Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH2:37][CH2:38][CH3:39])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCI
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added 1-iodopropane (0.036 mL) at 50° C., and the mixture was stirred overnight. Water was added to the reaction mixture, and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The resulting semi-purified material was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole (28 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:21])=[O:20])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Cc1onc(N)c1Br
Product: Cc1onc(NS(=O)(=O)c2cccc3ccccc23)c1Br
Yield: 51 %

Procedure:
N-(4-Bromo-5-methyl-3-isoxazolyl)-1 -naphthalenesulfonamide was prepared from 3-amino-4-bromo-5-methylisoxazole and 1-naphthalenesulfonyl chloride as described in Example 2 in 51% yield. Recrystallization from ethyl acetate/hexanes gave a crystalline solid, m.p. 167°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 590.3 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)CCC>>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[N:4][CH:3]=2)[CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2cccnc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-(tri-n-butylstannyl)pyridine. The title compound (87 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:32]=[CH:31][C:18]4[N:19]([CH2:28][CH2:29]O)[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.S(Cl)([Cl:42])=O>ClC(Cl)Cl>[Cl:42][CH2:29][CH2:28][N:19]1[C:18]2[CH:31]=[CH:32][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][N:8]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:13][CH2:12]3)=[CH:16][C:17]=2[N:21]=[C:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(Cl)Cl
Reactant: OCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCCn1c(-c2ccccc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reaction time: 0.33 h

Procedure:
A stirred mixture of 5.03 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazole-1-ethanol and 75 parts of trichloromethane is acidified by the introduction of gaseous hydrogen chloride. Then there are added dropwise 2.4 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 20 minutes at reflux. The reaction mixture is evaporated. 100 Parts of water are added to the residue and the whole is alkalized with sodium hydrogen carbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 3.1 parts of 1-(2-chloroethyl)-5-[4-(diphenylmethyl)-1-piperazinylmethyl]-2-phenyl-1H-benzimidazole; mp. 173.8°-179.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](I)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCI
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)cc1

Procedure:
p-Chlorophenol (10 g., 0.077 mole), ethyl iodide (13.1 g., 0.084 mole) and anhydrous potassium carbonate (10.6 g., 0.077 mole) were combined in 130 ml. of acetone and the stirred mixture heated to reflux for 16 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 300 ml. of chloroform, washed in sequence with two 120 ml. portions of 1 N sodium hydroxide, 50 ml. of brine and 50 ml. of water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 4-ethoxyphenyl chloride as an oil [10.5 g.; pnmr/CDCl3 /delta 1.4 (t, 3H), 4.0 (q,2H), 6.6-7.3 (m, 4H)].
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1>[C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCc1ccc(O)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
4-(4-Hydroxyphenyl)butylamine hydrobromide (4) (197 g, 0.80 mole), water (1 L), 1,4-dioxane (1 L) and sodium bicarbonate (336 g, 4 mole) were combined and stirred while cooled in an ice-methanol cooling bath. Benzyl chloroformate (141 mL, 0.96 mole) was dripped in over 5 min. at −2° C. with no appreciable exotherm observed. This was stirred and allowed to warm to room temperature as the cooling bath thawed overnight. An additional quantity of benzyl chloroformate (8 mL, 0.54 mol) was dripped in and this was allowed to stir for 2 h. The product mixture was then evaporated to approximately 500 mL and transferred to a 2 L separatory funnel with ethyl acetate while decanting away from the solids. The aqueous layer was extracted with ethyl acetate (3×1 L). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to afford 265 g of the crude product. A portion of the crude product (130 g) was chromatographed (silica gel, 5:1 hexanes/ethyl acetate) using toluene to load the column. The remaining crude material was crystallized from 1:1 toluene/heptane. This material was suction filtered to collect the solid and washed with 1:1 toluene/heptane. This material was vacuum desiccated at 45° C. for 2 h. The combined yield of compound (29) was 150 g (62%) of a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ 1.43-1.65 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 4.78 (br s, 1H), 5.09 (s, 2H), 5.77 (s, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 7.34 (s, 5). CI MS m/z=300 [C18H21NO3+H]+.
Reaction SMILES: C(OC1[O:5][CH:6]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:18]3[CH:36]=[CH:35][C:21]([O:22][C:23]4[CH:24]=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:20][CH:19]=3)[CH:10]=2)N=1)C.[BH4-].[Na+].CC[OH:41].C1COCC1>>[OH:41][CH:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH:30]=3)[C:28]#[N:29])=[CH:35][CH:36]=2)[CH:10]=1)[CH2:6][OH:5]
Reactant: CCOc1nc(-c2cn(-c3ccc(Oc4ccc(C(F)(F)F)c(C#N)c4)cc3)c3ccccc23)co1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)CO)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of compound 50 (0.15 g) and NaBH4 (100 mg) in 10 mL of EtOH/THF (1/1) was shaken at room temperature for 2 hours. The reaction was quenched with water, extracted with TCM and purified by column (MeOH/TCM 0.5/10, Rf 0.5) to give the title compound 51 as a white solid (90 mg, 70%): 1H-NMR (400 MHz, CD3OD) δ: 7.83 (d, 1H, 8.9 Hz), 7.76-7.78 (m, 1H), 7.6-7.63 (m, 2H), 7.57 (s, 1H), 7.54-7.56 (m, 1H), 7.49-7.5 (m, 1H), 7.39-7.42 (m, 1H), 7.15-7.3 (m, 4H), 4.68-4.71 (m, 1H), 3.97-4.02 (m, 1H), 3.8-3.84 (m, 1H); LC/MS: m/z=461.0 [M+Na+] (Calc: 438.4).
Reaction SMILES: [CH:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:15]>C(Cl)Cl>[CH:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][Br:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1C1CCCC1
Solvent: ClCCl
Product: BrCc1ccccc1C1CCCC1
Yield: 93 %

Procedure:
According to example 17, 5.47 g of 2-cyclopentylbenzyl alcohol was treated with 1.03 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 6.9 g (93%) of 2-cyclopentylbenzyl bromide as a clear liquid.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])[CH3:2].CC(C)=[O:17].I([O-])(=O)(=O)=O.[Na+].C(Cl)Cl>O>[CH2:1]([S:3]([CH2:4][C:5](=[C:9]1[NH:14][CH2:13][CH2:12][CH2:11][S:10]1)[N+:6]([O-:8])=[O:7])=[O:17])[CH3:2]
Reactant: CC(C)=O
Reactant: CCSCC(=C1NCCCS1)[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCS(=O)CC(=C1NCCCS1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.34 g of 25 and 10 ml of acetone was added all at once to a solution of 2.25 g of sodium periodate in 15 ml of water. The resulting exothermic reaction was controlled between 25° and 35° by cooling. The mixture then as stirred at room temperature for 90 minutes, then was poured into a mixture of water and methylene chloride. The separated organic phase was washed with saturated sodium thiosulfate solution, and saturated sodium chloride. It then was dried (MgSO4) and the solvent evaporated under reduced pressure to give an oil, which was triturated with ether to give a yellow solid. This was chromatographed by a preparative thin layer chromatographic technique, on silica gel and using a mixture of methanol (2%) in methylene chloride as eluent, to give 26, as a yellow solid, m.p.: 102°-104°.
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH2:34][F:35])=[O:31]>O>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:30]([O:32][CH2:33][CH2:34][F:35])=[O:31])[CH2:3]3)[CH2:8][CH2:9]2)[C@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]2[NH:15]1
Reactant: O=C(Cl)OCCF
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3aS,7aS)-1-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (1 mmol) in water (10 mL) was added with potassium carbonate (4.0 equiv.) followed by 2-fluoroethyl chloroformate (1.2 equiv.) at room temperature and stirred at rt for 30 minutes. Extracted in ethyl acetate (2×10 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography by eluting with methanol in ethyl acetate (0 to 5%) to afford the title compound (93 mg). 1H NMR (CD3OD, 400 MHz): δ 4.65 (t, 2H), 4.53 (t, 1H), 4.34 (m, 1H), 4.27 (m, 1H), 3.62 (m, 3H), 3.48-3.37 (m, 2H), 3.25 (t, 1H), 3.03-2.90 (m, 3H), 2.77 (br t, 1H), 2.47 (m, 3H), 1.98-1.60 (br m, 9H), 1.43 (m, 3H), 1.11 (s, 3H); MS (M+1): 397.30.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A mixture of the resulting thiourea (19.6 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.12 g, 42.3 mmol), and triethylamine (6.5 mL) in tetrahydrofuran (200 mL) was stirred at 50° C. for 3 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (15.4 g, 35.9 mmol, 71% in 2 steps).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:9][C@H:10]1[CH:14]=[CH:13][C@H:12]([CH3:15])[N:11]1[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C[C@H]1C=C[C@H](C)N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1[C@@H](C)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Ethyl 2-bromopropionate (9.8 g.) was added, dropwise, to a stirred mixture of trans-2,5-dimethyl-3-pyrroline (5 g.), potassium carbonate (6.9 g.), and dimethylformamide (12.5 cm3) maintained below 30° C. by external cooling. After addition was complete the mixture was stirred at room temperature overnight. The mixture was then diluted with water (25 cm3) and the product extracted into ether. The ether extract was dried and evaporated to give an oil which was distilled under vacuum to give ethyl 2-(trans-2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)propionate (2.5 g.) b.p. 90°-97° C./15 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21].Cl>C(#N)C.O>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:1][C:2]2[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(CNc2cccc(S(=O)(=O)O)c2)cc1
Yield: 57.3 %

Procedure:
After 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of warm (65° C.) water and 83.0 (0.61 mole) of sodium acetate trihydrate in 75 ml of acetonitrile was combined and the temperature stabilized at approximately 68°-70° C., 43.2 g (0.20 mole) of 4-nitrobenzyl bromide in 85 ml of warmed acetonitrile was added dropwise over 70 minutes. The orange-red solution was then refluxed for 2 hrs, then acidified with 42 ml of conc. HCl over 40 minutes while simultaneously distilling off 110 ml of acetonitrile. The mixture was filtered hot (70° C.) which gave a light yellow powder. The powder was slurried in 275 ml of hot (75° C.) water for 20 minutes and then filtered. The slurrying process was repeated with water and then with methanol which gave a cream-colored powder. The cream-colored powder was dried in vacuo overnight at 50° C. to afford 35.33 g (57.3% yield) of purified 3-(((4-nitrophenyl)methyl)amino)benzenesulfonic acid as a cream-colored powder having a melting point greater than 275° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][NH:28][CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30]2)[O:18]1.I[CH:46]([CH3:48])[CH3:47]>CC#N.CCOC(C)=O>[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]2[C@@H:19]([CH2:27][N:28]([CH:46]([CH3:48])[CH3:47])[CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:30]2)[O:18]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
K2CO3 (528.92 mg, 3.83 mmol) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (1.00 g, 1.91 mmol) and 2-iodopropane (0.57 ml, 5.74 mmol) in MeCN and stirred at 95° C. in a sealed tube for 18 hours. The reaction mixture was diluted with EtOAc (20 ml), filtered and evaporated to dryness. Purification by silica gel chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-5:95) gave the desired product as a colourless oil, 700 mg (65%); MS (ESI+) for C30H40N6O5 m/z 565.70 [M+H]+; HPLC purity 96% (ret. time, 1.48 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=3.5 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.44-7.29 (m, 5H), 6.03 (t, J=2.2 Hz, 1H), 5.62-5.42 (m, 3H), 5.10 (d, J=3.3 Hz, 2H), 5.06-4.92 (m, 1H), 4.26 (dt, J=9.9, 3.4 Hz, 1H), 3.46-2.84 (m, 2H), 2.88-2.61 (m, 1H), 2.51 (ddd, J=14.0, 9.1, 7.5 Hz, 1H), 2.33-2.15 (m, 2H), 2.50-2.13 (m, 2H), 2.16-1.74 (m, 4H), 1.60 (s, 3H), 1.43-1.35 (m, 4H), 0.96 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:12][C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]=1[CH3:1]
Reactant: Cc1cccc2c1OCCO2
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2c1OCCO2
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
In 30 ml of acetic acid, was dissolved 10 g of 5-methyl-1,4-benzodioxane and 11.8 g of bromine was added dropwise to the solution. After stirring for 30 minutes, the reaction mixture was poured into a sodium hydrogen sulfite aqueous solution and extracted with diethyl ether. The resulting diethyl ether layer was washed successively with a sodium hydrogen carbonate aqueous solution, water and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 15.0 g of 6-bromo-5-methyl-1,4-benzodioxane (bp. 126°-135° C. (7 mmHg)).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=1>C(OCC)(=O)C>[CH3:11][C:12]([NH:13][C:9](=[O:10])[CH3:8])([CH3:15])[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC1=NC(C)(C)CO1
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)(C)COc1ccccc1
Temperature: 220 °C

Procedure:
A mixture of phenol (33.2 g) and 2,4,4-trimethyloxazoline (18.1 g) was heated in a stirred pressure vessel at 220° C. for 48 hours. The oil obtained on cooling was dissolved in ethyl acetate, washed with 5M sodium hydroxide solution, water, brine, then dried and evaporated to give an oil which was distilled under high vacuum to give N-(1,1-dimethyl-2-phenoxyethyl)acetamide, b.p. 115-122° C. at 0.67 mbar.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(O)cc1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
Methyl 4-hydroxy-2-methyl-5-nitrobenzoate (12.9 g) was dissolved in dimethylformamide (200 ml), and thereto were added potassium carbonate (20.1 g) and benzyl bromide (13.7 g), and the mixture was stirred at 70° C. for 4 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The obtained organic layer was washed with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and the organic layer was concentrated under reduced pressure. The obtained solid was washed with hexane/ethyl acetate=10/1 to give the title compound (13 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:11]=2[C:12]#[N:13])[CH:5]=[N:6][C:7]=1[F:8].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[C:12]([C:11]1[CH:14]=[C:15]([CH:16]=[CH:17][C:10]=1[O:9][C:4]1[CH:5]=[N:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:18][O:19][C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1)#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cnc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-((5,6-difluoropyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile, NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.