Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[CH3:20][O:21][CH2:22]Br>C1COCC1>[CH3:20][O:21][CH2:22][CH:15]1[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]1
Reactant: COCBr
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1COCCC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
To a solution of diisopropylamine (6.1 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1.6 M solution of n-butyllithium in hexanes (37 mL, 60 mmol). The resulting solution was cooled to −78° C. To it was added tetrahydro-4H-pyran-4-one (5 g, 50 mmol) followed by phosphorous hexamethyltriamide (10 mL, 55 mmol). After 10 min, a solution of bromomethyl methyl ether (25 g, 200 mmol) in THF (50 mL) was added. Stirring was continued at 0° C. for 1 h and at room temperature overnight. The reaction was quenched by addition of a saturated solution of ammonium chloride in water. The resulting solution was extracted with ether three times. The combined extracts were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 20% ether/petroleum ether afforded the desired product (0.9 g oil). 1H NMR (CDCl3) δ 4.2 (2H, m), 4.1 (3H, s), 3.6-3.4 (4H, m), 2.4-2.3 (3H, m).
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([C:8]([CH2:10]C)=O)[CH3:7].C[O-].[Na+].[C:15](O)(=O)C>CO>[CH3:15][C:2]1[C:1](=[O:5])[CH:6]([CH3:7])[CH:8]([CH3:10])[CH2:4][CH:3]=1
Reactant: CCC(=O)CC
Reactant: C/C=C/C=O
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=CCC(C)C(C)C1=O
Reaction time: 0.5 h

Procedure:
70 g of crotonaldehyde is dripped in the course of one hour into a mixture of 400 g of diethyl ketone and 10 g of a 30% solution of sodium methylate in methanol which is boiling under reflux and the reaction mixture is boiled for another half hour under reflux. The whole is neutralized with glacial acetic acid and the mixture obtained is filtered. 325 g of diethyl ketone is recovered by distillation of the filtrate; 55 g of 2,5,6-trimethyl-2-cyclohexen-1-one having a boiling point of from 74° to 76° C. at 12 mm Hg is obtained. The yield with reference to crotonaldehyde is 40%.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH2:34][CH2:33]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 164 mg (1.640 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 352 mg (47% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=S(=O)(CCl)c1ccc(F)cc1
Reactant: CN1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)cc(CS(=O)(=O)c3ccc(F)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A stirred mixture of 1-(5-chloro-2-nitrophenyl)-4-methylpiperazine (1.0 mmol) and chloromethyl-(4-fluorophenyl)sulfone (1.0 mmol) in THF is treated with 2.2 mL of a 1M KOt-Bu (2.2 mmol) solution in THF at −78° C., warmed to room temperature over a 2 h period, quenched with acetic acid and concentrated in vacuo. The resultant residue is partitioned between EtOAc and aqueous Na2CO3. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase is combined with the extracts, dried over Na2SO4 and concentrated to dryness in vacuo to afford the title product.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16]CC)=[O:15]>C(#N)C>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[O:1][CH2:13][C:14]([OH:16])=[O:15])=[O:5]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(C=O)c1O
Solvent: CC#N
Product: COc1cccc(C=O)c1OCC(=O)O

Procedure:
The starting product is 2-hydroxy-3-methoxy benzaldehyde, known commonly as o-vanillin. Alkylation is conducted by the already described method, using ethyl bromoacetate under reflux in acetonitrile. In this manner 2-formyl-6-methoxy-phenoxyacetic acid is obtained in the form of the ethyl ester. The oily crude product is saponified to give the corresponding acid in the form of a white crystalline solid. Melting point 118/119° C. NMR (DMSO-d6): 13 (b, 1H), 10.5 (s, 1H), 7.4/7.1 (m, 3H), 4.8 (s, 2H), 3.85 (s, 3H). IR (KBr, cm-1): 3100/2600, 1735, 1700. This is transformed into the corresponding oxime using hydroxylamine hydrochloride.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C[Si]([C:18]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19]1)(C)C.O>O1CCCC1>[CH3:3][Si:2]([CH2:3][Si:2]([CH:21]1[CH:20]=[CH:19][CH:18]=[CH:22]1)([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:4])([CH3:5])[CH3:4]
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
Chloro-2-indenyldimethylsilane (5.15 g, 0.025 mol.) according to Example 1 was dissolved in 10 ml of tetrahydrofuran. The solution was cooled to 0° C. and a solution of trimethylsilylcyclopentadienyllithium (3.60 g, 0.025 mol.) in 20 ml of tetrahydrofuran was added. Stirring was carried out for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the yellowish oil that remained was purified by means of column chromatography. The solvents were removed to yield 2.12 g (34%) of trimethylsilylcyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: ClC1C=C(NN=C(Cl)S(C)(=O)=O)C=CC=1.IC1C=CC(N2CCC=C(N3CCOCC3)C2=O)=CC=1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]3(N4CCOCC4)[C:55](=[O:66])[N:56]([C:59]4[CH:64]=[CH:63][C:62]([I:65])=[CH:61][CH:60]=4)[CH2:57][CH2:58][CH:53]3[C:52]([S:73]([CH3:76])(=[O:75])=[O:74])=[N:51]2)[CH:47]=[CH:48][CH:49]=1>C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:45]=[C:46]([N:50]2[C:54]3[C:55](=[O:66])[N:56]([C:59]4[CH:60]=[CH:61][C:62]([I:65])=[CH:63][CH:64]=4)[CH2:57][CH2:58][C:53]=3[C:52]([S:73]([CH3:76])(=[O:75])=[O:74])=[N:51]2)[CH:47]=[CH:48][CH:49]=1
Reactant: CS(=O)(=O)C1=NN(c2cccc(Cl)c2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Agent: CS(=O)(=O)C(Cl)=NNc1cccc(Cl)c1
Agent: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7a-morpholin-4-yl-1,3a,4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
Reaction SMILES: CO.CN(C)C=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])([O-])=O>Cl.O.[Fe]>[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1ccccc1Sc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: N#Cc1ccccc1Sc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a mixture of 40 ml of concentrated hydrochloric acid, 60 ml of methanol and 40 ml of N,N-dimethylformamide was suspended 2-(2-nitrophenylthio)benzonitrile followed by addition of 8.64 g of powdered iron en bloc, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was then diluted with water and the precipitate was extracted with ether. This extract was washed with aqueous sodium hydrogen carbonate solution and water in that order and dried over magnesium sulfate. The solvent was then distilled off and the residue was subjected to column chromatography (Wakogel C200) using ethyl acetate-n-hexane (1:4) as the eluent. The crystals obtained were recrystallized from ethyl acetate-n-hexane to give 4.8 g of the title compound as white crystals, m.p. 86°-89° C.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH:40]([CH3:49])[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH:40]([CH3:49])[CH2:41][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:3][CH:4]=2)[CH:17]=1
Reactant: CC(Cl)C(=O)N1CCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OC(C)CN3CCCCC3)cc2)c1
Yield: 29.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphth alen-2-yl ester (30 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.4 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C(OCC)=O)C(OCC)=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C@H:22]([C:27]([OH:29])=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24].[OH-].[Na+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=NOC(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
A solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.9 g.) in tert-butyl alcohol (5 ml.) was added to a solution of L-isoleucine (656 mg.) in a 1N sodium hydroxide aqueous solution (5.0 ml.). The mixture was stirred for 3 hours at room temperature. The tert-Butyl alcohol was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was washed with ether, adjusted to pH 3 with a 5% citric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give N-tert-butoxycarbonyl-L-isoleucine (1.2 g.), oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29]C=[CH:27][CH:26]=2)=[CH:19][CH:18]=1.[CH3:34][O-].[Na+]>CN(C)C=O>[ClH:16].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:31])[C:24]([C:25]2[CH:26]=[CH:27][C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:29][CH:30]=2)=[CH2:34])=[CH:32][CH:33]=1
Reactant: O=C(Cc1ccccc1)NCc1ccc(Cl)cc1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C(=O)NCc1ccc(Cl)cc1)c1ccc(-c2ccccc2N2CCN(C)CC2)cc1
Product: Cl
Yield: 24.5 %

Procedure:
A mixture of 2-(4-methylpiperazin-1-yl)benzaldehyde (0.091 g, 0.45 mmol), N-(4-chlorobenzyl)-phenylacetamide (0.127 g, 0.49 mmol) and N,N-dimethylformamide (2 mL) was treated with anhydrous sodium methoxide (0.072 g, 1.34 mmol) under a nitrogen atmosphere as above to give the title product as an amorphous solid, (0.029 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Li+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: O=S([O-])c1ccc(CN2CCCCC2)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCCCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv), lithium 4-(piperidin-1-ylmethyl)benzenesulfinate (4.8 g, 19.59 mmol, 2.00 equiv) and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water (150 mL) was added and the resulting solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4 g (53%) of methyl 4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 510 [M+CH3CN+H]+, 469 [M+H]+, 120.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16](I)[C:11]=3[S:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[N:21]1([CH2:26][C:27]([NH2:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1.P([O-])([O-])([O-])=[O:31].[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.O1CCOCC1>[C:3]([OH:19])(=[O:28])[CH3:4].[C:27]([OH:28])(=[O:31])[CH3:26].[C:3]([OH:19])(=[O:28])[CH3:4].[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][S:10][C:11]=2[C:16]([NH:29][C:27](=[O:28])[CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][N:14]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1N
Reactant: NC(=O)CN1CCCC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)O
Product: COc1cc(-c2csc3c(NC(=O)CN4CCCC4)cnc(N)c23)ccc1N
Temperature: 110 °C

Procedure:
A schlenck tube was charged with 3-(4-amino-3-methoxyphenyl)-7-iodothieno[3,2-c]pyridin-4-amine (199 mg, 0.5 mmol), 2-pyrrolidin-1-ylacetamide (0.6 mmol), copper(I) iodide (4.8 mg, 0.025 mmol), potassium phosphate (225 mg, 1.06 mmol). Evacuated under vacuum and back filled with nitrogen. trans-Cyclohexane-1,2-diamine (6.5 uL, 0.05 mmol) and dioxane (1 mL) was added. The reaction tube was sealed and heated at about 110° C. overnight. The solvent was removed and the crude product was purified by reverse phase preparative HPLC to give the title compound as the tri-acetate salt. LCMS (Conditions a): MH+=398.2, Rt=1.55 min. (154 mg, 45%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][O:27][N:28]3[C:32](=[O:33])[C:31]4[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]3=[O:38])[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:26])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2c(N)nc3ccccc3c21
Product: CC(C)(C)OC(=O)NCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Yield: 66.7 %

Procedure:
Using the general method of Examples 43-68 Part C, tert-butyl[2-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (7 g, 19 mmol)) was reacted with N-hydroxyphthalimide (3.65 g, 22.3 mmol) to provide 6.37 g of tert-butyl (2-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}ethyl)carbamate as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43]Cl)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]2)[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Product: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OCc3ccccc3)c3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 1-benzyloxy-3-chloromethyinaphthalene there was obtained tert-butyl (3RS,4RS)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate as a pale yellow amorphous powder; MS: 582 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([OH:11])(=O)[CH3:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH:27]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1)#[N:13].C([O-])(=O)C.[NH4+:42]>CCCCCC.CC(C)=O>[C:8]([NH:42]/[C:32](/[CH2:33][CH2:34][CH2:35][CH3:36])=[C:27](/[CH2:26][C:23]1[CH:24]=[N:25][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]#[N:13])=[CH:21][CH:22]=1)\[C:28]([O:30][CH3:31])=[O:29])(=[O:11])[CH3:9]
Reactant: [NH4+]
Reactant: CC(=O)O
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCC/C(NC(C)=O)=C(\Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Process 2: A toluene (50 mL)-acetic acid (7 mL) solution of methyl 2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-3-oxoheptanoate (3.50 g, 10.0 mmol) and ammonium acetate (23.2 g, 300 mmol) was refluxed for 1 hour under heating. The solvent was distilled off and the residues were added anhydrous acetic acid (51.2 g) and acetic acid (5.7 g) under room temperature, and the reaction solution was stirred at 0° C. for 30 minutes, and then stirred at 70° C. for 1.5 hours. The reaction solution was added aqueous sodium bicarbonate, and extracted with chloroform. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (hexane/acetone=5:1), to obtain methyl(Z)-3-acetamido-2-{[6-(2-cyanophenyl)pyridin-3-yl]methyl}-2-heptenoate (0.975 g, 25%) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][N:13]=[C:12]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:28]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([O:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:12]2[C:11]3[CH:20]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=[CH:9][C:10]=3[S:14][N:13]=2)=[O:38])=[CH:40][CH:41]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCCNc1nsc2ccc(-c3ccccc3)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)NCCCNc2nsc3ccc(-c4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
The crude N1-(5-Phenylbenzo[d]isothiazol-3-yl)propane-1,3-diamine mixture (˜100 mg, 0.20 mmol) was dissolved in anhydrous methylene chloride with triethylamine (0.3 mL, 0.24 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of 4-butoxybenzoyl chloride (51 mg, 0.24 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and then washed successively with saturated sodium bicarbonate solution and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by prep-scale reverse phase high performance liquid chromatography to yield 4-butoxy-N-(3-(5-phenylbenzo[d]isothiazol-3-ylamino)propyl) benzamide (13 mg). 1H NMR (300 MHz, DMSO-d6): 8.23 (s, 1H), 8.17 (t, 1H), 7.98 (d, 1H), 7.76-7.82 (m, 4H), 7.50 (t, 3H), 7.37-7.40 (m, 1H), 6.97 (d, 2H), 4.00 (t, 2H), 3.50 (q, 2H), 3.39 (q, 2H), 1.90-2.00 (m, 2H), 1.62-1.78 (m, 2H), 1.40-1.49 (m, 2H), 0.96 ppm (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].Cl>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:25]
Reactant: CCNCC
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Agent: Cl
Product: CCN(CC)CCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 31 %

Procedure:
The procedure of Example 38 was followed starting with (H) of Example 38 (3.0 g, 8.7 mmol) and using diethylamine in place of dipropylamine to produce 1.2 g (31% yield) of the title compound as the HCl salt, mp 205°-207° C. IR(KBr): 3400, 1605 cm-1. MS: 381(MH+). 1H NMR (CD3OD): δ 8.14-7.04 (m, 10H), 4.14 (t, J=5.2 Hz, 2H), 3.25 (m, 6H), 1.98 (m, 4H), 1.34 (m, 6H).