Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:32])[C:15]([NH:17][C:18]2[N:22](C(OCCCl)=O)[N:21]=[C:20]([CH:29]3[CH2:31][CH2:30]3)[CH:19]=2)=[O:16])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O>[CH:29]1([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([C:11]3[CH:10]=[CH:9][C:8]([N:7]4[CH2:2][CH2:3][O:4][C:5]4=[O:6])=[CH:13][CH:12]=3)[CH3:32])[NH:22][N:21]=2)[CH2:31][CH2:30]1
Reactant: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OCCCl)c1ccc(NC(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1cc(C2CC2)n[nH]1)c1ccc(N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.9 %

Procedure:
431 mg (0.89 mmol) of 2-chloroethyl 5-{[2-(4-{[(2-chloroethoxy)carbonyl]amino}phenyl)propanoyl]amino}-3cyclopropyl-1H-pyrazole-1-carboxylate were dissolved in 3 ml of N,N-dimethylformamide and 124 mg (0.89 mmol) of potassium carbonate were added and the mixture stirred at room temperature for 19 hours. The reaction mixture was poured into 30 ml of methanol and stirred for 40 minutes, evaporated under vacuum, diluted with 40 ml of methanol and washed with a saturated aqueous ammonium chloride solution. The organic layer was further extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The crude was purified by chromatography on a silica gel column to afford 233 mg (77% yield) of the title compound. Analogously, but employing the suitable bisacylated amide derivatives, the following compounds can be prepared:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:17]2[CH:18]=[C:19]([C:22]([F:24])([F:25])[F:23])[CH:20]=[CH:21][C:16]=2[Br:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(C(F)(F)F)ccc1Br
Reactant: OCC1=CCN(Cc2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Br)c(OCC2=CCN(Cc3ccccc3)C2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)methanol (11.44 g) obtained in Example 50(2), 2-bromo-5-trifluoromethylphenol (16.04 g), DEAD (40% toluene solution, 11.06 mL) and triphenylphosphine (18.95 g) were dissolved in tetrahydrofuran (450 mL). The reaction solution was stirred at 50° C. overnight. Tetrahydrofuran was evaporated under reduced pressure, and the residue was purified by silica gel column (10% ethyl acetate/petroleum ether to 20% ethyl acetate/petroleum ether) to give the object product as a white solid (12.3 g, 49%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:26])([C:22]([F:25])([F:24])[F:23])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[CH3:13])[CH:8]=[CH:7][N:6]=1)=[O:4]>[OH-].[Li+].C1COCC1.CO>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:12]([CH3:13])[C:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1)([OH:26])[C:22]([F:23])([F:24])[F:25]
Reactant: COC(=O)c1cc(C(O)(C(C)c2ccc(F)cc2Cl)C(F)(F)F)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1ccc(F)cc1Cl)C(O)(c1ccnc(C(=O)O)c1)C(F)(F)F
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
4-[2-(2-Chloro-4-fluoro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridine-2-carboxylic acid methyl ester (24 mg) was dissolved in an aqueous lithium hydroxide solution (1N, 5 ml), THF (5 ml), and methanol (2.5 ml). The mixture was stirred for 10 min. LCMS indicated complete hydrolysis. Volatile solvents were evaporated. The residue was diluted with water (10 ml) and washed with diethyl ether. The aqueous layer was acidified to about pH 4 with HCl (aq., 1N) and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (22 mg) as a white solid. MS (m/e)=378.2 [M+H+].
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.FC1C=CC=CC=1.[Cl:17]Cl.[N+](C1C=CC=CC=1F)([O-])=O.[Cl:29][C:30]1[C:31]([F:39])=[C:32]([N+]([O-])=O)[CH:33]=[CH:34][CH:35]=1>>[CH:33]1[C:34]([Cl:17])=[CH:35][C:30]([Cl:29])=[C:31]([F:39])[CH:32]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: ClCl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1ccccc1F
Solvent: O=[N+]([O-])O
Solvent: Fc1ccccc1
Product: Fc1ccc(Cl)cc1Cl

Procedure:
Process for the preparation of 2,4-dichlorofluorobenzene in high yield and purity without intermediate separation of the isomers formed,(1) by nitrating 1 mol of fluorobenzene to give nitrofluorobenzene using a mixture comprising 35 to 65 parts by weight of 50 to 90% strength sulfuric acid and 35 to 65 parts by weight of a nitrating acid comprising 35 to 55 parts by weight of 95 to 98% strength sulfuric acid and 45 to 65 parts by weight of 96 to 98% strength nitric acid, with the proviso that 0.8 to 2.0 equivalents of the nitrating agent NO2+ are used per mol of fluorobenzene, at 20° to 90° C., (2) allowing 25 g to 150 g of chlorine, in the presence of a ring chlorinating catalyst, to act on each 100 g of the crude nitrofluorobenzene mixture obtained, at 20° to 100° C., and (3) allowing about 18 g to about 203 g of chlorine or equivalent amounts of a chlorine releasing agent to act on each 100 g of the crude chlorofluoronitrobenzene mixture obtained, after removal of the ring chlorinating catalyst, at 110° to 220° C., and isolating the 2,4-dichlorofluorobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:55]=[C:56]=[O:57])[CH2:53][CH3:54]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:56]([NH:55][CH2:52][CH2:53][CH3:54])=[O:57])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CCCN=C=O
Agent: O=C([O-])C(F)(F)F
Product: CCCNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and 1-propyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 0.86 (t, 7.5 Hz, 3H), 1.39 (s, 6H), 1.42 (m, 2H), 1.82 (m, 1H), 2.19-2.55 (m, 3H), 3.01 (t, 7 Hz, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H), 7.63 (d, 8 Hz, 1H). FAB-MS: calculated for C40H45N5O5 675; found 676 (M+H, 85%).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].C(O)CO>O>[F:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
A mixture of 24 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine, 70 parts of potassium hydroxide, 495 parts of 1,2-ethanediol and 80 parts of water is stirred and refluxed for 6 hours. The reaction mixture is cooled and 500 parts of water are added while stirring. The precipitated product is filtered off, washed with water and petroleumether and dried in vacuo at 80° C., yielding 16 parts of 6-fluoro-3-(4-piperidinyl)-1H-indole; mp. 224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[C:12](OCC)(=[O:14])[CH3:13]>>[C:12]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH2:1])[CH2:7]1)(=[O:14])[CH3:13]
Reactant: CCOC(C)=O
Reactant: Nc1cccc2c1CCNC2
Product: CC(=O)N1CCc2c(N)cccc2C1

Procedure:
A stirred mixture of 5-amino-1,2,3,4-tetrahydroisoquinoline (10.0 g) isopropenyl acetate (7.2 g) and ethyl acetate (150 ml) was heated under reflux for 24 hours. The cooled, filtered solution was evaporated under reduced pressure to a small volume. The residual oil was purified by elution from a silica column with ethyl acetate/methanol mixtures followed by crystallisation from ethyl acetate to give 2-acetyl-5-amino-1,2,3,4-tetrahydroisoquinoline as a white solid 6.6 g, m.p. 107°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][CH:19]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:40]>C(O)(=O)C.C(OCC)(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[NH:40][C:17]([CH:14]3[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:12][CH2:13]3)=[CH:18][C:19]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:23][CH:24]=1
Reactant: [NH4+]
Reactant: O=C(CC(C(=O)c1ccc(F)cc1)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1

Procedure:
The product of Step 2 was heated in 5 ml of acetic acid in the presence of 2.0 g ammonium acetate at 110° C. for 1.5 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water. The combined organic phases were washed with brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC over silica gel eluting with 2% MeOH/CH2Cl2 to give the desired product. H1-NMR (CDCl3, 300 MHz):1.67 (m, 2H); 2.02 (bd, 2h); 2.75-3.0 (m, 3H); 4.29 bd, 2H); 5.12 (s, 2H); 6.19 (d, 1H); 7.03 (t, 2H); 7.18 (dd, 2H); 7.25-7.39 (m, 6H); 8.39 (dd, 2H); 8.52 (bs, 1H). FAB ms: C28H26N3O2F:455; Observed: 456 (M++1).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.CO.B(F)(F)F.[CH3:27]COCC>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([O:19][CH3:27])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30×2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemether isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73°-74.5° C.; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a 1H NMR spectrum identical to that reported in the literature.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[O:11][CH3:12].C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:25](Cl)(=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[C:4]([O:11][CH3:12])[CH:5]=1)=[O:34]
Reactant: CCCCCCCCC(=O)Cl
Reactant: COc1cc(CN)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCC(=O)NCc1ccc(O)c(OC)c1
Reaction time: 0.5 h

Procedure:
58.5 parts of 4-hydroxy-3-methoxybenzylamine hydrochloride, 200 parts of benzene and 200 parts of water were charged into a reaction vessel equipped with a three-one motor the rotational frequency of which is variable and an outlet having a stopper at the bottom portion and stirred. 58 parts of potassium carbonate was added to the mixture and further 54 parts of pelargonoyl chloride was added dropwise to a resultant mixture at room temperature. In this state, the mixture was stirred for 3 hours until the end of the reaction. After the stirring was stopped and the mixture was allowed to stand for 30 minutes, the water layer in the lower layer was discharged from the bottom portion. The residue was distilled under a reduced pressure to remove solvent almost completely, thereby obtaining crude nonylic acid vanillylamide. As a result of quantitative analysis of a slight amount of product by HPLC, the purity of nonylic acid vanillylamide was determined to be 92.1%. The irritant nature thereof to skin, especially, to mucose was strong.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:35]([O:34][C:32]1[CH:31]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[CH:14]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
After a mixture of ethyl(E)-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (544 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred overnight at 50° C., and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystal obtained was filtered, and E-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoic acid (479 mg, yield: 93%) was obtained. This was recrystallized from ethanol. Melting point: 182–183° C.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7](=[CH2:26])[CH2:8][CH:9]1[NH+:21]([CH2:22][CH3:23])[C:12]2=[N:13][C:14]3[C:19]([N:20]=[C:11]2[N:10]1[CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3>C(#N)C>[CH2:24]([N:10]1[C:11]2=[N:20][C:19]3[C:14]([N:13]=[C:12]2[N:21]([CH2:22][CH3:23])[C:9]1=[CH:8][C:7]#[CH:26])=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:25]
Reactant: C=C(Cl)CC1N(CC)c2nc3ccccc3nc2[NH+]1CC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C#CC=C1N(CC)c2nc3ccccc3nc2N1CC
Reaction time: 0.02 h

Procedure:
A mixture of 2-(2-Chloro-2-propenyl)-1,3-diethyl-1H-imidazo[4,5-b]quinoxalinium perchlorate 2.00 g (0.005 mole) and dry acetonitrile (20 ml) is stirred astriethylamine (1.50 g) is added in one portion to give a clear solution from which solid soon begins to separate. After 1 minute, the solid is collected, washed with several small portions of acetonitrile and dried invacuum at room temperature. Yield 0.63 g (48%). m.w. 264. The elemental analysis, infrared and nuclear magnetic resonance spectral support the assigned structure.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@@H](O)CCCCC
Solvent: c1ccncc1
Product: C#C[C@H](CCCCC)OC(C)=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(S)-1-octyn-3-ol (100 g., 0.794 mole) is dissolved in pyridine (79 g., 1.0 mole) and acetic anhydride (81.6 g., 0.8 mole) is added dropwise with stirring during 1 hour. The temperature rises to 45° C. The solution is heated at 55° C. for 1 hour and then is cooled and poured into ice-cold 5% hydrochloric acid (200 ml.) providing a heterogeneous mixture which is extracted with ether. The organic extract is washed with water and saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. yields a residual oil which is distilled to give the title compound (106.4 g., 80%), b.p. 91°-92° C./15 mm.; [α]D26 -79° (C 3.0, CHCl3).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=4)[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(N(CC)CC)C>[Br:31][C:27]1[CH:26]=[C:25]([CH:20]2[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=3[C:17]3[N:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH3:36])=[CH:13][CH:12]=4)[N:24]=[CH:23][C:22]=3[CH2:21]2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2cccc(Br)c2)C3)cc1
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2cccc(Br)c2)C3)cc1
Yield: 44 %

Procedure:
This was synthesized by using 4-(6-(3-bromophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate and N-methylbutylamine and triethylamine as described in general procedure 2 to afford the desired product in 44% yield as a yellow solid. M.p.=66-68° C. 1H 400 MHz NMR (DMSO-d6) δ 9.60 (d, J=3.5 Hz, 1H), 9.36 (bs, 1H), 8.38-8.28 (m, 2H), 7.82 (d, J=8.6 Hz, 2H), 7.57-7.43 (m, 3H), 7.42-7.32 (m, 1H), 7.31-7.20 (m, 3H), 7.15-7.04 (m, 2H), 4.48-4.37 (m, 1H), 3.41-2.88 (m, 8H), 2.84 (d, J=4.7 Hz, 3H), 1.73-1.56 (m, 2H), 1.40-1.26 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). LCMS m/e 541 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 26.6 %

Procedure:
Triethylamine (1.18 mL, 8.5 mmol) was added to a mixture of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.1 mmol) and chloroform (200 mL). The resulting solution was chilled in an acetone/ice bath for 10 minutes. Benzenesulfonyl chloride (0.90 mL, 8.5 mmol) was slowly added over a period of 5 minutes. After 45 minutes 0.2 equivalents of triethylamine was added. After 6 hours the reaction mixture was washed with brine (2×250 mL) and with water (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from N,N-dimethylformamide. The recrystallized material and the filtrate were both slurried with methanol. The resulting solids were isolated by filtration, combined, and then dried in an Abderhalden drying apparatus overnight to provide 0.80 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a white solid, m.p. 180.6-182.0° C. Analysis: Calculated for C22H25N5O2S 0.25H2O: % C, 61.73; % H, 6.00; % N, 16.36; Found: % C, 61.79; % H, 6.04; % N, 16.43.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:25])(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc2ccccc2c1

Procedure:
Following the procedure described in example 1§B, but starting from 3-(2-naphtyl)propan-1-ol (11.7 mmol), triethylamine (2.5 mL), methanesulfonyl chloride (1.7 mL) and dichloromethane (50 mL), affords 1.7 g of 3-(2-naphtyl)propan-1-ol mesylate used without further purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O.[C:16](=O)([O-])[O-].[Na+].[Na+]>CO>[O:1]([CH3:16])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C([O-])[O-]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
5 g of D-Ribose was dissolved in 100 mL of methanol and cooled to 0° C. 0.5 mL of concentrated sulfuric acid was added and the solution was stored at −20° C. for 48 hrs. Solution was neutralized by passage through a bed of sodium carbonate and evaporated under vacuum to a viscous oil. Crude material was purified on a silica column eluting with 10% methanol in ethyl acetate to yield 2.1 grams of methyl β-D-ribofuranoside.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH:12]([O:16][CH3:17])[CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[B:19]1([OH:29])[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[CH2:21][O:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:28][C:26]2[CH:25]=[CH:24][C:23]3[B:19]([OH:29])[O:20][CH2:21][C:22]=3[CH:27]=2)=[N:4][C:5]([O:10][CH2:11][CH:12]([O:16][CH3:17])[CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB1OCc2cc(O)ccc21
Reactant: COCC(COc1nc(Cl)c(Cl)cc1C#N)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCC(COc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N)OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-neck-bottle purged and maintained with an inert atmosphere of nitrogen were placed a solution of 5,6-dichloro-2-(2,3-dimethoxypropoxy)nicotinonitrile (1.40 g, 4.59 mmol, 1.00 equiv, 95%) in DMSO (20 mL), benzo[c][1,2]oxaborole-1,5(3H)-diol (800 mg, 5.07 mmol, 1.10 equiv, 95%) and Cs2CO3 (1.88 g, 5.78 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The reaction mixture was then cooled and quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/petroleum ether (1:5). This resulted in 1.09 g (57%) of 5-chloro-2-(2,3-dimethoxypropoxy)-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile as a white solid. LC-MS (ES, m/z): 405 [M+H]+. 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.27 (1H, m); 8.61 (1H, m); 7.82 (1H, d, J=8.1 Hz); 7.34 (1H, m); 7.26 (1H, m); 5.00 (2H, s); 4.12-4.17 (1H, m); 3.97-4.03 (1H, m); 3.25-3.30 (1H, m); 3.17 (6H, s).