Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=N[C:5]2[C:6]3[O:15][C@@H:14]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[CH2:13][O:12][C:7]=3[CH:8]=[CH:9][C:10]=2C=1.[NH:28]1[CH2:31][CH:30]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[CH:35]=[CH:34]2)[CH2:29]1.C([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]=[CH:34][N:33]2[CH2:32][CH:30]2[CH2:31][N:28]([CH2:16][CH:14]3[O:15][C:6]4=[C:5]5[C:46](=[CH:47][CH:8]=[C:7]4[O:12][CH2:13]3)[N:45]=[C:48]([CH3:49])[CH:9]=[CH:10]5)[CH2:29]2)=[CH:37][CH:38]=1
Reactant: CCN(CC)CC
Reactant: Cc1cnc2c3c(ccc2c1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2ccn(CC3CNC3)c2c1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cn2ccc4ccc(F)cc42)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-]quinolin-2-ylmethyl ester (0.4 g, 0.93 mmol), 1-azetidin-3-ylmethyl-6-fluoro-1H-indole (0.19 g, 0.93 mmol) and triethylamine (0.19 ml, 1.4 mmol) in dimethylsulfoxide (20 ml) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.1 g of the (S)-enantiomer of the title compound as a brown oil. The hydrogen chloride salt was prepared in ethyl acetate and collected as a yellow solid: mp: 138° C. (dec).
Reaction SMILES: [C:1]12([CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][CH2:3][CH2:2]2.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:16][CH:13]1[CH2:12][CH2:11][C:1]2([C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:15][CH2:14]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CCCc3ccccc32)CC1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCC2(CCCc3ccccc32)CC1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
To an ice-cooled solution of 3.89 g. (0.018 M) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol -(obtained in Example 17A) in 40 ml. of pyridine, 4 ml. of methane sulfonyl chloride is added. The mixture is allowed to stand in the cold for about 6 hours and then diluted with water. The material that precipitates is extracted with ether and the combined extracts washed successively with ice cold 2.5 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residue is recrystallized from cyclohexane to give 5 g. (94.3% yield) of 3',4'-dihydrospiro[cyclohexane-1,1'(2'H)-naphthalen]-4-ol methane sulfonate(t), having a melting point of 118° to 120° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].[C:26](OC(C)=C)(=[O:29])[CH2:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:26](=[O:29])[CH2:27][CH3:28])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)OC(=O)CC
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCC(=O)OC1=CC[C@H]2[C@@H]3CCc4cc(OC)cc(OC(C)=O)c4[C@H]3CC[C@]12C

Procedure:
A solution of 1-acetoxy-3-methoxyestra-1,3,5(10)-trien-17-one (0.884 g, 26 mM), isopropenyl propionate (15.1 g, 123 mM) and p-toluenesulfonic acid monohydrate (0.134 g, 0.7 mM) is heated at 120° on a set-up employing a Vigreaux column as described in Example 9. After heating at 120° for 12 hrs, the temperature is raised to 150° for 1 hr. The pot residue is poured into ether. The ethereal solution is extracted with saturated sodium bicarbonate solution, cold H2O and dried over MgSO4. Evaporation of the solvent gives a residue which upon chromatography on neutral silica gel affords 1-acetoxy-3-methoxy-17-propionyloxyestra-1,3,5(10),16-tetraene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:15][CH2:14][CH2:13]N(CCCC)CC[O:9]1.[Li][CH2:21]CCC.CC(C)=O.Cl>C1COCC1>[CH3:21][C:14]1([CH3:13])[O:15][B:8]([OH:9])[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: CCCCN1CCOB(c2ccccc2Br)OCC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 2-(2′-bromophenyl)-6-butyl[1,3,6,2]dioxazaborocan (93.1 g, 277.1 mmol) in THF (2.3 L) at −78° C. was added n-BuLi (133.0 mL, 2.5M in hexane, 332.5 mmol, 1.2 equiv.) dropwise via a syringe over a period of 10 min while maintaining reaction temperature at −78° C. After the addition the reaction solution was stirred for 20 min at −78° C. before acetone (23.2 mL, 387.9 mmol, 1.4 equiv.) was added dropwise via a syringe over a period of 10 min while maintaining the reaction temperature at −78° C. The resulting mixture was allowed to stir for 20 min at −78° C. then warm to room temperature gradually. Once the reaction vessel reached room temperature, 6N HCl solution (1 L) was added and the mixture was stirred for an additional 30 min. The mixture was extracted with EtOAc (3×). The EtOAc extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The light yellow oil was then subjected to flash chromatography (Isco Companion, 80 g SiO2 cartridge, solid loaded SiO2, neat heptanes to 20:80 EtOAc gradient at 60 ml/min for 90 min). The title compound was recovered as clear colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 6 H) 7.31 (d, J=1.1 Hz, 1 H) 7.38-7.47 (m, 2 H) 7.66 (d, J=7.2 Hz, 1 H) 8.99 (s, 1 H). Amount obtained: 16.9 g (37.7% yield).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.O>CCOCC>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(c1ccccc1)c1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Temperature: -78 °C

Procedure:
To a solution of 2.35 g (4.90 mmol) of N-[(6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridin-2-yl) methyl]-2,6-diisopropylaniline in 50 ml of THF 20.0 ml (14.8 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The reaction mixture was heated to room temperature and stirred for 10 minutes. Further on, 2 ml of water was added, and the resulting mixture was poured into 50 ml of water. The crude product was extracted with 3×30 ml of ether. The organic extract was washed by 2×50 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 2.38 g (86%) of orange oil. Anal. calc. for C39H45N3: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.41; H, 8.17; N, 7.38. For 1H NMR (in CDCl3) see FIG. 1—Bottom spectrum.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[C@H:41]1[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]2[CH2:53][CH2:52][CH2:51][O:50]2)[CH2:43][CH2:42]1>O.C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C@H:41]4[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]5[CH2:53][CH2:52][CH2:51][O:50]5)[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CCCO3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC3CCCO3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogen carbonate (0.39 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydrofuran-2-ylmethoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.045 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.042 mL) were added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and HPLC to give the title compound as a colorless solid (0.062 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[BrH:16].O.N>O>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]=1[Br:16]
Reactant: Nc1ccc2c(ccc3ccccc32)c1
Reactant: Br
Agent: N
Solvent: O
Product: Nc1ccc2c(ccc3ccccc32)c1Br
Temperature: 25 °C
Yield: 89.5 %

Procedure:
First, 100 g of 2-aminophenanthrene were dissolved in 750 mL of N,N-dimethyl sulfoxide, and then 83 g of 48% hydrobromic acid were dropped to the solution over 4 hours while the solution was stirred at room temperature. The mixture was continuously stirred at room temperature for 20 hours, and was then stirred at 100° C. for 1 hour under heat. After having been cooled to room temperature, the reaction solution was poured into 3 L of water. After the mixed solution had been neutralized with ammonia water, the crystal was obtained through separation by filtration. The resultant solid was recrystallized with ethanol and water. Thus, 126 g of a colorless crystal were obtained (in 90% yield).
Reaction SMILES: [CH2:1](P(CCCC)CCCC)[CH2:2][CH2:3]C.ClCCCCl.[Cl:19][SiH:20]([Cl:22])[Cl:21]>>[Cl:19][Si:20]([Cl:22])([Cl:21])[CH2:1][CH2:2][CH2:3][Si:20]([Cl:22])([Cl:21])[Cl:19]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCCP(CCCC)CCCC
Solvent: ClCCCCl
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 343 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.30 g (1.5 mmol) of tri-n-butylphosphine, 0.85 g (7.5 mmol) of 1,3-dichloropropane, and 10.2 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 12 hrs. The resulting mixture was distilled to give 1.6 g of 1,3-bis(trichlorosilyl)propane (bp; 104° C./12.5 mmHg, yield; 70%) and 0.3 g of 3-(chloropropyl)trichlorosilane (bp; 88-90° C./12.5 mmHg, yield; 20%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[C:24]([CH:34]=1)[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH:16]([CH3:18])[CH3:17])[C@H:9]1[C:10]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]1[CH:34]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=1[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)=[O:33])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Reactant: CC(C)C1CCN(C(=O)OC(C)(C)C)C1C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)C1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1
Temperature: 25 °C

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-3-isopropyl-dl-proline, (77 mg, 0.30 mmol), N-[5-chloro-2-(1H1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 113 mg, 0.30 mmol), HOAt (20 mg, 0.15 mmol), EDC (86 mg, 0.45 mmol) and Et3N (80 μL, 0.60 mmol) in 1.5 mL DMF was stirred at room temperature. The diastereomeric products were separated by reverse phase HPLC (30 min gradient elution with 95:5 H2O/0.1% TFA:CH3CN/0.1% TFA to 5:95 H2O/0.1% TFA:CH3CN/0.1% TFA) and carried on directly to deprotection.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([O:13][CH3:14])=[C:4](Cl)[N:3]=1.[NH3:16]>CS(C)=O.O>[NH2:16][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]=1[O:13][CH3:14]
Reactant: N
Reactant: COc1c(Cl)nc(Cl)nc1-c1ccco1
Solvent: O
Solvent: CS(C)=O
Product: COc1c(N)nc(Cl)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2,6-Dichloro-5-methoxy-4-furan-2-ylpyrimidine (500 mg, 2.0 mmol) (see Example 5 for the preparation of 2,6-dicholor-5-methoxy-4-furan-2-yl pyrimidine) was dissolved in dry DMSO (10 mL) and heated to 60° C. This mixture was treated with a gentle stream of ammonia. After approximately 2 h, conversion was complete to about a 95:5 ratio of mono-amino isomers (having a molar weight of 225 g/mol). This mixture was cooled and diluted with water (50 mL), and the product extracted with ethyl acetate (2×50 mL). Then, the product was washed with ethyl acetate, twice with water (25 mL), and once with saturated sodium chloride (25 mL). The result was dried and concentrated. The product was purified by column chromatography using silica with a 5 to 20% ramp of ethyl acetate/hexane to give the title compound (400 mg, 89% yield). The various isomers were not separated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].[OH-:25].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:25])[C:8]=1[CH3:24]
Reactant: [OH-]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: [Na+]
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Yield: 32.7 %

Procedure:
2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole (25.0 g (72.8 mmol)) was dissolved in dichloromethane, and then the solution was cooled, and mcpba (70.2% purity; 7.16 g (29.1 mmol)) was added little by little such that the internal temperature did not exceed −15° C. After the addition, a 10% sodium hydroxide aqueous solution (70.8 ml) was added, the mixture was stirred and then left to stand, and then the aqueous layer was separated off. The separated aqueous layer was washed twice with dichloromethane (48 ml). A 2N ammonium acetate aqueous solution was then put into the solution, and then extraction was carried out twice with dichloromethane (48 ml). The dichloromethane layers were washed twice with water (48 ml), vacuum concentration was carried out, crystallization was carried out using dichloromethane (18 ml) and acetone (120 ml), and then filtration was carried out, thus obtaining 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole (8.56 g) (HPLC purity 99.7%, yield 32.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C.N12CCCN=C1CCCCC2>ClCCl>[CH2:29]([C:16]1[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:9]2[CH2:2][CH2:3][CH2:4][S:5]2(=[O:7])=[O:6])[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCN1CCCS1(=O)=O
Reaction time: 20 h
Yield: 42.6 %

Procedure:
Under a nitrogen atmosphere, chloropropylsulfonyl chloride (0.05 ml, 0.46 mmol) was added dropwise to a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.12 g, 0.37 mmol) and triethylamine (0.065 ml, 0.46 mmol) in dichloromethane (5 ml). The reaction was stirred for 20 hours followed by removal of the solvent in vacuo. The resulting off-white solid was dissolved in N,N-dimethylformamide (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 ml, 0.58 mmol) was added. The reaction was stirred for 18 hours under an atmosphere of nitrogen and then quenched with water and extracted with dichloromethane (2×). The organic fractions were combined, washed with water followed by brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide an off-white solid. Recrystallization from ethyl acetate yielded 0.068 g of 2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, m.p. 152-154° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH3:24][O:25][C:26](=[O:53])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:38](=[O:39])[CH2:37][S:36][C:35]2=[N:40][C:41]2[CH:46]=[C:45]([C:47](=[O:49])[CH3:48])[CH:44]=[CH:43][C:42]=2[NH:50][CH2:51][CH3:52])=[CH:29][CH:28]=1>>[C:47]([C:45]1[CH:44]=[CH:43][C:42]([NH:50][CH2:51][CH3:52])=[C:41]([N:40]=[C:35]2[N:34]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:26]([O:25][CH3:24])=[O:53])=[CH:28][CH:29]=3)[C:38](=[O:39])[C:37](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:36]2)[CH:46]=1)(=[O:49])[CH3:48]
Reactant: CSc1sc2c([n+]1C)CCCC2
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccc(C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-ium p-toluenesulfonate with 4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-yl methyl]benzoic acid methyl ester.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[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+].Br[CH2:35][CH2:36][CH2:37][OH:38].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]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[N:15]([CH2:35][CH2:36][CH2:37][OH:38])[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: OCCCBr
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCCO)c2C)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.020 g) and cesium carbonate (0.11 g) in N,N-dimethylformamide (0.5 mL) was added 3-bromopropanol (0.022 mL), and the mixture was stirred at 40° C. overnight. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 3-(β-D-glucopyranosyloxy)-1-(3-hydroxypropyl)-5-methyl-4-[(4methylthiophenyl)methyl]-1H-pyrazole (0.011 g).
Reaction SMILES: O1CCOCC1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C(N(CC)CC)C>[C:32]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 500 ml of dry dioxane in a reaction flask are added 9.0 g of 4-(6-hydroxyhexyloxy)-4'-nitrostilbene and 5 g triethylamine. The solution is heated to 50° C., and 3.7 g of methacryloyl chloride is added dropwise. The reaction is stirred at 45°-50° C. for about 6 hours and an additional 3.7 g of methacryloyl chloride is added. The reaction mixture is stirred for about 10 hours at 50° C., the dioxane is removed and the resultant residue is slurried with water in a blender. The solid is filtered, washed with water, and dried. The crude product is recrystallized from ethanol, mp 90°-95° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1(C)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[CH4:28].Cl>O>[C:19]1([CH3:28])[C:20]([S:23]([C:6]2[CH:5]=[C:3]([NH2:4])[C:2](=[CH:8][CH:7]=2)[C:1]([OH:10])=[O:9])(=[O:24])=[O:25])=[CH:21][CH:22]=[CH:17][CH:18]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccccc1S(=O)(=O)c1ccc(C(=O)O)c(N)c1
Temperature: 65 °C
Yield: 110.1 %

Procedure:
13.7 g (0.1 mol) of anthranilic acid was added in three portions to the warmed solution of 26.0 g of sodium carbonate in 150 ml of water, 23.0 g (0.12 mol) of p-toluenesulfonyl chloride was added to the solution in 5 portions over a period of 20 minutes. Maintained the reaction mixture at 60-70° C. for additional 0.5 h, and rised to 85° C., 1.0 g of Norit was added cautiously and the solution was fitered. The filtrate was cooled and acidified with dilute HCl, the product was isolated by filtration and washed with dilute hydrochloric acid and then water. After recrystallized from 95% ethanol there was obtained the title compound (20.0 g) as white crystal, yield 68.7%, m.p. 229-232° C.