Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1.[F:21][C:22]([F:35])([F:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][N:14]([C:31](=[O:32])/[CH:30]=[CH:29]/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:34])([F:35])[F:21])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of methyl 2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (400 mg, 1.46 mmol) in anhydrous CH2Cl2 (10 mL) was added (E)-3-(2-(trifluoromethyl)phenyl)acrylic acid (315 mg, 1.46 mmol), HOBt (394 mg, 2.92 mmol), EDCI (576 mg, 2.92 mmol) and DIEA (942 mg, 7.30 mol) at 0° C. and then stirred overnight at rt under N2. Then the reaction mixture was washed with 1 N aq HCl and water. The organic layer was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by preparative TLC to give (E)-methyl 2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (328 mg, 49%). 1H NMR (CDCl3): 1.58 (m, 4H), 1.97 (m, 3H), 3.91 (m, 3H), 4.15 (m, 1H), 4.40 (m, 1H), 6.85 (m, 1H), 6.98 (m, 1H), 7.48 (m, 1H), 7.56 (m, 1H), 7.72 (m, 1H), 7.99 (m, 2H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3.[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:2]4[CH:3]=[CH:4][C:5]5[C:6]6[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=6)[CH2:12][C:13]=5[CH:1]=4)=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc4c(c3)Cc3ccccc3-4)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)Cc4ccccc4-5)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.08 mmol), 0.2 mL of t-butanol, and potassium t-butoxide (27 mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 26 mg (82%) of the title compound as an off-white solid. mp 175° (decomp). FDMS: m/e=393.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)n2)CC1
Temperature: 0 °C
Yield: 49 %

Procedure:
2,6-Dichloro-3-nitropyridine E-3.1″(1.5 g; 7.151 mmol) is suspended in NMP and cooled to 0° C. DIPEA (2.31 ml, 14.3 mmol) and benzylamine (800 μl; 7.47 mmol) are added, the reaction mixture is stirred at RT. To this suspension 1-methylpiperazine (875 μl; 7.87 mmol) is added and the resulting mixture is stirred for 16 h at 50° C. The crude intermediate is purified using reversed phase chromatography (prep. HPLC1). The product containing fractions are combined and freeze-dried (Yield: 49%; 1.144 g; 3.494 mmol)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([OH:25])=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1.[ClH:27].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][CH2:11][C:6]=2[C:5]2[C:12]([O:25][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][O:28][CH2:33][CH2:32]3)=[CH:13][C:14]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[CH:15][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCCS1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCCS1

Procedure:
The benzopyran of Example 25 is reacted with γ-morpholinobutyric acid, hydrochloride salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9](OC1C=CC([N+]([O-])=O)=CC=1)=[O:10].C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1>C(Cl)Cl.CO>[Cl:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([N:41]3[CH2:46][CH2:45][N:44]([C:9]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)=[O:10])[CH2:43][CH2:42]3)=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccccn1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 78, 2-aminopyridine (142 mg, 1.51 mmol), 4-nitrophenyl chloroformate (304 mg, 1.51 mmol), diisopropyl(ethyl)amine (650 mg, 5.05 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (250 mg, 1.01 mmol) are reacted affording the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][OH:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:10]([O:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:9])([CH3:8])[CH3:1])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C#CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCC#CC(C)(C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
100 g (0.78 mol) of 5-methylhex-3-yne-1,5-diol were dissolved in 800 ml of dichloromethane and cooled to 0° C. 113 ml (1.11 mol) of acetic anhydride were added in one portion. 127 ml (1.25 mol) of triethylamine were cooled to 0-2° C. and added within 20 min. The reaction mixture was stirred at 0° C. for 2 h. The cooling was removed and the reaction mixture was stirred a 20° C. for 16 h. The mixture was cooled to 0° C. and 1200 ml of a 5% hydrochloric acid solution were added, in the course of which the temperature of the reaction mixture was kept below 5° C. The mixture was extracted three times with 150 ml each time of tert-butyl methyl ether (MTBE), and the combined organic phases were stirred four times with 400 ml each time of 5% aqueous sodium hydrogen carbonate solution for 1 h each time, until no further evolution of gas was observable in each case. The organic phase was washed with 1 l of demineralized water and dried over sodium sulfate, and the solvent was removed. This gave 122.21 g (yield 92%) of a clear, dark yellow liquid. The purity was determined by gas chromatography to be 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[I:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:33]([C:30]2[CH:31]=[CH:32][C:27]([I:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(I)cc1
Yield: 52.3 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 175 mg, 0.58 mmol) in THF. 153 mg (53%) of 100 was obtained as a pale yellow solid.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].Cl.ClC[C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[CH3:22]O>>[N:21]1([CH2:22][O:2][N:3]2[C:4](=[O:13])[C:5]3[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:8])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CO
Reactant: ClCc1ncc[nH]1
Agent: Cl
Agent: [Na]
Product: O=C1c2ccccc2C(=O)N1OCn1ccnc1

Procedure:
5.1 g sodium salt of N-hydroxyphthalimide and 1.9 g 2-chloromethyl imidazole hydrochloride (Journal of Chem. Soc. 1965,4577) are stirred at room temperature in dry methanol for 2 hours. The solvent is distilled off in vacuo and the residue treated with aqueous sodium bicarbonate and extracted 3 to 4 times with chloroform. The combined organic layers are dried over sodium sulfate, filtered and evaporated to dryness 1.7 g of 2-(1H-Imidazol-1-yl-methoxy)-1H-isoindole-1,3(2H)dione remains as crystalline solid with a melting point of 158°-160° C.
Reaction SMILES: [I:1]I.N(OC(C)(C)C)=O.N[C:11]1[C:12]([Cl:21])=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=[O:15].N(OCCCC)=O>CS(C)=O.O>[Cl:21][C:12]1[C:11]([I:1])=[CH:19][C:18]([Cl:20])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: II
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: CC(C)(C)ON=O
Agent: CCCCON=O
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Cl)cc(I)c1Cl
Temperature: 35 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
In a flask 48.35 grams (0.191 mole) of iodine was dissolved in 90 mL of dimethyl sulfoxide. To this solution was added 29.47 grams (0.286 mole) of tertiary butyl nitrite. A solution of 39.25 grams (0.191 mole) of 3-amino-2,5-dichlorobenzoic acid in 130 mL of dimethyl sulfoxide was added dropwise to the solution of iodine and butyl nitrite. During this addition the temperature rose from 20° C. to 50° C., at which temperature the addition was stopped until the reaction mixture had cooled to 35° C. The addition was then completed. When the addition was complete, the reaction mixture was stirred for approximately 16 hours, then poured into water, and this mixture was extracted with ethyl acetate. The extracts were combined and washed with an aqueous solution of sodium hydrogen sulfite and finally with water. The combined extracts were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, yielding 51.34 grams of 2,5-dichloro-3-iodobenzoic acid as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:30])[CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:31](OC(=O)C)(=O)[CH3:32].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:31][C:32]1[O:1][C:2]2[C:3]([C:9](=[O:30])[CH:10]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c2cccc(C)c2o1
Temperature: 25 °C

Procedure:
27.5 g (67 mmol) of 1-(2-hydroxy-3-methylphenyl)-2-(triphenylphosphoranylidene)ethanone are heated to reflux in 200 ml of absolute toluene. 13.7 g (134 mmol) of acetic anhydride and 11.1 g (141 mmol) of pyridine are slowly added dropwise to this solution. The reaction mixture is then heated under reflux for 6 h. After cooling to room temperature, the solution is washed with saturated sodium carbonate solution and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate 7:3→4:6). 7.5 g (64% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46]([NH:1][C@@H:2]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24]C(O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.ClC1C=CC(C2CCNCC2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[C:17]=3[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Fc1ccc(N2CCN(CCc3[nH]nc4c3CCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 2-(4,5,6,7-tetrahydro-2H-indazol-3-yl)acetic acid obtained in Starting Material Synthesis Example 2 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Staring Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2H-indazole is obtained.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][Mg]Br.O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[CH3:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in tetrahydrofuran (5 mL) was added methylmagnesium bromide (3M diethyl ether solution, 450 μL) at 0° C., and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (83.0 mg, yield 40%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 481 (MH+).
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[OH-:78].[Na+].[CH2:80]1[O:83][CH:81]1[CH3:82]>>[CH3:1][CH:2]([OH:7])[CH2:3][O:70][CH2:69][C@H:28]1[O:29][C@@H:30]2[O:35][C@H:36]3[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]4[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]5[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]6[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]7[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]8[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]1[C@H:32]([OH:33])[C@H:31]2[OH:34])[O:20][C@@H:19]8[CH2:71][O:72][CH2:4][CH:5]([OH:78])[CH3:6])[O:11][C@@H:10]7[CH2:73][O:74][CH2:14][CH:9]([OH:8])[CH3:10])[O:7][C@@H:2]6[CH2:1][O:77][CH2:28][CH:27]([OH:26])[CH3:32])[O:56][C@@H:55]5[CH2:63][O:64][CH2:37][CH:36]([OH:35])[CH3:41])[O:47][C@@H:46]4[CH2:65][O:66][CH2:19][CH:18]([OH:17])[CH3:23])[O:38][C@@H:37]3[CH2:67][O:68][CH2:80][CH:81]([OH:83])[CH3:82]
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Reactant: CC1CO1
Reactant: [OH-]
Agent: [Na+]
Product: CC(O)COC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCC(C)O)O[C@@H]7COCC(C)O)O[C@@H]6COCC(C)O)O[C@@H]5COCC(C)O)O[C@@H]4COCC(C)O)O[C@@H]3COCC(C)O
Reaction time: 5 h

Procedure:
β-Cyclodextrin (500 g hydrate, i.e., 432 g anhydous, 0.382 mole) was as above dissolved in a solution of sodium hydroxide (45 g, 1.1 mole in 750 mL distilled water, i.e., 5.7% W/W) and under the same conditions as above treated with propylene oxide (260 mL, 217 g, 3.73 mole). The reaction mixture was left for five hours in an ice bath and kept at room temperature for two days. After processing similar to that described above and including extraction of oligopropylene glycols with acetone a white powder of hydroxypropyl-β-cyclodextrin (490 g) was obtained.
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].Cl>CO>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Temperature: 150 °C
Yield: 79.7 %

Procedure:
To a solution of 4.3 ml of 0.5 M sodium methoxide in methanol was added 75 mg of 4-mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 181 mg of glycine. The mixture was heated to 150° C. for 10 minutes using a CEM Discover microwave reactor (City, State). The resultant solution was cooled, and acidified with 1N HCl solution to produce a yellow precipitate. The precipitate was collected by filtering the solution through a (medium) porous buchner filter funnel, and triturated with methanol to give 68 mg of product; MS (−): m/z 353.02 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[CH2:16]([O:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>C1COCC1>[CH2:16]([O:18][C:19]1[S:20][C:21]([S:10]([NH:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:15])(=[O:12])=[O:11])=[CH:22][CH:23]=1)[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOc1cccs1
Solvent: C1CCOC1
Product: CCOc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of 4-chloroaniline (0.99 g, 7.8 mmole) in 30 ml of anhydrous THF at -78° C. under nitrogen was added chlorosulfonylisocyanate (1.09 g, 7.8 mmole). This mixture was stirred at -78° C. for 1 hr. 2-Ethoxythiophene (1 g, 7.8 mmole) was added, the ice bath was removed, and the reaction was stirred at room temperature for 2 hrs. The reaction was partially concentrated under vacuum, added to water and extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered and concentrated under vacuum. The oil was chromatographed (4% methanol/methylene chloride) on silica gel. The desired fractions concentrated under vacuum and the resulting oil was dissolved in ethyl acetate (20 ml) and triturated with hexanes (450 ml) to provide 0.6 g of solid after drying under vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCOCC#Cc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCOCCCc1ccccc1
Reaction time: 3 h
Yield: 28.4 %

Procedure:
2-Methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.202 mmol) from Example 149 was combined with toluene (15 mL) in a Parr flask and heated to reflux. The resulting solution was purged with nitrogen. Palladium (1 g 10% palladium on carbon) was added to the solution under nitrogen, and the flask was pressurized with hydrogen at 310 kPa for 3 hours. Monitoring by HNMR indicated complete reaction. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and basified with 1 N potassium hydroxide to a pH of about 14. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, washed with 0.5 N potassium hydroxide (2×), water (3×), and brine (3×), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile, and the resulting shinny tan crystals were dried for 2 days, triturated with ether, collected by vacuum filtration, and dried to provide 0.5744 g of 2-methyl-1 [4-(3-phenylpropoxy)butyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 105.1-106.0° C.