Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[O:10][C@@H:9]1[CH2:11][OH:12].[N+:13]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C1OC1CO>ClCCl>[CH2:8]1[O:10][C@@H:9]1[CH2:11][O:12][S:22]([C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=[CH:20][CH:19]=1)(=[O:23])=[O:24]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: OCC1CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 ml rounded bottom flask was charged with triethylamine (3.3 g, 4.5 ml, 32 mmol), R-glycidol (2.0 g, 27 mmol)(Arco Company, Newton Square, Pa.) and dichloromethane (50 ml) then cooled to 0° C. A solution of 3-nitrobenzenesulfonyl chloride (6.0 g, 27 mmol) in dichloromethane (40 ml) was added dropwise over a 5-minute period to the glycidol solution and the reaction mixture was stirred at 0° C. under N2 for 3 hrs. The reaction mixture was poured into a separatory funnel and washed successively with 1N aqueous hydrochloric acid (90 ml), 5% aqueous sodium bicarbonate solution (90 ml), and saturated aqueous sodium chloride. The organic layer was separated, dried over anhydrous magnesium sulfate (10 g), filtered and concentrated in vacuo to yield (2S)-(+)-glycidyl-3-nitrobenzenesulfonate as a pale colored solid. Recrystallization from hexanes/EtOAc (1:1, 50 ml) provided 5.89 g (83%) of pure (2S)-(+)-glycidyl- 3-nitrobenzenesulfonate, m.p. 61°-63° C., [α]D +22.3° (c 0.41, chloroform), >95% optical purity.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1ccccn1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSc1ccccn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 53 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 53% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:14][CH2:15][O:16][CH3:17])=[C:4]([CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1)[CH2:12][O:13][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCOc1cc(Br)c(OCOC)c(CO)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(Br)c(OCOC)c(CO[Si](C)(C)C(C)(C)C)c1
Yield: 97.2 %

Procedure:
Prepare a solution of (3-bromo-2,5-bis-methoxymethoxy-phenyl)-methanol (1.46 g, 4.76 mmol) and imidazole (0.357 g, 5.24 mmol) in DMF (50 mL). Add tertbutyldimethylsilyl chloride (TBSCl) (0.790 g, 5.24 mmol). Stir the reaction for 3 hours and pour into cold H2O (150 mL). Extract the H2O with EtOAc (3×50 mL), combine the extracts, and wash with H2O (2×50 mL) and brine (20 mL). Dry (MgSO4), filter and concentrate to afford the subtitled product (1.95 g, >95%) as an oil that may be used without purification. 1NMR (CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H),3.47 (s, 3H), 3.51 (s, 3H), 4.84 (s, 2H), 5.02 (s, 2H), 5.12 (s, 2H), 7.15 (d, J=2.9 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H).
Reaction SMILES: CCCC[N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])(CCCC)CCCC.[F-].O1C2C=CC=CC=2C=C1[C:28]1[C:29](=[O:64])[NH:30][C:31](=[O:63])[C:32]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[N:35]([CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=1>C1COCC1>[OH:45][CH2:44][CH2:43][CH2:42][N:35]1[C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]([C:32]2[C:31](=[O:63])[NH:30][C:29](=[O:64])[C:28]=2[C:16]2[CH:15]=[CH:14][NH:5][CH:17]=2)=[CH:34]1
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cc4ccccc4o3)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cc[nH]c1
Yield: 84 %

Procedure:
TBAF (0.12 mL, 1 M solution in THF, 0.12 mmol) as added dropwise to a solution of 3-benzofuran-2-yl-4-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyrrole-2,5-dione Compound 16a (0.044 g, 0.06 mmol) in THF (1 mL) under nitrogen. After 18 hours the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 24 (0.017 g, 84%) as an orange solid. 1H NMR (300 MHz, Acetone-d6) δ 10.47 (s, 1H), 9.57 (s, 1H), 8.3 (dd, J=4.7, 1.5 Hz, 1H), 7.9 (s, 1H), 7.56 (m, 1H), 7.49 (dd, J=7.9, 1.5 Hz, 1H), 7.01 (dd, J=7.9, 4.7 Hz, 1H), 6.75 (m, 1H), 6.22 (m, 1H), 4.55 (t, J=6.6 Hz, 2H), 4.02 (t, J=5.7 Hz, 1H), 3.56 (q, J=5.8 Hz, 2H), 2.11 (m, 2H); MS (ES) m/z: 388 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:14][C:13]=1[CH:25]=[O:26].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:25]([OH:26])[C:13]3[CH:14]=[C:15]([NH:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])[CH:16]=[CH:17][C:12]=3[F:11])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 170.0 mg, 0.86 mmol) in methanol (7.0 mL) were added propane-1-sulfonic acid (4-fluoro-3-formyl-phenyl)-amide (672, 220.0 mg, 0.90 mmol) and potassium hydroxide (0.50 g, 0.0089 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water, acidified with 1N HCl to pH=5, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in methylene chloride to give the compound (673, 55.0 mg, 14.0%). MS (ESI) [M+H+]+=442.1, 444.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[H-].[Na+].C([O:16][C:17]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][C:20]([CH2:27][CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][C:18]=1[C:41]([CH3:44])([CH3:43])[CH3:42])(=O)C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:41]([C:18]1[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][O:10][CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:21]=[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:16])([CH3:43])([CH3:44])[CH3:42]
Reactant: OCCCc1cccnc1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCOCCCc2cccnc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of 3.66 g (26.68 mmol) of 3-(3-pyridyl)propanol in 30 ml anhydrous THF and 3.5 ml dry HMPA is added via syringe to a stirred suspension of 2.56 g (60% oil dispersion, 53.33 mmol) of NaH in 35 ml of anhydrous THF under an inert atmosphere at O° C., followed by a 2 h period at reflux. The sodium alcoholate solution is then recooled to 0° C. and 10.68 g (23.19 mmol) of 3-(4-acetoxy-3,5-di-tert-butylphenyl)-1-(tosyloxy)propane, dissolved in 35 ml of anhydrous THF, is added, fo-Wowed by refluxing for 2 h and stirring overnight at room temperature. After usual workup, the crude product (9.88 g; brown oil) is purified by flash-chromatography over silica gel, eluting with n-hexane/ethyl acetate 3:1, yielding 2.88 g (62% of 2,6-ditert-butyl-4-[7-(3-pyridyl)-4-oxaheptyl]phenol as amber oil. (C25H37NO2 ; F.W. 383.6).
Reaction SMILES: I[CH2:2][CH:3]([CH3:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:28][C:29]([O:31][CH3:32])=[O:30])[CH2:14][C@@H:15]2[O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1.[C:34]1([S:40]([O-:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C)C=O>[CH3:33][CH:3]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:28][C:29]([O:31][CH3:32])=[O:30])[CH2:14][C@@H:15]2[O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1)[CH2:2][S:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:42])=[O:41]
Reactant: O=S([O-])c1ccccc1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 40 °C
Reaction time: 7 h
Yield: 57.7 %

Procedure:
A mixture of 71 mg of 21-iodo-20-methyl-1α,3β-bis-(methoxycarbonyloxy)pregna-5,7-diene, 80 mg of sodium benzenesulfinate and 3 ml of dimethylformamide was stirred at 40° C. for 7 hours. The reaction mixture was subjected to the same isolation and purification procedure in Example 5 to give 42 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:26][O:27][CH3:28])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNC(=O)OC(C)(C)C)c(OC)c1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(Cc1ccc(OC)cc1OC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
Tert-butyl 2,4-dimethoxybenzylcarbamate (3.96 g, 14.8 mmol) was dissolved in THF (74 mL) and cooled to −78° C. The solution was treated with butyl lithium (7.44 mL, 16.3 mmol) dropwise over a five minute period to afford a pale-yellow solution. The solution was allowed to stir for 15 minutes before the chloro(methoxy)methane (1.35 mL, 17.8 mmol) was added dropwise (neat). The reaction was stirred at −78° C. for 10 minutes, then allowed to warm slowly to ambient temperature overnight. The reaction was concentrated in vacuo to afford a yellow gel which was partitioned between half-saturated NH4Cl solution and ether. The aqueous layer was extracted once, and the organics were combined. The organic layer washed with water, then brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. 1H NMR supports the desired near-pure (>90%) tert-butyl 2,4-dimethoxybenzyl(methoxymethyl)carbamate (4.81 g, 104% yield) as a pale-yellow oil which was used without purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[O:13])[C:8]3=2)[O:3][CH2:2]1.[CH3:14][C:15]([CH3:17])=O.IC#N>O1CCCC1>[CH3:14][C:15](=[C:11]1[C:10](=[O:13])[C:8]2=[C:9]3[CH2:1][CH2:2][O:3][C:4]3=[N:5][CH:6]=[C:7]2[CH2:12]1)[CH3:17]
Reactant: CC(C)=O
Reactant: O=C1CCc2cnc3c(c21)CCO3
Agent: N#CI
Solvent: C1CCOC1
Product: CC(C)=C1Cc2cnc3c(c2C1=O)CCO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
1,2,6,7-Tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (610 mg, 3.48 mmol), acetone (1.28 mL, 17.4 mmol) and ICN Alumina B (manufactured by ICN, Akt. 1, 10 g) were suspended in tetrahydrofuran (15 mL), and the suspension was stirred at room temperature for 3 hr. Acetone (1.28 mL, 17.4 mmol) was added, and the mixture was further stirred for 3 hr. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to give the title compound (539 mg, yield 72%).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][O:7][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)CCC2)cc1

Procedure:
To a solution of (1-methylcyclobutyl)methanol (32 mmol) in CH2Cl2 (100 mL) are added triethylamine (65 mmol), trimethylamine hydrochloride (6 mmol), and a solution of p-toluenesulfonyl chloride (49 mmol) in CH2Cl2 (50 mL) at 0° C., then the mixture is stirred at 0° C. for 0.5 h. The reaction is quenched by the addition of water, and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester, which is directly used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([C:19]([F:22])([F:21])[F:20])[CH2:14]2)[C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)([O-])=O.NN>C1COCC1.CCO.[Ni]>[F:21][C:19]([F:20])([F:22])[CH:15]1[NH:16][CH2:17][CH2:18][N:13]([C:6]2[C:7]3[O:11][CH:10]=[CH:9][C:8]=3[CH:12]=[C:4]([NH2:1])[CH:5]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1cc(N2CCNC(C(F)(F)F)C2)c2occc2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(N2CCNC(C(F)(F)F)C2)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
1-(5-Nitro-1-benzofuran-7-yl)-3-(trifluoromethyl)piperazine (96.6 mg, 0.31 mmol; Intermediate 46) was dissolved in THF (6 mL) and EtOH (25 mL). Raney nickel (slurry in ethanol; 1 mL) and H2NNH2 (61.4 mg, 1.23 mmol) were added and the mixture was stirred at room temperature overnight. Filtration through Celite and concentration gave 7-[3-(trifluoromethyl)piperazin-1-yl]-1-benzofuran-5-amine (55 mg, 63%). This material was used in the next reaction step without further purification.
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:25][CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[C:18](=[O:26])[CH:17]=1.C(OC)(=O)C#C>>[NH:15]1[C:16]2[CH2:25][CH:24]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[C:18](=[O:26])[C:17]=2[CH:8]=[CH:3][C:2]1=[O:1]
Reactant: NC1=CC(=O)C2CCCCC2C1
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Agent: C#CC(=O)OC
Product: O=C1c2ccc(=O)[nH]c2CC2CCCCC12

Procedure:
In close analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-4a,5,6,7,8,8a-hexahydro-4H-naphthalen-1-one was reacted with methyl propiolate to give the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C:15]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[CH:7]=[N:8][CH:9]=[CH:10][C:2]2=3)=[O:16])[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)OCCN2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(C(=O)N2CCOc3cnccc32)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a 10 ml flask, 2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine (57 mg, 0.42 mmol) and 3-chloro-4-methoxy-5-nitro-benzoyl chloride (117 mg, 0.47 mmol) were dissolved in dichloromethane. Triethylamine (0.29 ml, 2.1 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the reaction mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4) and filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica with a solvent of ethyl acetate:n-hexane=1:2. The fractions containing the product were collected and evaporated to obtain yellow solid (118 mg, 81%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:66]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[S:75](Cl)(=[O:77])=[O:76])([O-:68])=[O:67]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:75]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=3[N+:66]([O-:68])=[O:67])(=[O:76])=[O:77])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 46) in dry methylene chloride (2 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:42]3[CH2:43][CH2:44][CH:39]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:40][CH2:41]3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc(-c2nc3ccc(OCCCl)cc3n2Cc2ccccc2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3ccc(OCCN4CCC(N5CCCCC5)CC4)cc3n2Cc2ccccc2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
The title compound was prepared by reacting the compound of Example 76, supra, (0.45 g, 1.0 mmol) with 4-(piperdin-1-yl)piperidine (2.0 g, 11.9 mmol) in the presence of the base N,N-diisopropylethylamine, tetra-n-butylammonium iodide and acetonitrile at 80° C. After incubating overnight at 80° C. the reaction was washed with water (2×500 ml), followed by a wash with a saturated sodium chloride solution (1×500 ml). The organic phase was then dried over potassium carbonate and the solvents were removed in vacuo to yield a light brown oil. The desired product was purified by chromatography and triturated with diethyl ether to yield a light brown powder, which was removed by filtration and washed with diethyl ether to yield the purified title compound. MS 584, 585, NMR, IR, mp 143° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[N:34]([CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)=[N+:35]=[N-:36]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CN=[N+]=[N-]
Yield: 83 %

Procedure:
A slurry of Compound 3 (950 mg) and sodium azide (255 mg) in dry N,N-dimethylformamide (10 mL) was heated at 70° C. for 3 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and directly eluted on a silica gel using 2% ethanol in dichloromethane to afford the required product in 83% yield (800 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[I:20](O)(=O)(=O)=O.II.S([O-])([O-])=O.[Na+].[Na+]>CO.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[I:20]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)cc2F)n1
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1I
Yield: 38.9 %

Procedure:
Methyl 6-amino-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (6.17 g, 21.91 mmol, see US 20090088322 for preparation) was diluted with methanol (100 ml). Periodic acid (2.10 g, 9.21 mmol) and iodine (5.26 g, 20.72 mmol) were added and the reaction was heated at reflux overnight. The cooled reaction mixture was diluted with dichloromethane and poured into a 1N solution of sodium sulfite. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1N sodium sulfite, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated onto celite. Purification by flash chromatography (SiO2, 30% EtOAc:Hex) provided the title compound (1.46 g, 16% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 3.89 (s, 3H), 7.34-7.46 (m, 1H), 7.53 (dd, J=10.7, 2.0 Hz, 1H), 7.89 (t, J=8.4 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −110.23; ESIMS m/z 408 ([M+H]+), 406 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11]C(OC(C)(C)C)=O)([CH3:10])[CH3:9])[CH3:2].[ClH:29]>C(OCC)(=O)C.CO>[ClH:29].[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)[NH:6][C:7](=[O:19])[C:8]([NH2:11])([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)(C)N

Procedure:
Into a stirred solution of N-[2-(t-butoxycarbonylamino)-2-methyl-1-oxopropyl]-L-tyrosine ethyl ester (1.46 g, 3.70 mmol) in ethyl acetate (50 mL) and methanol (10 mL) is bubbled hydrochloric acid gas for 10 minutes. The solvent is removed to give N-(2-amino-2-methyl-1-oxopropyl)-L-tyrosine ethyl ester monohydrochloride as a white foam which is used without any further purification.