Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@@:10]12[C:27]([CH3:29])([CH3:28])[C@@H:13]([C:14]3[C:15](=[O:26])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[NH:17][C:18]=31)[CH2:12][CH2:11]2.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([N:17]1[C:18]2[C@@:10]3([CH3:9])[C:27]([CH3:29])([CH3:28])[C@H:13]([CH2:12][CH2:11]3)[C:14]=2[C:15](=[O:26])[N:16]1[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:26][C:15]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:17]=[C:18]2[C:14]=1[C@@H:13]1[C:27]([CH3:29])([CH3:28])[C@@:10]2([CH3:9])[CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2c(=O)c3c(n2Cc2ccccc2)[C@]2(C)CC[C@H]3C2(C)C)cc1
Product: Cc1ccc(-n2nc3c(c2OCc2ccccc2)[C@H]2CC[C@]3(C)C2(C)C)cc1
Yield: 53 %
Yield: 3.5 %

Procedure:
Benzyl bromide (0.18 mL, 1.5 mmol) was added to (4S,7R)-7,8,8-trimethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 9; 400 mg, 1.4 mmol), potassium iodide (34 mg, 0.14 mmol) and potassium carbonate (400 mg, 2.8 mmol) in dimethylformamide (5 mL). The mixture was heated at 80 degrees under argon overnight. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-65% ethyl acetate/hexanes to give (4S,7R)-1-benzyl-7,8,8-trimethyl-2-p-tolyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (19 mg, 3.5%) as an off-white solid and (4S,7R)-3-benzyloxy-7,8,8-trimethyl-2-p-tolyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (279 mg, 53%) as a yellow oil. ES(+)-MS (M+H) 373.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[CH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCN(CC)CC.C1[CH2:30][O:29][CH2:28]C1.[OH2:31]>>[C:15]1([C:16]2[C:28](=[O:31])[O:29][CH2:30][C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[CH:14]=[CH:13][CH:12]=[CH:17][CH:18]=1
Reactant: C#Cc1ccccc1-c1ccc(S(C)(=O)=O)cc1
Reactant: C1CCOC1
Reactant: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1
Reaction time: 5 h

Procedure:
Into a 20 ml glass ampule are added 1 g of 2-(4-(methylsulfonyl)phenyl)phenylacetylene, 20 mg of Rh4 (CO)12, 1.5 g of Et3N, 10 mL of THF and 1 mL of H2O under a nitrogen atmosphere, and the ampule is placed in a 100-ml stainless steel autoclave. The reaction system is flushed three times with CO then charged at r.t. to a initial CO pressure of 100 atm. The reaction is kept at 100° C. for 5 hr. The solution is then diluted with 50 mL of benzene and washed with brine and 1N HCl. The benzene solution is dried over Na2SO4, and concentrated. The crude products are separated by column chromatography on silica gel, eluting with 2:1 EtOAc/hexane to give the title compound and its regioisomer.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7](Br)([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[F:16][C:17]1[C:30]([NH:31][NH2:32])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1>O>[F:16][C:17]1[C:30]([NH:31][N:32]=[C:7]([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reactant: CC(Br)(Br)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(NN=C(C)C(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 8.0 g (97.2 mmol) of sodium acetate and about 50 ml of water was added under ice cooling 6.9 g (24.3 mmol) of 3,3-dibromo-1,1,1-trifluorobutanone, and the reaction was allowed to proceed at 80° C. for 30 minutes. Then, the reaction mixture was cooled to 0° C., to which 4.4 g (18.7 mmol) of 7-fluoro-6-hydrazino-4-propargyl-2H-1,4-benzoxazin-3-one was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of water, and dried, which afforded 6.1 g (17.0 mmol) of 1,1,1-trifluoro-2,3-butandione 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-ylhydrazone).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(Cl)Cl>O.C1COCC1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Yield: 83 %

Procedure:
To a solution of NaOH (1.69 g, 42.2 mmol) in H2O (11 mL) was added a solution of triethylene glycol monomethyl ether (5.00 mL, 31.9 mmol) in THF (11 mL) under nitrogen, while the temperature was maintained below 5° C. by cooling with an ice-salt bath. At the same temperature, a solution of p-toluenesulfonyl chloride (6.08 g, 31.9 mmol) in THF (13 mL) was added dropwise over 1 h. The reaction mixture was poured into water and DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (three times). The combined organic layers were washed with water (twice) and brine (twice), dried over anhydrous MgSO4, filtered off and evaporated to dryness to give 16 (8.43 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 4.16 (t, 2H), 3.50-3.70 (m, 10H), 3.32 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][O:21][CH2:22][CH3:23])[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[C:4]=2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[C:14]1[CH2:20][O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CCCCn1c(COCC)nc2c(N)nc3ccc(Br)cc3c21
Product: CCCCn1c(COCC)nc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (10% methanol in CH2Cl2) followed by recrystallization from isopropanol afforded 1-butyl-2-ethoxymethyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, m.p. 186–187° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].Cl[C:25]([O:27][CH3:28])=[O:26].C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][NH:21][C:25](=[O:26])[O:27][CH3:28])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C

Procedure:
To a solution of 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (166 mg, 0.51 mmol) and methyl chloroformate (107 μL, 1.39 mmol) in CH2Cl2 (5 mL) was added N,N-diisopropylethylamine (485 μL, 2.79 mmol). The reaction was stirred at room temperature for twenty minutes and then was poured into H2O (50 mL). The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 20% EtOAc/hexanes afforded methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.29 (15% EtOAc/hexanes). LCMS=382.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.68 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.17 (m, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.89 (m, 1H), 1.25 (d, J=7.0 Hz, 6H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>C1COCC1>[N:1]1([C:6]2[N:11]=[C:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)Cc1cccc(-n2cnnn2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-n2cnnn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl [6-(1H-tetrazol-1-yl)pyridin-2-yl]acetate (367 mg, 1.67 mmol) in THF (5 mL) was added 1.5 mL of 1N aqueous lithium hydroxide solution. The reaction mixture was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in 4 mL of a 1N aqueous hydrochloric acid solution and extracted with DCM (3×20 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo to afford crude [6-(1H-tetrazol-1-yl) pyridin-2-yl]acetic acid which was used without further purification. LC/MS (M+H−28)+178.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:8][CH2:9][CH2:10]O>>[Cl:8][CH2:9][CH2:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCCl
Reactant: C1=COCCC1
Agent: Cl
Product: ClCCC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dihydropyran (85 g, 1.01 moles) and 0.2 mL of concentrated HCl were added to a 500 mL 3-necked round-bottomed flask equipped with a magnetic stirrer, a thermocouple, a reflux condenser and a nitrogen bubbler. The mixture was cooled to 0° C., and then 2-chloro-ethan-1-ol (80.5 g, 1.01 moles) was added dropwise at a rate sufficient to maintain the temperature below 10° C. After the addition was complete (about 2 hr.), the mixture was allowed to warm to room temperature and stirred for 1 hr. The clear yellow solution was distilled under vacuum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.C[CH:14]([NH:18][C:19](=[O:21])[CH3:20])[C:15](=O)[CH3:16].[CH:22]1C=CC=CC=1>B(F)(F)F.CCOCC>[CH3:22][C:16]1([CH2:15][CH2:14][NH:18][C:19](=[O:21])[CH3:20])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: c1ccccc1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)NC(C)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)NCCC1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of indole-3-ethanol (16 lg), benzene (1200 ml), N-(1-methyl-2-oxopropyl)-acetamide[12.7 g, described by A. Triebs and W. Sutter, Chem. Ber. 84, 96(1951)] and boron trifluoride-etherate (5 drops) is refluxed using a water separating condenser for 60 minutes. After cooling, the mixture is washed with concentrated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a residue of the title compound as a 1:1 mixture of diastereoisomers:
Reaction SMILES: O[N:2]=[C:3]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].C(O)(=O)C.[OH-].[NH4+].C(Cl)Cl>[Zn].CCOC(C)=O>[NH2:2][CH:3]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1ccc(C(=NO)C(C)C)cc1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(N)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To the crude ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate in a 100-mL round-bottom flask was added acetic acid (8 mL) and zinc dust (1.33 g, 20.3 mmol). The mixture was stirred at rt for 1 h, then filtered through a pad of Celite. The pad was rinsed with ethanol (50 mL). Combined filtrate was concentrated to give a solid. To the solid residue was added ammonium hydroxide (20 mL) and DCM (50 mL). The solution was stirred at rt for 10 min. After separation, the aqueous layer was extracted with DCM (2×50 mL). Combined organic phases were washed with brine, dried (MgSO4), and concentrated to give an oil. Flash column chromatography (EtOAc:hexanes:TEA, 20:80:2 to 100:0:2) afforded ethyl 4-(1-amino-2-methylpropyl)benzoate (0.563 g, 55%) as a clear oil. LC-MS: (FA) ES+ 222; 1H NMR (CDCl3, 300 MHz) δ7.99 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 4.37 (q, J=7.2 Hz, 2 μl), 3.68 (d, J=7.0 Hz, 1H), 1.86 (m, 1H), 1.39 (t, J=7.0 Hz, 3H), 0.96 (d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C(OC(C)C)(C)C>>[O:19]([CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH2:13][CH3:14])[N+:20]([O-:22])=[O:21]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCCC(Oc1ccccc1)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CCCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.69 g of 2-phenoxyvaleric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ClCCl.Br[CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>CCCCCC>[Cl:24][CH2:23][CH2:22][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCBr
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(CCCl)CC2)c1
Temperature: 25 °C

Procedure:
To a 100 mL flask was added 4-(3-trifluoromethylphenyl)piperazine HCl (5035 mg, 18.88 mmol) and 60 mL dichloromethane. 1-Bromo-2-chloroethane (1730 μl, 20.78 mmol, 1.10 eq) was added, then triethylamine (5.25 mL, 37.7 mmol, 2.00 eq). The solution was refluxed for 9 hours, then cooled to 25° C. 100 mL of hexane was then added, and the resulting suspension was vacuum filtered. The filtrate was concentrated in vacuum and purified by column chromatography using dichloromethane as eluant resulting in an oil of 1-(2-Chloroethyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([N:24]([CH2:26][C:27](O)=[O:28])[CH3:25])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(N[C@H](C(NCC(N[C@H](C(O)=O)C)=O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.C(OC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)N)C1C=CC=CC=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][N:24]([C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN(C)C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosylglycylsarcosine and L-phenylalanyl-L-methionine benzyl ester are substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine and the L-phenylalanyl-L-leucine benzyl ester, respectively, of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosylglycylsarcosyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: ClCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Product: C(=C/c1ccccc1OCCCn1ccnc1)\c1nc2ccccc2o1

Procedure:
The title compound was prepared by the procedure of Example 1 starting with (A) of Example 1 (8.0 g, 25 mmol) and using imidazole in place of dibutylamine to produce 2.1 g (24% yield) of the free base of the title compound which was converted to the HCl salt, mp 158°-159° C. IR(KBr): 3400, 1600 cm-1. MS: 346(MH+). 1H NMR (CD3OD): δ 9.09 (s, 1H), 7.82-6.81 (m, 12H), 4.51 (t, J=5.4 Hz, 2H), 4.08 (t, J=5.1 Hz, 2H), 2.41 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3C(C=C)=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[N+]1([O-])CC[O:30]CC1.[C:34]([OH:38])([CH3:37])([CH3:36])C>O.[Os](=O)(=O)(=O)=O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Br:1])[C:3]=3[O:24][CH3:25])[CH3:11])[N:13]=[C:36]([CH:34]([OH:38])[CH2:37][OH:30])[C:15]=12
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(C)c(Br)c2OC)c2ncnc(N)c12
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.236 mmol) in t-butyl alcohol (2 mL) was added N-methylmorpholine N-oxide (30.5 mg, 0.260 mmol) and water (0.74 mL). To the solution was then added aqueous osmium tetraoxide (0.075 mL, 4%). After 3 hr, another equivalent of N-methylmorpholine N-oxide was added. The reaction was stirred at room temperature overnight. The solution was diluted with water, extracted with ethyl acetate, dried over MgSO4 and concentrated to give the product which was used directly in the next step. LCMS calculated for C17H20BrClN5O3 (M+H)+: m/z=456.0; Found: 456.0
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][O:22][S:23]([O:26]C)(=[O:25])=[O:24]>CC(C)=O>[CH3:21][O:22][S:23]([O-:26])(=[O:25])=[O:24].[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N+:2]([CH3:21])([CH3:1])[CH3:20])(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCC(=O)NCCCN(C)C
Reactant: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NCCC[N+](C)(C)C
Product: COS(=O)(=O)[O-]

Procedure:
0.036 moles (10.3 g) N-(3-dimethylaminopropyl)-lauramide and 25 ml acetone were placed in a 100 ml round bottom flask. 0.036 moles (3.4 ml) dimethylsulfate was added slowly to the flask, a condenser attached, and the reaction mixture refluxed for two hours. After cooling, the product crystallized out of the acetone, was filtered off, and recrystallized from acetone to a constant melting point. Melting point 98.5°-100° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1([C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:13][CH2:12]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C@:17]12[CH2:21][O:22][C@@H:14]([C:11]3([CH3:10])[CH2:12][CH2:13]3)[CH2:15][C@H:16]1[CH2:20][O:19][NH:18]2
Reactant: Fc1ccc(I)c(F)c1
Reactant: CC1([C@H]2C[C@H]3CON=C3CO2)CC1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1([C@H]2C[C@H]3CON[C@@]3(c3ccc(F)cc3F)CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (7.86 g, 25.9 mmol) was added drop-wise to a solution of rel-(3aR,5R)-5-(1-methylcyclopropyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C56) (4.255 g, 23.5 mmol) in toluene (500 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 6.22 g, 25.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 9.9 mL, 24.8 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (350 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (400 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 3.2 g, 10.8 mmol, 46%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.4, 2.4 Hz, 1H), 6.78 (ddd, J=11.6, 8.8, 2.4 Hz, 1H), 6.28 (br s, 1H), 4.04 (dd, J=12.4, 1.6 Hz, 1H), 3.82 (d, J=12.8 Hz, 1H), 3.72 (d, J=6.8 Hz, 1H), 3.53 (dd, J=6.8, 4.8 Hz, 1H), 3.01-3.06 (m, 1H), 2.95 (d, J=12.0 Hz, 1H), 1.83 (dd, J=13.2, 6.0 Hz, 1H), 1.62 (q, J=12.4 Hz, 1H), 1.09 (s, 3H), 0.52-0.56 (m, 1H), 0.43-0.48 (m, 1H), 0.36-0.41 (m, 1H), 0.28-0.33 (m, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[I:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=O)=[CH:10][CH:9]=1.CCCCCC.CCOCC>C(Cl)(Cl)Cl>[ClH:2].[I:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][N:14]=2)=[CH:10][CH:9]=1
Reactant: COc1cccc(CCNC(=O)c2ccc(I)cc2)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc2c(c1)CCN=C2c1ccc(I)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
Phosphorus pentachloride (11 g, 52.8 mmol) was added in portions to a solution of 4-iodo-N-[2-(3-methoxyphenyl)-ethyl]benzamide (10.1 g, 26 mmol) in CHCl3 (60 ml) at 0° C. under N2. The resulting reaction was stirred at 0° C. for 10 min, then warmed to rt and stirred at rt for 18 hr. After cooling to 0° C., hexane (500 ml) was added and the resulting suspension was allowed to settle. The solvent was decanted off from the oil that separated and the remaining oil was triturated with EtOH (20 ml) to give a white solid. Et2O (200 ml) was added, the resulting suspension was stirred for 1 hr, the solid was collected and dried in vacuo to give 7.5 g (72% yield) of white solid.