Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=O)=[C:4]([Cl:16])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:16])[CH:3]=1
Reactant: O=C(c1cc(F)c(Br)cc1Cl)N1CCCC1
Agent: B
Solvent: C1CCOC1
Product: Fc1cc(CN2CCCC2)c(Cl)cc1Br
Temperature: 65 °C
Yield: 93.9 %

Procedure:
To Intermediate 10, 1-(4-bromo-2-chloro-5-fluorobenzoyl)pyrrolidine (48.0 g, 156.5 mmol) in THF (200 mL) at rt was slowly added a solution of BH3.THF complex (400 mL, 400 mmol, 1M THF). The resulting reaction was heated to 65° C. (oil bath) for 16 hr, and then the reaction was cooled to rt and slowly quenched with MeOH (dropwise addition). The reaction mixture was heated to reflux for 2 hr, cooled to rt, and concentrated under reduced pressure. This material was taken up in EtOAc and further quenched slowly with 6N HCl, then neutralized with aqueous NaOH (15%). The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75L column, eluting with a gradient of 5%, 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to give the title compound (43 g, 94% yield) as a light yellow oil: Rf=0.6 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C11H12BrClFN, 292.6, found, 292, 294, 296 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J=6.6 Hz, 1H), 7.33 (d, J=9.5 Hz, 1H), 3.66 (s, 2H), 2.59-2.55 (m, 4H), 1.82-1.79 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 158.3 (d, JC-F=247.2 Hz), 139.3, 133.3, 128.9, 117.8 (d, JC-F=24.9 Hz), 107.3 (d, JC-F=22.6 Hz), 56.7, 54.4, 23.9.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1cccc(C2OCCO2)c1
Yield: 74.5 %

Procedure:
A solution of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}phthalimide (119.4 g, 0.3 mole) and hydrazine hydrate (78.6 mL, 1.62 mole) in 95% ethyl alcohol (1.5 L) was heated at reflux temperature for 17.5 hours. The thick white mixture was cooled in an ice-water bath, filtered and the solid washed with ice cold 95% ethyl alcohol. The combined filtrate and washings were evaporated under reduced pressure and the residue was partitioned between 940 mL of 5% aqueous sodium hydroxide and 500 mL of dichloromethane. The aqueous phase was extracted with 500 mL of dichloromethane and the combined organic phase was extracted with 300 mL of saturated aqueous sodium chloride. The organic phase was dried, evaporated under reduced pressure and the residue was distilled under high vacuum to give 49.9 g of the title compound; bp=143°-147° C. at 0.25 mmHg.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)NCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinolin-7-ol (200 mg, 1.34 mmol) from step 1 in anhydrous N,N-dimethyl-formamide (5 mL) was added bromomethyl-benzene (229 mg, 1.34 mmol), and potassium carbonate (556 mg, 4.02 mmol). The reaction mixture was stirred at 60° C. overnight. Added some water to the reaction mixture and extracted it with methylene chloride several times. The organic layer was combined, dried over magnesium sulfate, and filtrated. The solution was evaporated under vacuum. The crude residue was purified by MPLC (biotage) to afford 297 mg (93%) of the title compound. 1H-NMR (CDCl3) δ 7.35-7.20 (m, 5H), 6.81 (d, J=8.1 Hz, 1H), 6.05 (dd, J=7.8 Hz, 2.2 Hz, 1H), 5.98 (d, 2.5 Hz, 1H), 4.53 (bs, 1H), 4.44 (s, 2H), 3.34 (t, J=5.0Hz, 2H), 2.73 (t, J=5.8Hz, 2H) 1.98 (m, 2H); MS LC-MS (MH+=240.1), LC MS RT: 3.08 min.
Reaction SMILES: C1COCC1.[H-].[Na+].[C:8]([O:12][CH3:13])(=[O:11])[CH2:9][OH:10].[F:14][C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>O>[F:14][C:15]1[CH:20]=[C:19]([O:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To 20 ml of THF, 0.24 g (60 mmol) of 60% sodium hydride was suspended under cooling with ice, and 0.32 g (6.6 mmol) of methyl glycolate, was added thereto, followed by stirring for 15 minutes. To this mixture, 2 g (6.0 mmol) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluormethyl-2(1H)-pyridone was added, followed by stirring at room temperature for 3 hours. The product was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. After distilling off ethyl acetate under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 1.57 g (yield: 65%) of the desired product.
Reaction SMILES: C([S:4][CH2:5][CH:6]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][S:8]C(=O)C)(=O)C.[OH-].[Na+].II>C(O)C.ClCCl>[C:16]([O:15][C:13](=[O:14])[NH:12][CH:6]1[CH2:7][S:8][S:4][CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)SCC(CSC(C)=O)NC(=O)OC(C)(C)C
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CSSC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of thioacetic acid S-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester (330 mg) in ethanol (5 ml) was treated with 2.5 ml of 1N sodium hydroxide for 1 hour at room temperature. The yellow solid turned green-brown. The reaction mixture was diluted with dichloromethane (25 ml) and then an aqueous solution of 0.1M iodine (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and quenched by addition of 1M sodium bisulfite solution. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent evaporated in vacuo to afford the title product (170 mg). 1H-NMR (CDCl3, 400 MHz): 5.00 (br s, 1H), 4.90 (m, 1H), 3.15 (d, 2H), 3.05 (d, 2H), 1.40 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:30])([CH3:29])[CH2:17][C:16]3([CH3:32])[CH3:31])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:26]1([N:24]([CH2:23][C:21]2[CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][CH:7]=3)[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([CH3:29])([CH3:30])[CH2:17][C:16]3([CH3:32])[CH3:31])[CH3:25])[CH2:28][CH2:27]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of (4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}phenyl)-acetic acid methyl ester (Intermediate 12, 0.057 g, 0.13 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodium hydroxide (0.4 mL, 0.4 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was washed with hexane, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow oil (0.046 g, 84%).
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:19][NH2:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]([C:24]1[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:33]([CH3:35])[CH3:34])=[C:22]=[O:23]>>[C:1]1([S:7]([C:10]2([CH2:19][NH:20][C:22]([NH:21][C:24]3[C:25]([CH:33]([CH3:34])[CH3:35])=[CH:26][CH:27]=[CH:28][C:29]=3[CH:30]([CH3:32])[CH3:31])=[O:23])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Yield: 36 %

Procedure:
Similarly to Example 1(c), by reaction of 168 mg (0.6 mmol) of C-(2-benzenesulfonyl-indan-2-yl)-methylamine with 131 mg (0.64 mmol) of 2-isocyanato-1,3-diisopropyl-benzene. 106 mg of 1-(2-benzenesulfonyl-indan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white solid. (Yield=36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:22])([F:23])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(SC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2cccc(SC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Yield: 87 %

Procedure:
Starting from 850 mg (1.99 mmol) of ethyl 1-(3-chlorophenyl)-5-{3-[(trifluoromethyl)thio]phenyl}-1H-pyrazole-3-carboxylate from example 5A and 1.12 g (19.9 mmol) of potassium hydroxide, 691.5 mg (1.7 mmol, 87% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:19]([CH2:28][CH2:29][CH3:30])[C:18]=1[OH:31])(=[O:16])[CH3:15].[OH-].[K+].Cl>C(O)C>[C:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:19]([CH2:28][CH2:29][CH3:30])[C:18]=1[OH:31])(=[O:16])[CH3:15]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 110.3 %

Procedure:
A mixture of 2-mercaptobenzimidazole-5-carboxylic acid (3.25 g), 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylbromide (2.00 g) and potassium hydroxide (1.27 g) in ethanol (30 ml) was refluxed for 4 hours. Then, the reacting mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from n-hexane-ethyl acetate to give the title compounds (3.00 g, 67.1%) as pale yellow crystals, mp 106-108 ° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]#[N:25]>CN(C=O)C>[C:24]([CH2:23][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)#[N:25]
Reactant: N#CCBr
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCn1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 75 °C
Yield: 84.7 %

Procedure:
To 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.210 g, 1.00 mmol) in DMF (20 mL), was added Cs2CO3 (0.489 g, 1.50 mmol) and bromoacetonitrile (0.180 g, 1.50 mmol). The reaction mixture was heated at 75° C. under an N2 atmosphere for 1 hr. Dilution with water was followed by extraction with Et2O. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded 0.211 g of the title compound: MS (ESI): m/z 250 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([Cl:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
A mixture of commercially available 2-(3-nitrophenyl)acetic acid [CAS no. 1877-73-2] (25.8 g, 142 mmol, Eq: 1.00) and thionyl chloride (25.4 g, 15.5 ml, 214 mmol, Eq: 1.5) in toluene (141 ml) and DMF (208 mg, 221 μl, 2.85 mmol, Eq: 0.02) was stirred at 80° C. for 2 h. The hot solution was filtered through a Sartorius filter, the filtrate was evaporated and dried in HV to give the 2-(3-nitrophenyl)acetyl chloride (28.12 g, 141 mmol, 98.9% yield) as a yellow solid, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][C:19]([O:21]C)=[O:20])=[C:13]([F:23])[CH:12]=1.[OH-].[Na+].O>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[C:13]([F:23])[CH:12]=1
Reactant: COC(=O)Cc1cc(Cl)c(Nc2nc3ccccc3s2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(Cl)c(Nc2nc3ccccc3s2)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
Methyl (4-(2-benzothiazolyl)amino-5-chloro-2-fluorophenyl)acetate (613 mg, 1.68 mmol) was dissolved in THF (5 ml). To the resulting solution was added 1N NaOH (5.0 ml, 5.00 mmol). The resulting mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture. The mixture was washed with ether. The water layer was poured in ice-1N HCl to acidify the water layer. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(2-benzothiazolyl)amino-5-chloro-2-fluorophenyl)acetic acid (464 mg, 82%) as a pale yellow solid.
Reaction SMILES: [O-][N+:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH:13]=[N:14][C:4]=2[CH:3]=1.ClC(Cl)(Cl)C([N:36]=C=O)=O>ClCCl>[NH2:36][C:3]1[C:4]2[N:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:2]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CN(C(=O)CCCCOCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)CCCCOCCn1cnc2c(N)nc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Using the general method of Parts C and D of Example 11, 2-(1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.63 g, 2.9 mmol) and 5-bromo-N-methyl-N-phenylpentanamide (1.3 g, 4.8 mmol) were combined to provide 0.24 g of 5-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a colorless oil. The resulting N-oxide product was dissolved in dichloromethane and trichloroacetyl isocyanate (0.11 ml) was added dropwise. The reaction was stirred at room temperature for 2 hours and then the solvent was removed under vacuum. The resulting oil was dissolved in methanol and sodium methoxide (0.2 ml, 25% by weight in methanol) was slowly added. The reaction was maintained overnight and then concentrated under vacuum. Purification by flash column chromatography (silica gel, 9:1 ethyl acetate\methanol) provided 24 mg of 5-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]-N-methyl-N-phenylpentanamide as a white solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1(C)C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C1CCNC1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C2CC=C(N3CCCC3)CC2)CC1

Procedure:
200 g of 4-(trans-4-propylcyclohexyl)cyclohexanone and 135.2 g of pyrrolidine were dissolved in 800 ml of toluene. The solution was heated and stirred for 6 hours while water which is evaporated by azeotropic distillation was removed. Azeotropic distillation of the solution was carried out with toluene so that excessive pyrrolidine was removed, and 1-(4-(trans-4-propylcyclohexyl)-cyclohexen-1-yl)-pyrrolidine was obtained. The product as it was was cooled to room temperature, and 800 ml of toluene was added again. The mixture was cooled in a water bath, and 150 ml toluene solution of 89 ml of methyl vinyl ketone was added dropwise over a period of 2 hours at 20° C. or less. After the dropwise addition was completed, the temperature was increased over a period of 2 hours to reach the reflux temperature. The solution was cooled to room temperature, and a buffer solution of pH 5 which was prepared from B5.2 g of sodium acetate, 104.2 ml of acetic acid, and 104.2 ml of water was added. Reflux was further continued for 5 hours. After the solution was cooled to room temperature, the organic phase was separated and rinsed with water and a saturated saline solution. The organic phase was dried on anhydrous sodium sulfate. The solvent was evaporated, and 313 g of 6-(trans-4-propylcyclohexyl)-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH2:51])=[CH:48][CH:47]=1.C(N(CC)C(C)C)(C)C>>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][NH:51][C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])=[CH:48][CH:47]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4-fluorobenzylamine and N,N-diisopropylethylamine to give the desired product as a light yellow solid (29%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[CH2:14](Br)[C:15]#[CH:16]>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:16][C:15]#[CH:14])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC[C@@H](O)C1

Procedure:
To a solution of (R)-3-hydroxy-pyrrolidine (2.00 g, 22.95 mmol) (Aldrich) and Et3N (9.00 g, 88.93 mmol) in 45 mL of CH2Cl2 at 0° C. it was added propargyl bromide (3.00 g, 25.21 mmol) in a dropwise manner. Upon completion of the addition, the reaction mixture was filtered and the filtrate was washed with brine, dried over Na2SO4 and concentrated. (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine was obtained after Krugerhor distitation (Yield 700 mg, 24%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[CH3:41][N:36]([S:37]([CH3:40])(=[O:39])=[O:38])[C:33]1[CH:32]=[CH:31][C:30]([NH:29]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:35][CH:34]=1
Reactant: CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-(4-aminophenyl)-N-methyl-methanesulphonamide Rf value: 0.8 (aluminium oxide, ethyl acetate) C26H25N3O5S
Reaction SMILES: [Na+].[C:2]1([CH3:11])[C:3]([S:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.O.Cl>C(OC)(C)(C)C>[C:2]1([CH3:11])[C:3]([S:8]([OH:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccccc1S(=O)O
Yield: 73.2 %

Procedure:
Toluenesulfinic acid sodium salt (150 g, 0.84 mol), H2O (500 mL), and t-butylmethyl ether (TBME) (250 mL) were vigorously stirred, and concd HCl (75 mL) was added dropwise. The resulting two phases were separated and the aqueous phase was extracted with TBME (100 mL). The TBME phases were dried (Na2SO4) and concentrated to near dryness and the white solid was combined with hexane (350 mL) and filtered and dried in vacuo to afford 96 g of toluenesulfinic acid.