Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:22][C@@H:23]1[C@H:27]([O:28]C(=O)C2C=CC=CC=2)[C@@H:26]([CH2:37][O:38]C(=O)C2C=CC=CC=2)[O:25][C@H:24]1[N:47]1[CH:55]=[N:54][C:53]2[C:48]1=[N:49][C:50]([Cl:57])=[N:51][C:52]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:57][C:50]1[N:51]=[C:52]([NH:1][N:2]2[CH2:7][CH2:6][CH:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[C:53]2[N:54]=[CH:55][N:47]([C:48]=2[N:49]=1)[C@@H:24]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[OH:22]
Reactant: NN1CCC(c2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 35.4 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-4-phenylpiperidine (prepared as outlined in Example 6) (0.77 g, 3.6 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3.0 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenyl-1-piperidinyl)adenosine (0.49 g, 37%) as a solid which precipitated on evaporation of column chromatography fractions, mp 142°-149° C. 1H NMR (DMSO-d6) δ 3.53-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-0H), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1H, d, H-1'), 7.18-7.35 (5H, 2m, Ar--H), 8.43 (1H, s, H-8) 9.45 (1H, s, N--H).
Reaction SMILES: [CH3:1][NH:2]/[N:3]=[CH:4]/[C:5]1[C:10](F)=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[F:13]>C(Cl)Cl>[F:13][C:6]1[CH:7]=[C:8]([F:12])[CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1]
Reactant: CN/N=C/c1c(F)cc(F)cc1F
Solvent: ClCCl
Product: Cn1ncc2c(F)cc(F)cc21
Yield: 56 %

Procedure:
N-Methyl-N′-[1-(2,4,6-trifluoro-phenyl)-meth-(E)-ylidene]-hydrazine (3.85 g, 20.46 mmol) was heated in a seaed tube at 210° C. for 2 h. After cooling, the black residue was dissovled in DCM and purified by flash chromatography (EtOAc:hexane 10:90) to give the title compound as a light yellow crystal (1.926 g, 56%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.05 (s, 1H), 7.16 (d, 1H), 6.75 (t, 1H), 3.32 (s, 3H). LCMS (method B): [MH]+=169, tR=2.28 min.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
Benzyl alcohol (682 mg, 6.3 mmol), 18 crown ether (2.5 g, 9.4 mmol) and KOH (637 mg, 11.3 mmol) were added to a solution of 2-chloro-5-nitro-pyridine (1 g, 6.3 mmol) in toluene (15 mL) and the reaction mixture was maintained at 80° C. for 2 hours, then diluted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using neutral alumina (2% ethyl acetate in hexane) to afford 410 mg (28%) of 2-benzyloxy-5-nitro-pyridine. LCMS: 231.07 (M+1)+, 98.4%
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].Cl.Cl.[CH2:10]([NH:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:10]([N:17]1[C:4]([CH3:5])=[CH:3][C:2]([CH3:1])=[N:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cc(C)n(Cc2ccccc2)n1
Yield: 92 %

Procedure:
Dissolve 2,4-pentanedione (5.09 g, 50.8 mmol) and benzylhydrazine dihydrochloride (10.91 g, 55.9 mmol) in acetic acid (40 mL). Slowly add triethylamine (15.6 mL, 0.112 mol) and stir the mixture for 18 hr. Concentrate the solution then dilute the residue with saturated aqueous sodium bicarbonate and extract 3 times with ethyl acetate. Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 40:60 hexanes:ethyl acetate), to give 1-benzyl-3,5-dimethyl-1H-pyrazole as a yellow oil (8.703 g, 92%).
Reaction SMILES: [C:1]([C:4]1C=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[C:7](C(=O)C)=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2)(=[O:3])C.C1C[O:27][CH2:26]C1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:3][C:1]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([C:14]1[CH:15]=[CH:16][C:17]([CH2:26][OH:27])=[CH:18][CH:19]=1)=[CH:7][C:6]2=[O:23]
Reactant: CC(=O)c1c(-c2ccccc2)oc2cccc(C(C)=O)c2c1=O
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1cc(-c2ccc(CO)cc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
In a 100 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2′-hydroxy-5′-acetoxyacetophenone (2.63 g, 13.54 mmol), 4-acetoxymethyl benzoic acid (2.63 g, 13.54 mmol) and pyridine (20 mL). POCl3 (2.07 g, 13.54 mmol) was added slowly on cooling. Then the reaction mixture was stirred for 24 h at rt under nitrogen. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried and concentrated to give product (3.0 g, 60%). A solution of this product (3.0 g, 8.10 mmol) in THF (50 mL), was added potassium t-butoxide (1.187 g, 9.72 mmol) and the reaction mixture was stirred for 24 h at rt under N2. The reaction mixture was poured into saturated aqueous solution of NH4Cl. The organic layer was separated, washed with water, dried and concentrated to give crude diketone (3.0 g, 99%). The mentioned diketone (3.0 g, 8.10 mmol) was taken into a mixture of 48% HCl (2 mL) and AcOH (25 mL) and heated at 100° C. for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried and concentrated to give the di-acetyl flavone (1.2 g, 74%). To a solution of the di-acetyl flavone (228 mg, 0.676 mmol) in methanol:THF (5 ml:5 mL), K2CO3 (112 mg, 0.811 mmol) was added and stirred for 2 h at rt, then the reaction mixture was neutralized by dilute HCl and extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by column chromatography using 2% MeOH in dichloromethane, to give 100 mg of 6-hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one (50%). MS (ES) m/z: 269.90 (M+1), 268.91 (M); Mp. 262-265° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-])=O)[CH:5]=1)[CH3:2]>[Pd].C1COCC1.CCO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:8])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-ethoxy-2-nitroaniline (963 mg) and THF/EtOH (1/1, 10 mL) was added 10% Pd/C (281 mg), followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 4-ethoxybenzene-1,2-diamine.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][NH:65][C:64](=[O:67])[CH:63]2[NH:68][C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][C:76]([N+:79]([O-:81])=[O:80])=[CH:75][CH:74]=2)=[O:70])[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][NH:65][C:64](=[O:67])[CH:63]4[NH:68][C:69]([O:71][CH2:72][C:73]4[CH:74]=[CH:75][C:76]([N+:79]([O-:81])=[O:80])=[CH:77][CH:78]=4)=[O:70])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C(NC1C(=O)NCC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CNC(=O)C4NC(=O)OCc4ccc([N+](=O)[O-])cc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 48.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (155.4 mg, 0.26 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidine (110 mg, 0.197 mmol, compound of Reference Example 20-6) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[3-[(p-nitrobenzyloxycarbonyl)amino]-2-pyrrolidon-4-yl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (87 mg, yield: 48.9%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A round-bottomed separable flask (3,000 cc) equipped with a mechanical stirrer was charged with cyclopentyl alcohol (500 g, 5.80 mol) and p-toluenesulfonyl chloride (1,210 g, 6.35 mol), followed by the addition of pyridine (2,000 mL) under ice cooling to form a solution. The mixture was stirred for 8 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water (3,000 mL) and stirred thoroughly. The precipitating solids were isolated by filtration, washed thoroughly with water and dried to give a white crystal of cyclopentyl p-toluenesulfonate (1,117 g; yield=80.1%). MP: <30° C. 1H-NMR(CDCl3,TMS,ppm): δ1.23-2.07(8H,m), 2.45(3H,s), 4.98(1H,m), 7.38(2H,d,J=9.0Hz), 7.85(2H,d,J=9.0Hz).
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][C:30](=[O:32])[CH2:31][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1
Reactant: CC(=O)CCN(C)C
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCN(C)C)nc2n1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
Sodium hydride (0.7 g) is added in small portions at a temperature in the region of -5° C. to a solution, maintained under an argon atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (8.0 g) in anhydrous dimethylformamide (125 cc). The suspension obtained is stirred for 30 minutes at a temperature in the region of -5° C. and then treated with a solution of 4-dimethylamino-2-butanone (3.5 g) in anhydrous dimethylformamide (5 cc). The mixture is stirred for 3 hours at a temperature in the region of 20° C., and is then poured into distilled water (500 cc) and extracted with dichloromethane (3×200 cc). The organic phases are combined, washed with distilled water (4×25 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is dissolved in ethyl acetate (400 cc) and the solution obtained is extracted with 1 N aqueous hydrochloric acid solution (2×100 cc). The aqueous phases are combined, washed with ethyl acetate (50 cc), alkalinized with 10 N aqueous sodium hydroxide solution to a pH in the region of 11 and extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with distilled water (3×30 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in acetonitrile, 3-(4-dimethylamino-2-oxobutyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (2.6 g), m.p. 140° C., is obtained.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[CH3:16][NH2:17]>>[CH3:16][NH:17][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Product: CNC(=O)c1ccc2c(N)cccc2n1
Temperature: 25 °C

Procedure:
76 mg (0.376 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is dissolved with 10 ml of a 2.0 M methanolic methylamine solution. After 90 minutes under reflux and another 16 hours at room temperature, the solvent is removed under reduced pressure, and the residue is purified on silica gel with hexane-ethyl acetate (0–80%). 72 mg (95% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:7]=1.CO>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:24])=[O:25]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)phenyl]-acrylic acid methyl ester (14e) (0.25 g, 0.68 mmol) in methanol (3.5 ml) 2N NaOH solution (1.0 ml, 2.0 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.21 g, 87%). 1H NMR (DMSO-d6 HMDSO), δ: 6.56 (1H, d, J=16.0 Hz); 7.21-8.01 (11H, m); 8.12 (1H, s); 10.56 (1H, br s); 12.54 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 2,3-dichloro-5-nitro-pyridine (5 g, Synthesis, 1990 (6), 499-501), 2,2,2-trifluoroethanol (2.6 g) and potassium carbonate (5.4 g) in N,N-dimethylformamide (50 ml) was stirred at 80° C. for 1 hour. The reaction mixture was poured into ice water. The precipitate was isolated by filtration and dried under high vacuum to afford 3-chloro-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (5.65 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:16])=[O:8])[CH2:4][O:3]1.[C:39]([O:42][CH2:43][CH2:44]Br)(=[O:41])[CH3:40]>>[C:39]([O:42][CH2:43][CH2:44][N:9]([C:10]1[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH:18]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:38])([CH3:1])[O:6]1)=[O:8])(=[O:41])[CH3:40]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Yield: 83 %

Procedure:
The alkylation of 5-(2,2-dimethyl-1,3-dioxolane-4-carboxamido)-3-acetoxymethyl-N-(1,3-diacetoxyprop-2-yl)-2,4,6-triiodobenzamide with 2-bromoethyl acetate was performed according to the procedure of Example 30a. The crude product was isolated in 83% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].Cl.N[CH:18]([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21].N1C=CN=C1.CCN(CC)CC>O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH:18]([CH3:23])[CH2:19][N:20]([CH3:22])[CH3:21])[C:5]2=[O:15]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CC(N)CN(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(CN(C)C)N1C(=O)c2cc(N)c([N+](=O)[O-])cc2C1=O
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (1.66 g, 8.0 mmol), HCl salt of 2-amino-N,N-dimethyl-propylamine (5.3 g, crude, <30 mmol), imidazole (1.36 g, 20 mmol) and Et3N (8.4 mL, 6.07 g, 60 mmol) in dioxane (80 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 130° C. for 72 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (240:10:1) afforded the title compound (1.49 g, 64%). 1H NMR (DMSO-d6) δ 1.32 (d, J=6 Hz, 3H, CH3), 2.09 (s, 6H, 2CH3), 2.25 (m, 1H), 2.95 (m, 1H), 4.35 (m, 1H), 7.43 (s, 1H), 8.29 (s, 1H), 8.39 (br s, 2H, NH). ESI-MS m/z 293.1 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[C:6](=[O:16])[CH2:7][CH2:8]2
Reactant: CCCOC1CCNCC1
Reactant: O=C1CCc2cc(F)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOC1CCN(CCCN2C(=O)CCc3cc(F)ccc32)CC1
Reaction time: 20 h
Yield: 47.4 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79) (0.242 g, 1.00 mmol), 4-propoxypiperidine (0.143 g, 1.00 mmol), KI (0.250 g, 1.50 mmol), and K2CO3 (0.207 g, 1.50 mmol) in MeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH70) (0.165 g, 47%). 1H NMR (CD3OD) δ 7.19-7.15 (m, 1H), 7.01-6.97 (m, 2H), 3.96 (t, J=7.4 Hz, CH2), 3.40 (t, J=6.6 Hz, CH2), 3.35-3.30 (m, 3H), 2.88 (t, J=6.8 Hz, 2H), 2.76 (m, 2H), 2.60-2.57 (m, 2H), 2.43-2.39 (m, 2H), 2.22-2.17 (m, 2H), 1.90-1.78 (m, 4H), 1.61-1.50 (m, 4H), 0.91 (t, J=7.4 Hz, CH3); 13C NMR (CD3OD) δ 172.2, 160.0 (d, J=242.2 Hz), 136.7 (d, J=2.3 Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.5 Hz), 115.9 (d, J=23.1 Hz), 114.64 (d, J=22.3 Hz), 75.6, 70.7, 56.5, 52.0, 41.6, 32.4, 31.8, 26.1, 25.5, 24.2, 11.0; HPLC-MS (ammonium acetate) [M+H+]=349.30.
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=[O:10])[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[BH4-].[Na+].Cl.O>CO>[CH2:3]1[CH:2]2[CH:6]([CH:7]3[CH2:11][CH:1]2[CH2:9][CH:8]3[OH:10])[CH2:5][CH2:4]1
Reactant: O=C1CC2CC1C1CCCC21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CC2CC1C1CCCC21
Reaction time: 8 h

Procedure:
25 g of tricyclo[5.2.1.0 (2,6)]decan-8-one (Aldrich) were dissolved in 100 ml of methanol and, at room temperature and with slight cooling and stirring, admixed a little at a time with 6.3 g of solid sodium borohydride over a period of 2 h. The mixture was then stirred for another 2 h and allowed to stand overnight. With cooling, about 40 ml of 2 N HCl were then added dropwise, followed by 20 ml of water. The mixture was concentrated, the residue was admixed with ethyl acetate, and the ethyl acetate phase was washed once with water and once with sodium bicarbonate solution. The ethyl acetate phase was dried using magnesium sulfate and then filtered and concentrated. This gave 26 g of an oil which was purified by distillation under reduced pressure. This gave 20.7 g of an oily liquid (bp0.5 76° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH3:10])[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[N:20]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[N:24][C:19]2=[N:18][CH:17]=1)CCC>>[CH3:10][O:9][CH2:8][C:4]1[N:3]=[C:2]([C:16]2[N:20]3[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[N:24][C:19]3=[N:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: COCc1cccc(Br)n1
Product: COCc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 3.6 %

Procedure:
2-Bromo-6-methoxymethylpyridine (0.27 g, 1.34 mmol; prepared according to Shawcross et al. in J. Heterocyclic Chem., 1993, 33(2), 563-565) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.34 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 3-(6-methoxymethylpyridin-2-yl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (15 mg) as a yellow solid: δH (400 MHz, CDCl) 3.54 (3H, s), 4.68 (2H, s), 7.34 (1H, d, J 7), 7.39 (1H, d, J 7), 7.73 (1H, d, J 7), 7.84 (1H, t, J 7), 8.52 (1H, s), 10.51 (1H, d, J 7); m/z (ES+) 309 (M++H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OCc3ccccc3)C2)C(=O)O1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (112 mg, 0.35 mmol) and Et3N (71 mg, 0.70 mmol) in CH2Cl2 (10 mL) was added CbzCl (71 mg, 0.7 mmol) at 0° C. Then the mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-benzyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (78 mg, 49%). 1H NMR (CDCl3): 1.63 (m, 3H), 2.07-2.26 (m, 2H), 2.54 (m, 3H), 2.21 (m, 2H), 3.09 (m, 1H), 3.68 (m, 1H), 3.99 (m, 1H), 4.93-5.09 (m, 4H), 5.09-5.18 (m, 1H), 6.87-7.03 (m, 2H), 7.14 (m, 1H), 7.31 (m, 6H).