Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:15])[CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O>[Br:16][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9]([CH3:13])([CH3:14])[CH2:8][C:7]2=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)OC(C)(C)CC2=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-chroman-4-one (Compound 1, 5.81 g, 28.2 mmol) in anhydrous N,N-dimethylformamide (15 mL) under argon at 25° C. was added N-bromosuccinimide (5.02 g, 33.8 mmol). The mixture was stirred at ambient temperature for 12 h. The product was extracted with diethyl ether. The organic layers were washed with water, brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:3]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N)C>[CH2:19]([NH:20][C:21]([C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][N:20]2[CH2:24][CH2:23][O:22][C:21]2=[O:25])[CH:3]=1)=[O:22])[CH3:4]
Reactant: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCN
Product: CCNC(=O)c1ccc(Oc2cccc(CC(=O)O)c2)c(CN2CCOC2=O)c1
Temperature: 100 °C

Procedure:
{3-[4-Bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid (0.2 g, 0.49 mmol) and ethylamine (2M in THF; 10 mL) were combined in a sealed tube and flushed with carbon monoxide for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.057 g, 0.05 mmol) was added, and the solution was flushed with carbon monoxide for 10 minutes. The tube was sealed and heated to 100° C. overnight. The crude mixture was purified by preparative HPLC to give the desired product.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of 1-hexylbenzene (5.00 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 81% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7 Hz), 1.30-1.35 (m, 6H), 1.55-1.63 (m, 2H), 2.59 (t, 2H, J=8 Hz), 7.38 (d, 2H, J=8 Hz), 7.89 (d, 2H, J=8 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:11]3[CH2:12][C@H:13]([CH3:14])[N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:9]([CH3:15])[CH2:10]3)[CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: C[C@@H]1CNC[C@H](C)N1Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(Br)cc21
Product: CC(=O)N1CCc2ccc(N3C[C@@H](C)N(Cc4ccccc4)[C@@H](C)C3)cc21

Procedure:
The title compound was prepared from cis-1-benzyl-2,6-dimethylpiperazine (Org. Prep. Proc. 1976, 8, 19) and 1-acetyl-6-bromoindoline (Heterocycles 1987, 26, 2817) using a similar procedure to Description 2 as an off-white solid (53%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CS[C:7](SC)=[C:8]1[C:13](=[O:14])[O:12][C:11]([CH3:16])([CH3:15])[O:10][C:9]1=[O:17]>CO>[NH:3]1[CH2:2][CH2:1][NH:4][C:7]1=[C:8]1[C:9](=[O:17])[O:10][C:11]([CH3:15])([CH3:16])[O:12][C:13]1=[O:14]
Reactant: NCCN
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Solvent: CO
Product: CC1(C)OC(=O)C(=C2NCCN2)C(=O)O1
Reaction time: 18 h

Procedure:
1,2-Ethanediamine (1.6 mL) was added under nitrogen to a solution of 5-[bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (6 g, 24 mmole, described in example 3) in dry methanol (45 mL). The mixture was stirred at 20°-22° C. for 18 hr. The resultant precipitate was collected and dissolved in 5% methanol in chloroform (v/v). The solution was filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was crystallized from methanol-diethyl ether to give 4.4 g of the title compound; mp 181°-182° C.; NMR (CDCl3) δ 1.65 (s, 6H), 3.8 (s, 4H), 8.25 (m, 2H); IR (CHCl3) 3350, 1690, 1660, 1645, 1590 cm-1 ; UVλmax (MeOH) 243 nm (ε 25,500).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[F:14][C:15]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:15]=2[F:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: Cc1cccc(CBr)c1F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(COc2cccnc2N)c1F
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxypyridine (2.8 g, 0.026 mol), dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20 ml) was stirred for five minutes, then 2-fluoro-3-methylbenzyl bromide (5.0 g, 0.026 mol) and Adogen 464 (3 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 3.99 g (66%), m.p. 115°-118 ° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[O:2].CO.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(=O)(O)[O-].[Na+].O>[CH2:20]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Formyl-benzoic acid (2.0 g, 13.3 mmol) was made 0.2 M in 10:1 MeOH:Water and stirred. The stirring slurry was adjusted to pH=8 with 20% aq Cs2CO3. The resulting homogenous solution was stirred at ambient temperature for 20 mins then concentrated to dryness in vacuo. The residue was dried under high vacuum then treated with benzyl bromide (3.4 g, 20.0 mmol) 0.5 M in DMF. The slurry was stirred under nitrogen at ambient temperature for 18 hours. The reaction mixture was diluted with ½ saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated and again washed with ½ saturated aqueous sodium bicarbonate, then washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by MPLC (5-45% EtOAc in Hexanes) to afford the title compound: MS: cal'd 241 (MH+), exp 241 (MH+)
Reaction SMILES: Br[CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CC(C)=O.O>[N:22]([CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC1C=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of rac-3-bromo-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (13.2 g, 36.0 mmole) in 180 ml acetone and 24 mL water was treated with a solution of sodium azide (3.51 g, 54.0 mmole) dissolved in 24 mL of water and stirred at ambient temperature. After 30 minutes, 500 mL of water was added. The precipitated product was collected and dried, yielding 10.6 g (89%) of the title compound as a solid.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=O)[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]2[OH:17])[CH:2]=1.[C@@H]1(N2C=CC(N)=NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.P(=O)(O)(O)O>>[CH:1]1[C:7](=[NH:8])[N:6]=[C:4]2[N:3]([C@@H:9]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@@H:10]3[O:17]2)[CH:2]=1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Agent: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: O=P(O)(O)O
Product: N=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12

Procedure:
Roberts et al (J. Org. Chem. 32, 816 (1967)) teach the production of cytarabine from cytidine (or from 2'(3')-cytidylic acid). Specifically, cytidine is reacted with phosphoric acid at 80° C. for a period of 30 hours to produce a 2,2'-O-cyclocytidine analogue intermediate. This intermediate is then hydrolyzed at a pH of 9 utilizing lithium hydroxide to produce the 3',5'-diphosphate of cytarabine. The diphosphate is then treated with magnesium chloride, ammonium chloride and concentrated ammonium hydroxide, and thereafter purified by column chromatography to yield pure cytarabine. The overall yield of pure cytarabine is limited to 53% based on the unrecovered portion of the starting cytidine.
Reaction SMILES: C1(=O)OC(=O)C=C1.OC[CH:10]1[CH2:18][CH:17]2[CH:12]([CH:13]3[CH2:19][CH:16]2[CH:15](CO)[CH2:14]3)[CH2:11]1.C(OCC1OC1)(=O)C(C)=C>>[CH:13]12[CH2:19][CH:16]([CH2:15][CH2:14]1)[CH:17]1[CH:12]2[CH2:11][CH2:10][CH2:18]1
Reactant: OCC1CC2C3CC(CO)C(C3)C2C1
Agent: C=C(C)C(=O)OCC1CO1
Agent: O=C1C=CC(=O)O1
Product: C1CC2C3CCC(C3)C2C1

Procedure:
From maleic anhydride, 4,8-bis(hydroxymethyl)-tricyclo[5.2.1.02,6 ] decane, and glycidyl methacrylate 4,8-bis [(3'-methacroyl-2'-hydroxypropyl)maleato methyl] tricyclo [5.2.1.02,6 ] decane was prepared according to the procedure outlined in Example A. (a): ##STR16##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[Cl:13])=[O:6])[CH3:2].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:13][C:12]1[N:11]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:10]2[N:9]=[C:8]([CH3:22])[C:7]=1[C@H:5]([OH:6])[C:4]([O:3][CH2:1][CH3:2])=[O:23]
Reactant: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(Cl)n2n1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a stirred yellow solution of ethyl 6-(2-ethoxy-2-oxoacetyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (264 mg, 0.777 mmol) in anhydrous toluene (5 mL) was added 1.0M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.311 mL, 0.311 mmol). The mixture was cooled to −35° C. and a solution of 50% catechoborane/toluene (0.272 mL, 1.088 mmol) was added over the course of 10 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h, then diluted with EtOAc (30 mL) and sat.aq. Na2CO3 (5 mL). The mixture was stirred vigorously for 30 min, and the organic phase was washed with sat. aq. Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated. The residue was purified by silica gel chromatography (5-100% EtOAc/hexane) to afford the desired (S)-ethyl 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.585 mmol, 75% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.77 (d, J=2.7 Hz, 1H), 4.53 (d, J=7.1 Hz, 2H), 4.33 (dd, J=7.1, 5.5 Hz, 2H), 3.61 (br. s., 1H), 2.68 (s, 3H), 1.50-1.46 (t, J=7.09 Hz, 3H), 1.28 (t, J=7.09 Hz, 3H). LCMS (M+1)=342.13.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[N:16]=[C:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:14]2[C:26]([O:48][CH3:49])=[N:27][N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13]=2[CH:12]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[Si:19]([O:18][CH2:17][C:15]1[C:14]2[C:26]([O:48][CH3:49])=[N:27][N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13]=2[CH:12]=[C:11]([NH2:10])[N:16]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)nc(CO[Si](C)(C)C(C)(C)C)c12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)nc(CO[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a 50 mL round bottom flask charged with crude benzyl(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (199 mg, 0.291 mmol) in ethyl acetate (10 ml) and methanol (5 ml) was added palladium on carbon (61.8 mg, 0.058 mmol). The flask was evacuated and back-filled with hydrogen gas using an attached balloon. This procedure was attempted a further two times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The palladium was filtered off by passing the reaction mixture through celite and washing through with methanol (20 mL). The volatiles were removed in vacuo to afford crude 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (132 mg, 0.240 mmol, 82% yield) as a yellow oil. The product was carried forward without purification. MS: [M+H]+ m/z 551.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:15]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cccc(C2CCCN(CCCC(=O)c3ccc(F)cc3)C2)c1
Yield: 39.4 %

Procedure:
A mixture of 1.9 g (0.01 mole) of 3-(3-methoxyphenyl)piperidine, 4.0 g (3.3 ml, 0.02 mole) of 4-oxo-4-(4-fluorophenyl)butyl chloride, 27.6 g (0.20 mole) of potassium carbonate and 75 ml of methyl isobutyl ketone was heated under reflux for ca. 40 hours. The reaction mixture was then poured onto ice-water and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried and evaporated in vacuo. The residue was chromatographed on 250 ml of silica gel, eluting with chloroform/metanol (95:5). The appropriate fractions were combined and evaporated in vacuo to give 1.4 g of the title compound as an amber oil (39% yield).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1([NH2:29])[CH2:23][N:22]([S:24]([O-:27])(=[O:26])=[O:25])[C:21]1=[O:28].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.N1C=CC=CC=1>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH3:18][O:19][C:20]1([NH:29][C:36](=[O:37])[CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)[CH2:23][N:22]([S:24]([O-:27])(=[O:26])=[O:25])[C:21]1=[O:28]
Reactant: COC1(N)CN(S(=O)(=O)[O-])C1=O
Reactant: O=C(Cl)Cc1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Solvent: c1ccncc1
Product: COC1(NC(=O)Cc2cccs2)CN(S(=O)(=O)[O-])C1=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
3-Methoxy-3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (102 mg) is dissolved in 10 ml of dry acetonitrile. Dry pyridine (56.5 μl) is added and the solution is stirred well at -10° C. under dry nitrogen. Thienylacetyl chloride (44 μl) in 1 ml of dry acetonitrile is added dropwise. In 15 minutes the reaction is complete as shown by thin layer chromatography. Potassium phosphate buffer (0.5M, pH 5.5, 4.2 ml) and tetrabutylammonium sulfate (8.5 mg, 0.1 equiv.) are added and most of the acetonitrile is removed in vacuo. The residue is diluted with water and extracted with three 20 ml portions of methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo to yield 107 mg of a gum. The crude product is purified by chromatography on silica gel using methylene chloride-methanol, yielding 66 mg of the title compound.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]#[N:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([C:43]#[N:44])[CH2:41][CH2:42]4)=[CH:36][CH:35]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CC1(C)OB(c2ccc(C3(C#N)CC3)cc2)OC1(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C#N)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:15]3[CH2:16][CH:12]([CH2:13][NH:14]3)[CH2:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1.[CH2:17]=O>C(O)=O>[CH3:17][N:14]1[CH2:13][CH:12]2[CH2:16][CH:15]1[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:10][CH2:11]2
Reactant: COc1cncc(C2=CCC3CNC2C3)c1
Reactant: C=O
Solvent: O=CO
Product: COc1cncc(C2=CCC3CC2N(C)C3)c1
Yield: 56 %

Procedure:
A mixture of 4-(5-methoxy-3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene (15 mg, 0.07 mmol), aqueous formaldehyde (37%, 0.25 mL) and 90% formic acid (1 mL) was heated at reflux for 1½ h. The mixture was concentrated under reduced pressure, and the remaining volatiles were removed by azeotropic evaporation with methanol (three times). The residue was made basic with dilute aqueous sodium hydroxide and extracted into dichloromethane. The extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on a silica gel column, eluting with 90:10:1 dichloromethane/methanol/concentrated ammonium hydroxide. Concentration of selected fractions gave the product as an oil (9.0 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1nccc(Cl)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-chloro-2-methylpyrimidine in Step 4. LC-MS Method 2 tR=1.196, m/z=446; 1H NMR (CD3OD) 0.92 (s, 3H), 1.27 (s, 3H), 1.58 (d, 3H), 2.12 (s, 2H), 2.23 (m, 1H), 2.51-2.66 (m, 2H), 2.70 (s, 3H), 3.07 (m, 1H), 5.59 (m, 1H), 7.09 (d, 2H), 7.16-7.42 (m, 5H), 7.65 (d, 1H), 7.89 (d, 2H), 8.61 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@@H]1COC(C)(C)O1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@@H]1COC(C)(C)O1
Yield: 65.5 %

Procedure:
(R)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 6.9 mmol) and pyridine-3-boronic acid (1.02 g, 8.27 mmol) were coupled according to the method described in Examples 118–121. The work-up procedure described in Part F of Examples 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitrile to provide 1.96 g of (R)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 155–156° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].C[Zn]C.[C:9]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)(=[O:11])[CH3:10]>CCOCC.C1(C)C=CC=CC=1.C1COCC1>[C:9]([O:12][C@H:13]1[C@H:14]([CH2:1][CH2:2][CH3:3])[CH2:15][C:16](=[O:18])[CH2:17]1)(=[O:11])[CH3:10]
Reactant: CC(=O)O[C@H]1C=CC(=O)C1
Reactant: CCC[Mg]Cl
Agent: C[Zn]C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)C[C@H]1OC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Propylmagnesium chloride (15.7 ml of a 2M solution in ether, 31.4 mmol) was added slowly to a stirred solution of dimethylzinc (15.7 ml of a 2M solution in toluene, 31.4 mmol) in THF (80 ml) under argon at 0° C. After 30 minutes, the mixture was cooled to −78° C. and (R)-4-acetoxycyclopent-2-enone (4.0 g, 28.5 mmol) in THF (45 ml) was added dropwise over 1 hour. The reaction mixture was stirred for a further 20 minutes and then quenched by the addition of saturated ammonium chloride solution (20 ml). The reaction mixture was allowed to warm to room temperature, diluted with 1N hydrochloric acid (100 ml) and extracted with ether (3×200 ml). The organic layer was washed with brine (200 ml), dried (MgSO4) and the solvent was removed under reduced pressure to yield the acetoxy cyclopentanone 1 as a solution in toluene which was used without further purification in the next step. νmax(film)/cm−1 1740 (C═O).