Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[OH:1][C:2]1[CH:10]=[C:9]([NH:11][C:14](=[O:16])[CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)[O-])c(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 100 °C
Yield: 56 %

Procedure:
Sodium 2-hydroxy-4-aminobenzoate (76 g, 0.437 mole) was dissolved in water (2-300 ml) and concentrated hydrochloric acid (36.2 ml) was added after which the precipitated crystalline free acid was isolated by filtration. The acid was suspended in water (700 ml), acetic anhydride (48 ml) was added and the mixture was heated to about 100° C. (supplied with a reflux condenser) for 15 minutes under nitrogen. After cooling, the crystalline material was filtered off and dried in vacuo to give the title compound (48 g, 56%), m.p. 221°-223° C. Found (Calc. for C9H9NO4) C 55.14 (55.38), H 4.73 (4.62), N 7.12 (7.18).
Reaction SMILES: NC1C=CC(N[C:9]2[CH:10]=[CH:11][C:12]3[N:13]=[C:14]4[C:27]([O:28][C:29]=3[C:30]=2S(O)(=O)=O)=[C:26](Cl)[C:25]2[C:16]([O:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[C:20](NC2C=CC(N)=C(S(O)(=O)=O)C=2)[C:19]=3S(O)(=O)=O)=[C:15]4Cl)=CC=1S(O)(=O)=O>O.CC(C)=O>[CH:22]1[C:23]2[N:24]=[C:25]3[C:16](=[CH:15][C:14]4[C:27](=[CH:26]3)[O:28][C:29]3[C:12](=[CH:11][CH:10]=[CH:9][CH:30]=3)[N:13]=4)[O:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(Nc2ccc3c(c2S(=O)(=O)O)Oc2c(Cl)c4c(c(Cl)c2=N3)Oc2c(ccc(Nc3ccc(N)c(S(=O)(=O)O)c3)c2S(=O)(=O)O)N=4)cc1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: O
Product: c1ccc2c(c1)N=c1cc3c(cc1O2)=Nc1ccccc1O3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,10-bis(4-amino-3-sulphophenylamino)-6,13-dichlorotripheno dioxazine-4,11-disulphonic acid (M.I. 2585, 25.85 g, 0.01M) was dissolved in water (300 ml) at pH 7. A solution of N-(2,4-dichlorotriazin-6-yl) methanesulphonmethylamide (5.93 g, 0.02M) in acetone (80 ml) was added and the mixture stirred at 25° C. and pH 7 for 3 hours. Salt (5% w/v) was added with stirring and the precipitated solid was collected, washed and dried. Yield 1.7 g, M.I. 1472.
Reaction SMILES: [CH3:1][Si:2]([CH3:50])([CH3:49])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:9]=1.C1C(=O)N([Br:58])C(=O)C1>CC#N.C(Cl)Cl>[CH3:50][Si:2]([CH3:49])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:29][CH2:30][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]2)[C:9]=1[Br:58]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (200 mg, 0.277 mmol) in CH3CN/DCM (5/3 mL) was added NBS (54.3 mg, 0.305 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-35% EtOAc/Hexanes, Rf=0.7 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow oil (201 mg).
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.CCCCCC>CCO>[Br:24][C:25]1[CH:26]=[N:27][C:28]([N:10]2[CH2:9][CH2:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:13]#[N:14])[CH2:12][CH2:11]2)=[N:29][CH:30]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCCCCC
Product: N#CC1(c2ccccc2)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 4-phenylpiperidine-4-carbonitrile (0.35 g, 1.55 mmol) in EtOH (5 mL) was added DIPEA (0.8 mL, 4.55 mmol) at rt. The mixture was stirred at rt for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.15 g, 1.3 mmol). The mixture was heated up to 70° C. for 1 h. After reaction completion (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 10% EtOAc:hexane to obtain the product as a yellow solid (0.31 g, 70% yield). MS: 343.09 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:38][CH2:37][C@@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:34])[CH2:41][CH2:40]1)([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:33])[C:15]2[CH:20]=[N:19][C:18](S(C)(=O)=O)=[N:17][C:16]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:33])[C:15]2[CH:20]=[N:19][C:18]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:17][C:16]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=[O:12])[CH3:9]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN(C)C)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from N′,N′-dimethyl-propane-1,3-diamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 35 Step E, 20 mg, 0.05 mmol). 8-Cyclohexyl-2-(3-dimethylamino-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (17 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C21H31N5O3: 402.24 (M+H). Found: 402.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>N1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccc(C#CCOCCCCCCBr)nc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CCCOCCCCCCBr)nc1
Temperature: 25 °C
Yield: 5.9 %

Procedure:
A mixture of 2-[3-[(6-bromohexyl)oxy]-1-propynyl]-5-nitropyridine (5 g) and dipotassium azodicarboxylate (30 g) in pyridine (200 ml) was stirred at room temperature, and acetic acid (18 ml) added. The mixture was stirred overnight and evaporated in vacuo to give a residue oil which was partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic phase was dried and concentrated to give an oil which was purified by FCC eluting with hexane-ether (1:2→methanol) to give the title compound as an orange oil (300 mg), t.l.c. (toluene:ethanol 0.88 ammonia 80:20:1) Rf 0.75.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12](I)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[Cl-].[NH4+].[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C)C=O.C(N(CC)CC)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.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of N2-(3-fluorophenyl)-5-iodo-N4-propylpyrimidine-2,4-diamine (F2, 500 mg), bis(triphenylphosphine)palladium(II) dichloride (94 mg) and copper(I) iodide (51 mg) in N,N-dimethylformamide (10 mL), triethylamine (934 μL) and trimethylsilylacetylene (285 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and saturated aqueous ammonium chloride were added. The organic layer was separated, washed successively with saturated aqueous ammonium chloride, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 95 to 85% hexane in ethyl acetate) to obtain N2-(3-fluorophenyl)-N4-propyl-5-((trimethylsilyl)ethynyl)pyrimidine-2,4-diamine (S1, 509 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:27][O:28][C:29]([CH3:40])([CH3:39])[CH2:30][C:31]=4[C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:4][C:3]=1[Cl:41].[OH-].[Li+]>O1CCCC1.CO.ClCCl.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH2:27][O:28][C:29]([CH3:39])([CH3:40])[CH2:30][C:31]=4[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[Cl:41]
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)OC3)CC2)cc1Oc1cnc(N)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)O)c(Oc4cnc(N)c(Cl)c4)c3)CC2)CO1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 387B (0.300 g) in tetrahydrofuran (5 mL) and methanol (1 mL) was added 1.0M lithium hydroxide (1.506 mL) and the suspension was heated to 55° C. After 3 hours, the reaction was cooled, diluted with dichloromethane (20 mL) and water (10 mL), and quenched with 1N aqueous HCl (1.5 mL). The organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. The combined organic extracts were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17]Br)=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]>CCOCC.O1CCCC1>[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17][CH3:1])=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]
Reactant: [Li]C
Reactant: CCOc1nc2cccc(CBr)c2c(=O)o1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1nc2cccc(CC)c2c(=O)o1
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
Methyl lithium (4.69 ml, 1.4M, Aldrich) was added to a suspension of cuprous iodide (0.62 gm) in anhydrous ether under argon at -78° C. The solution was stirred at -25° C. for 25 min. This solution was added to a solution of 2-ethoxy-5-bromomethyl-4H-3,1-benzoxazin-4-one (200 mg) in 15 ml anhydrous ether and 3 ml dry tetrahydrofuran at -60° C. Reaction was monitored by TLC until reaction completion. The reaction was quenched with saturated ammonium chloride solution and filtered. The filtrate was extracted in the usual manner. The ethereal layer was washed with water, dried over magnesium sulphate and evaporated to give an oil. The material was purified by thick layer chromatography (Rf =0.75, 3-% ethyl acetate: petroleum ether), to give 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one, m.p. 89°-91° C., H NMR: 1.3, 1.5 (2t, 6H, 2CH3), 3.2 (q, 2H, CH2), 4.5 (q, 2H, OCH2CH3), 7.2 (m, 2H, ArH), 7.6 (t, 1H, ArH).
Reaction SMILES: C([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[O:18][CH2:19]2)[C:14]([Cl:28])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C.CO.C[O-].[Na+].O1CCCC1>O>[Cl:28][C:14]1[C:15]2[C@:20]([CH3:21])([CH2:19][O:18][C:17](=[O:27])[CH:16]=2)[C@@H:22]2[C@H:12]([C@H:11]3[C@:25]([CH3:26])([CH2:24][CH2:23]2)[C@@:5]([OH:4])([C:6](=[O:8])[CH3:7])[CH2:9][CH2:10]3)[CH:13]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 70 °C
Yield: 67.3 %

Procedure:
A mixture of 116 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione, 0.5 ml of an about 28% methanol solution of sodium methylate, 0.1 ml of tetrahydrofuran and 5 ml of methanol was heated at 70° C. for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a 30% aqueous solution of hydrogen chloride and then with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (19/1)] to give 70 mg of 6-chloro-17α-hydroxy-2-oxapregna-4,6-diene-3,20-dione.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][S:6][CH2:5][N:4]1[C:8]([C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9].CS(C)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[CH:2]([CH:3]1[CH2:7][S:6][CH2:5][N:4]1[C:8]([C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12]([NH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:9])=[O:1]
Reactant: O=C(NCc1ccccc1)c1ccccc1C(=O)N1CSCC1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CSCN1C(=O)c1ccccc1C(=O)NCc1ccccc1
Yield: 27.3 %

Procedure:
1.1 g (3.1 mmol) of the title compound of Example 4 was oxidized as described in Example 2 using 1.1 ml (15 mmol) DMSO, 1.9 ml (12.4 mmol) TFAA, 2.2 ml (16 mmol) triethylamine in 25 ml methylene chloride. The crude product was chromatographed on silica gel with chloroform as the eluant to yield 0.3 g of material which was triturated with hot diisopropyl ether to yield 10 mg (1%) crystalline title product. 1H NMR (CDCl3) δ: 9.60(s); 9.30(s,1H); 7.15-7.60(m,10H); 4.10-5.20(m,8H). High Resolution Mass Spectrum: 326.1147±5.8 ppm (C18H18N2O2S).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:15][O:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:1]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 138 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred suspension of 1-methylamino-2,4-dinitrobenzene (1.00 g, 5.07 mmol) in xylenes (10 mL) was added methyl-5-chloro-5-oxo-valerate (3.50 mL, 25.28 mmol, 5.0 equiv.) at 20° C. The reaction mixture was then heated to reflux, approximately 138° C. Reaction progress was monitored periodically by HPLC Method A. The reaction was complete after stirring for approximately 24 hours at 138° C. The reaction mixture was cooled to 0° C. and hexanes was added (10 mL) to crystallize the product. The resultant slurry was stirred for approximately 1 hour at −10° C. to 0° C. and then filtered. The wet cake was dried at 60° C. under vacuum/N2 sweep overnight to give 1.30 g (79% yield) as an off-while solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@@:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])([CH3:12])[CH2:10][CH2:11][C:6]=2[C:5]([CH3:29])=[C:4]([OH:30])[CH:3]=1.[C:31]([O-])(=O)C.C([O-])(=O)C1C=CC=NC=1.C([O-])(=O)CCC([O-])=O.CC(C)=CCC/C(/C)=C/CC/C(/C)=C/CCC1(C)OC2C=CC(O)=CC=2CC1>>[CH3:31][C:3]1[C:2]([CH3:1])=[C:7]2[C:6]([CH2:11][CH2:10][C@:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([CH2:18][CH2:19][CH2:20][C@@H:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])([CH3:12])[O:8]2)=[C:5]([CH3:29])[C:4]=1[OH:30]
Reactant: Cc1cc(O)c(C)c2c1O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Reactant: CC(=O)[O-]
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1
Agent: O=C([O-])CCC(=O)[O-]
Agent: O=C([O-])c1cccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
d,l-α-tocopherol; d-β-tocopherol; d,l-β-tocopherol; d-η-tocopherol; and d,l-η-tocopherol (including acetate, hemisuccinate, nicotinate, and succinate-PEG ester forms of each of the foregoing); tocotrienol isomers, and their esters;
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].B1([C:30]2[N:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)OCCN(C2C=CC=CC=2)CCO1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:35]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1ccc(N2CCOB(c3ccccn3)OCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccccn2)c1
Yield: 59 %

Procedure:
To dimethyl 5-iodoisophthalate (Matrix Scientific, 800 mg, 2.5 mmol) in THF (20 ml), 2-pyridine boronic acid N-phenyldiethanol amine ester (Aldrich, 1.8 g, 6.6 mmol), K2CO3 (912 mg, 6.6 mmol), triphenyl phosphine (173 mg, 0.66 mmol) were added followed by Pd(OAc)2 and cuprous iodide (251 mg, 1.32 mmol). After refluxing for 24 h, reaction mixture was filtered through a pad of celite. Residual solvent was evaporated on a rotavap under reduced pressure and the crude was dissolved in ethyl acetate. Insoluble material was filtered off and the remaining residue was evaporated to dryness and column purified (60% ethylacetate/40% hexanes) to yield 400 mg of dimethyl 5-(pyridin-2-yl)isophthalate as yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:78]([O:83][CH2:84][CH3:85])(=[O:82])[C@H:79]([CH3:81])O.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:79]([C:78]([O:83][CH2:84][CH3:85])=[O:82])[CH3:81])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Reactant: CCOC(=O)[C@H](C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Yield: 74.1 %

Procedure:
A solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol), PyBOP (234 mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate (53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperature for 1 hour when complete consumption of the starting materials was observed. The reaction was worked up by addition of saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated and washed with 5% aqueous solution of lithium chloride. The organic layer was dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (0-20%) to provide 57 mg (74%) of the desired product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz), 3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9 Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61 (m, 2H); 31P (121.4 MHz, CDCl3) δ 28.9, 29.9; MS (m/z) 791.4 [M+Na]+.
Reaction SMILES: Br[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1.[C:13]([Si](C)(C)C)#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC([O-])=O.[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[C:13]([C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][O:5][CH:6]=1)#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC#C[Si](C)(C)C
Reactant: Brc1conc1-c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1conc1-c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To anhydrous DMF (20 ml) containing compound 64 (1.08 g, 4.8 mmol), were added 1.5 eq of hept-1-ynyl-trimethyl-silane (1.21 g), 3 eq of KOAc (1.41 g) and 1 eq of TBAF (1.0 M in THF). The resulting mixture was stirred for another 2 hours under N2. Successively were added 10 mol % of Pd(OAc)2 (108 mg) and 20 mol % of PPH3 (251 mg). After the addition, the resulting solution was warmed at 90° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(4-Hept-1-ynyl-isoxazol-3-yl)-pyridine (69A) as an oil (0.34 g, 30%). 1H-NMR (400 MHz, CDCl3): δ 9.3 (d, J=2 Hz, 1H), 8.7 (dd, J=5 Hz, 2 Hz, 1H), 8.58 (s, 1H), 8.34 (dt, J=8 Hz, 2 Hz, 1H), 7.44-7.39 (m, 1H), 2.42 (t, J=7 Hz, 2H), 1.65-1.57 (m, 2H), 1.45-1.29 (m, 4H), 0.91 (t, J=7 Hz, 3H).