbonate (4° C.) and 500 ml of cold heptane (4° C.) to remove traces of trimethylhydroquinone and by-products. The white waxy residue was dried for 3 hours under high vacuum. The so produced phytyltrimethylhydroquinone was found to have a purity of about 95%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([Cl:31])[CH:22]=3)[O:18][N:17]=2)[C:9]([CH2:32][CH2:33][C:34]([O:36]CCC)=[O:35])=[CH:8]1)[CH2:4][CH2:5][CH3:6].Cl>O1CCCC1.C(O)(C)C.O>[CH2:3]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([CH3:30])[CH3:29])=[C:23]([Cl:31])[CH:22]=3)[O:18][N:17]=2)[C:9]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCn1cc(CCC(=O)OCCC)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Sodium hydroxide (94 mg) was added to a solution of propyl 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D123) (61 mg) in tetrahydrofuran (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[1-butyl-7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E29) (30 mg). δH (DMSO-d6, 400 MHz): 0.65 (3H, t), 0.96 (2H, m), 1.37 (8H, m), 2.62 (2H, t), 2.98 (2H, t), 4.10 (2H, t), 4.88 (1H, m), 7.17 (1H, t), 7.25 (1H, s), 7.44 (2H, m), 7.81 (1H, dd), 8.13 (1H, dd), 8.19 (1H, d), 12.05 (1H, br s); MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:8]1[O:12][N:11]=[C:10]([N:13]=[C:14]=[O:15])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5]>C1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:14]([NH:13][C:10]1[CH:9]=[C:8]([C:4]([CH3:7])([CH3:5])[CH3:6])[O:12][N:11]=1)=[O:15]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: CNC
Solvent: c1ccccc1
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
1,1-Dimethyl-3-(5-tert.-butyl-3-isoxazolyl)urea is prepared by condensing dimethylamine with 5-tert.-butyl-3-isoxazolyl isocyanate in benzene. After removal of the reaction solvent and purification by chromatography or crystallization, there is obtained 1,1-dimethyl-3-(5-tert.-butyl-3-isoxazolyl)urea. M.P. 119.5°-120.5° C.
Reaction SMILES: [Br:1][C:2]1C(C#N)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[OH-:11].[Na+].Cl.[CH3:14][CH2:15][OH:16]>>[Br:1][C:2]1[C:14]([C:15]([OH:11])=[O:16])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(C#N)n1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(Br)c(C(=O)O)n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To 3-bromo-6-methylpicolinonitrile (4 g, 20.3 mmol) in EtOH (40 mL) in a sealed tube was added aqueous 4M NaOH (15 mL). The reaction was heated at 90° C. for 24 h. Additional aqueous 4M NaOH was added and heating continued at 90° C. for 24 h. The reaction was cooled to rt, acidified to pH=3 with 1N HCl (aq), concentrated and used without further purification in subsequent steps. MS (ESI) mass calcd. for C7H6BrNO2, 216.0; m/z found 218 [M+H]+.
Reaction SMILES: C(Cl)(Cl)=[O:2].[CH3:5][C@H:6]1[C@@H:37]([CH:38]([CH3:40])[CH3:39])[O:36][C:34](=[O:35])[C:33]2[N:29]([CH2:30][CH2:31][CH:32]=2)[C:27](=[O:28])[C:24]2=[CH:25][O:26][C:22](=[N:23]2)[CH2:21][C:19](=[O:20])[CH2:18][C@H:17]([OH:41])[CH:16]=[C:15]([CH3:42])[CH:14]=[CH:13][CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7]1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.CO>[CH3:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].[C:22]([O-:26])(=[O:2])[C:21]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[CH3:5][C@H:6]1[C@@H:37]([CH:38]([CH3:39])[CH3:40])[O:36][C:34](=[O:35])[C:33]2[N:29]([CH2:30][CH2:31][CH:32]=2)[C:27](=[O:28])[C:24]2=[CH:25][O:26][C:22](=[N:23]2)[CH2:21][C:19](=[O:20])[CH2:18][C@H:17]([OH:41])[CH:16]=[C:15]([CH3:42])[CH:14]=[CH:13][CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7]1
Reactant: O=C(Cl)Cl
Agent: CC1=C[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)C=CC(=O)NCC=C1
Agent: CC1=C\[C@@H](O)CC(=O)Cc2nc(co2)C(=O)N2CCC=C2C(=O)O[C@H](C(C)C)[C@H](C)/C=C/C(=O)NC\C=C\1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCC(=O)O
Product: O=C([O-])c1ccccc1

Procedure:
The n-propionate, n-valerate, n-phenylacetate and benzoate derivatives of Virginiamycin M1 were prepared using the respective carbonyl chlorides. The respective carbonyl chloride (1.0 mmole) was added to a stirring solution of virginiamycin M1 (0.50 g, 0.95 mmole), pyridine (84 μl) and 4-dimethylaminopyridine (20 μg) at room temperature for 2 hours. Methanol (0.5 ml) was added to destroy excess reagent. The reaction mixture was partitioned between dichloromethane (3×5 ml) and saturated NaCl (aq) (50 ml). The pooled organic layers were dried over anhydrous Na2SO4 and flash evaporated to dryness (dry weight=0.63, 0.81, 1.0 and 1.4 g respectively). Purification over a column of 50 g E. Merck silica gel 60 (43-60 μm particle size) in 40-80% acetone/hexane stepwise gradients yielded 0.43, 0.33, 0.29 and 0.56 g of the respective esters.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](O)(=[O:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1.C(P(C#N)(CC)=O)C.Cl>O.C(N(CC)CC)C.CN(C)C=O>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1)(=[O:25])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2ccc(NC(=O)c3ccc4c(c3)OCO4)cc2)S1
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Into 20 ml of dimethylformamide were dissolved 1.00 g of 5-(4-aminophenyl)thiazolidine-2,4-dione and 0.80 g of piperonylic acid, and, after added 1.12 g of diethylphosphoryl cyanide and then 0.50 g of triethylamine at 0° C., the mixture was stirred for 1 hour as it was. Thereafter, the reaction mixture was brought to room temperature and stirred for 2 hours. Then, it was poured into 200 ml of water and, after made acidic with hydrochloric acid, the crystals deposited were collected by filtration. These were recrystallized from ethanol to obtain 1.05 g of title compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4](O)=[O:5].[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[O:12]1.C[N:23](C=O)C>>[O:12]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:1]1[CH:2]([C:7]([F:10])([F:9])[F:8])[CH2:3][C:4]([NH2:23])=[O:5]
Reactant: NC(CC(=O)O)C(F)(F)F
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)C=O
Product: NC(=O)CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F
Yield: 54 %

Procedure:
A solution of 3-amino-4,4,4-trifluorobutanoic acid (628 mg, 4 mmol) and isobenzofuran-1,3-dione (592 mg, 4 mmol) in DMF (5 mL) was heated to 140° C. under microwave irradiation for 15 min. The reaction mixture was purified by preparative HPLC (Axia luna column, 30×75 mm, 10-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield 3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluorobutanamide (620 mg, 54% yield). LCMS: RT=1.54 min [M+H] 288.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:4][CH3:5].[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CC(C)=O.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][S:6]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])(=[O:8])=[O:7])=[O:21])=[CH:15][CH:14]=1
Reactant: CCC(CC)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCC(CC)S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The general method of procedure A was followed with 3-pentanesulfonamide (10 g), acetone (300 ml), 1N sodium hydroxide (56 ml), and 4-chlorophenyl isocyanate (9.6 g) dissolved in 70 ml of acetone. After two hours of stirring, 1N HCl (66 ml) was added followed by more water. The acetone was stripped off, and the resulting solid collected, to give, after drying at 65° C. under vacuum, 13.1 g of product.
Reaction SMILES: [CH3:1][P:2](=[O:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:12][P:2]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)([CH3:1])=[O:13]
Reactant: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CP(C)(=O)c1ccc(N)cc1
Yield: 86 %

Procedure:
The dimethyl(4-nitrophenyl)phosphane oxide) produced as described above was hydrogenated in the presence of 10% Pd/C (15 mg) in MeOH (5 mL) for 2 h. The mixture was then filtered and the filtrate concentrated in vacuo to yield 19 mg of the desired 4-(dimethylphosphoryl)aniline (yield: 86%) which was used directly in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.67 (d, J=12.8 Hz, 6H), 4.11 (s, br, 2H), 6.73 (dd, J=2.0, 8.4 Hz, 2H), 7.48 (dd, J=8.4, 11.2 Hz, 2H). MS (ES+): m/z 170.04 (MH+). HPLC: tR=1.23 min (ZQ3, polar—5 min).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.C(N(CC)CC)C.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41]>C(Cl)Cl>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:2]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(Nc2ccc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (0.0589 mmol, Example 22) in methylene chloride (1.25 mL) were added triethylamine (0.065 mL, 0.466 mmol, Aldrich) and a solution of ethanesulfonyl chloride (8.1 mg, 0.062 mmol, Aldrich 99+%) in methylene chloride (0.33 mL) at 0° C. After 5 minutes the reaction mixture was allowed to stir at room temperature for 1 hr before it was concentrated in vacuo. The residue was absorbed on silica gel and purified with 99.5/0.5495/5 of methylene chloride/methanol to give [2-amino-6-(1-ethanesulfonyl-piperidin-4-ylamino)-pyridin-3-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (16.0 mg, 63% yield). HRMS, observed: 437.1660, Calcd for (M+H)+: 437.1654.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Yield: 92.1 %

Procedure:
A solution of 2-hydroxybenzaldehyde (500 mg, 0.44 ml, 4.09 mmol), imidazole (685 mg) and tert-butyldimethylsilyl chloride (680 mg) in DMF is stirred for 24 hours at room temperature. After hydrolysis and customary extraction, chromatography gives 28 (890 mg, 93%).