Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:5])[CH3:2].Cl.C(NC(C1(C2C=CC(Cl)=C(Cl)C=2)CCC1)C)C.[OH-].[Na+].C(O[C:42](=[O:44])[CH3:43])(=O)C>>[C:42]([N:3]([CH:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:5])[CH2:1][CH3:2])(=[O:44])[CH3:43]
Reactant: CCNC(C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(C(C)=O)C(C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A mixture of N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (0.5 g prepared by treating the product of Example 21 with aqueous sodium hydroxide) and acetic anhydride (1 ml) was heated at 40°-45° C. for thirty minutes. The reaction mixture was basified and extracted with ether. The ether extract was washed, dried and evaporated to give N-acetyl-N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine as an oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11]>>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][Si:10]([Cl:11])([CH2:12][Si:13]([Cl:15])([Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C#Cc1ccccc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Product: Cl[Si](Cl)(C=Cc1ccccc1)C[Si](Cl)(Cl)C=Cc1ccccc1
Yield: 28.1 %
Yield: 61.3 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of H2PtCl6. Into the same apparatus as described in Example 1 were placed 25 μl of 0.1 M H2PtCl6 /IPA under nitrogen and the isopropyl alcohol was removed. Then 4.95 g of bis(dichlorosilyl)methane, 20 ml of dried benzene, and 2.5 ml of phenylacetylene were added to the flask and the flask content refluxed for 2 hours. The solvent was removed from the flask at atmospheric pressure and the products distilled at 67 Pa to yield a mixture comprising 3,3,5,5-tetrachloro-1 -phenyl-3,5-disilapent-1 -ene (TCD-GC area 61.3%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 28.1%). 3,3,5,5-Tetrachloro-1-phenyl-3,5-disilapent-1-ene=1H-NMR (CDCl3, ppm): 1.45 (s, 2H, SiCH2Si), 5.71 (s, 1H, SiH), 6.45 (d, J=18.8Hz, 2H, SiCH=CHPh), 7.26-7.53 (m, 7H, CHArH); 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene=1H-NMR (CDCl3, ppm): 1.43 (s, 2H, SiCH2Si), 6.18 (s, 2H, SiCH=CHPh), 7.27-7.47 (m, 7H, CHArH).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.C(OCC)C>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.6 %

Procedure:
To a solution of morpholine-4-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) in N,N-dimethylformamide (1.0 ml) was added phenylacetyl isothiocyanate (42 mg), followed by stirring at room temperature for 22 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated to give a solid, which was suspended in diethyl ether. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (22 mg, 0.043 mmol, 29%) as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.I[CH2:16][CH3:17].[H-].[Na+]>>[CH2:16]([N:11]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:14]=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])[CH3:17]
Reactant: CCI
Reactant: COc1ccc2c(c1)NC(=O)CCC2
Agent: [H-]
Agent: [Na+]
Product: CCN1C(=O)CCCc2ccc(OC)cc21

Procedure:
As shown in Scheme 3, 8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3A) was alkylated using iodoethane as an alkylating reagent and one equivalent of sodium hydride as a base to provide 1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (9A). A bromination in methanol at ambient temperature using bromine as a brominating agent afforded exclusively 7- bromo regioisomer (10A) which was transformed further employing a catalytic cross coupling methodology. This coupling reaction was conveniently carried out by use of 4-methylpiperazine as a reagent, BINAP as a chelating reagent, palladium acetate as a catalyst in the presence of cesium carbonate as a base.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.Cl.[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].[OH-].[Na+]>C1COCC1.CO>[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:29]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: COCc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-methoxymethyl-aniline-hydrochloride in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1.C[Si](C)(C)NC(=O)C.C(OC(C)C)(C)C>CS(C)=O>[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][N:58]([C:9]([C:4]5[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][N:5]=5)=[O:11])[CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1
Reactant: O=C(O)c1cc(O)c(O)cn1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)N[Si](C)(C)C
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a solution of 4,5-dihydroxy-2-pyridinecarboxylic acid (3.1 g) and 1-hydroxybenzotriazole (4.0 g) in dimethyl sulfoxide (30 ml) was added N,N'-dicyclohexylcarbodiimide (6.2 g). After being stirred at room temperature for 1 hour, the reaction mixture was added to a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (10.0 g) and N-trimethylsilylacetamide (3.0 g) in dimethyl sulfoxide (50 ml), and the stirring was continued for 30 minutes. The mixture was added dropwise to diisopropyl ether (1.5 l) and the resulting precipitate was collected by filtration, which was dissolved in an aqueous solution of sodium bicarbonate, After the insoluble material was filtered off, the filtrate was adjusted to pH 3.0 with 1N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" with 5% aqueous isopropyl alcohol as an eluent. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (0.5 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:16])[NH:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].[CH3:17][C:18]([O:20][CH2:21][C@H:22]1[O:27][C@H:26](Br)[C@H:25]([O:29][C:30]([CH3:32])=[O:31])[C@@H:24]([O:33][C:34]([CH3:36])=[O:35])[C@@H:23]1[O:37][C:38]([CH3:40])=[O:39])=[O:19]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:26]3[O:27][C@H:22]([CH2:21][O:20][C:18](=[O:19])[CH3:17])[C@@H:23]([O:37][C:38](=[O:39])[CH3:40])[C@H:24]([O:33][C:34](=[O:35])[CH3:36])[C@H:25]3[O:29][C:30](=[O:31])[CH3:32])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a suspension of 4-[(4-ethylphenyl)methyl]-5-methyl-1,2-dihydro-3H-pyrazol-3-one (0.65 g) and acetobromo-α-D-glucose (1.2 g) in tetrahydrofuran (15 mL) was added silver carbonate (0.83 g), and the mixture was stirred at 60° C. overnight under light shielding. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran), and successively by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.61 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1>FC(F)(F)C(O)=O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(-c3ccccc3CO)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(OCc2cccc(-c3ccccc3CO)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
tert-Butyl 3-(4-((2′-(hydroxymethyl)biphenyl-3-yl)methoxy)phenyl)propanoate (0.25 g, 0.60 mmol) was dissolved in trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (gradient cycle A) to give the title compound (10 mg, 5%) as colorless crystals. MS (APCI−): 361 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:21])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[F:20])[S:21][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=S)Nc2ccc(Br)cc2F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(Br)cc3s2)c(F)c1
Temperature: 110 °C
Reaction time: 17 h
Yield: 63.4 %

Procedure:
Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml) and added Na2CO3 (156 mg, 1.47 mmol). This mixture stirred at 110° C. for 17 h. Work up (EtOAc/H2O) afforded the crude. Crude was triturated with Petether and dried to obtain the titled compound (360 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.65 (m, 1H), 8.13 (d, J 1.9, 1H), 8.01 (d, J 8.7, 1H), 7.91-7.83 (m, 2H), 7.66 (dd, J 1.9, 8.7, 1H), 3.12 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+:12]1[C:20]2[C:15](=NC=C[CH:19]=2)[N+]([O-])=N1)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[CH:39]=[C:38]4[CH2:41][CH2:42][CH2:43][CH:44]5[CH2:49][C:48]([O:54][Si:55]([CH2:60][CH3:61])([CH2:58][CH3:59])[CH2:56][CH3:57])([C:50]([F:53])([F:52])[F:51])[CH2:47][CH2:46][C:45]5([C:62]([OH:64])=O)[C:37]4=[CH:36][C:35]=3[CH:34]=[N:33]2)=[CH:28][CH:27]=1.C1(N)CC1.C(Cl)Cl>CN(C=O)C>[CH:20]1([NH:12][C:62]([C:45]23[CH2:46][CH2:47][C:48]([O:54][Si:55]([CH2:60][CH3:61])([CH2:56][CH3:57])[CH2:58][CH3:59])([C:50]([F:52])([F:51])[F:53])[CH2:49][CH:44]2[CH2:43][CH2:42][CH2:41][C:38]2[C:37]3=[CH:36][C:35]3[CH:34]=[N:33][N:32]([C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)[C:40]=3[CH:39]=2)=[O:64])[CH2:15][CH2:19]1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)NC3CC3)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reaction time: 24 h
Yield: 92 %

Procedure:
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.201 g, 0.530 mmol) was added to a solution of rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carb oxylic acid (43, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.235 g, 0.407 mmol), cyclopropanamine (0.093 g, 1.6 mmol), N-ethyl-N,N-diisopropylethylamine (0.285 mL, 1.63 mmol), DCM (5 mL), and DMF (1 mL). After about 24 h, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.020 g, 0.053 mmol) was added. After about 24 h, the reaction mixture was partitioned between DCM (50 mL) and sat. aq. NaHCO3 (10 mL). The organic layer was washed with water (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-17% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aR,12bS)—N-cyclopropyl-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxamide (44, R1=4-Fluorophenyl, R2′=Cyclopropyl, R3=Trifluoromethyl) (0.230 g. 92% yield); LC/MS, method 4, Rt=2.65 min.; MS m/z: 616 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=0.9 Hz 1H), 7.86 (s, 1H), 7.73-7.65 (m, 2H), 7.45 (s, 1H), 7.29-7.22 (m, 2H), 4.99 (s, 1H), 2.93-2.72 (m, 2H), 2.72-2.46 (m, 4H), 2.26-2.08 (m, 2H), 2.08-1.87 (m, 3H), 1.75-1.63 (m, 2H), 1.42-1.29 (m, 1H), 1.05-0.96 (m, 9H), 0.78-0.60 (m, 8H), 0.32-0.15 (m, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([OH:40])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][C@H:16]1[C@@:38]2([CH3:39])[C:28](=[CH:29][CH2:30][C@@H:31]2[C:32]2([O:37][CH2:36][CH2:35][O:34]2)[CH3:33])[C@H:27]2[C@@H:18]([C@:19]3([CH3:41])[C:24](=[CH:25][CH2:26]2)[CH2:23][C@@H:22]([O:40][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:21][CH2:20]3)[CH2:17]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](O)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@@H]1C[C@H]2[C@@H](CC=C3C[C@@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@@]32C)C2=CC[C@H](C3(C)OCCO3)[C@]21C
Yield: 84.8 %

Procedure:
A solution of p-toluenesulphonyl chloride (650 mg, 3.4 mmol) in pyridine (10 ml) was added dropwise to a mixture of the 20,20-Ethylenedioxypregna-5,14-diene-3β,12β-diol 12-acetate (22) (1.3 g, 3.1 mmol) in pyridine (15 ml) at 0° C. The reaction mixture was left stirring at room temperature for 24 hours after which water was added to the reaction mixture. The solution was extracted with ethyl acetate (2×50 ml), the ethyl acetate layer was washed citric acid (5×50 ml), saturated sodium bicarbonate solution (100 ml), saturated sodium chloride solution (100 ml) and water (100 ml) The ethyl acetate was dried (MgSO4), filtered, and evaporated and purified by flash column chromatography using hexane-ethyl acetate (8:2 v/v) as the eluant to give the β-O-tosyl steroid (26), (1.5 g, 84%), as a yellow oil, (Found M 570.271, C32H42O7S requires: M 570.273).
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[NH2:33][C@H:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1.CN(C)C=O>[NH2:23][C:3]1[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)=[C:5]([CH:9]=[C:10]([Cl:11])[CH:2]=1)[C:6]([NH:33][C@H:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1)=[O:8]
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Nc1cc(OCc2cccc(I)c2)c(C(=O)O)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(Cl)cc(C(=O)N[C@@H]2CN3CCC2CC3)c1OCc1cccc(I)c1
Reaction time: 0.75 h
Yield: 26.9 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-iodophenyl)methoxy]benzoic acid (3.23 g, 8.0 mmol) in anhydrous tetrahydrofuran (4 mL) and anhydrous N,N-dimethylformamide (4 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.9 mmol), stirred for 45 minutes, and degased over 15 minutes under a stream of nitrogen. A solution of (S)-3-aminoquinuclidine (1.54 g, 12.2 mmol) in anhydrous tetrahydrofuran (4 mL) was added, and the mixture was stirred at room temperature for 18 hours, warmed to 55°±5° C. for three hours, and concentrated in vacuo. The residue was partitioned between 3.0N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol, and the organic layer was separated. The aqueous solution was extracted with toluene (50 mL) containing some 2-propanol, and the combined organic solution was concentrated in vacuo. The residue was washed with water to remove most of the imidazole, then dried azeotropically with toluene, taken up in tetrahydrofuran, and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, taken up in warm acetone, and filtered. After a few hours, a solid had crystallized, and this was collected and dried in vacuo to afford (following second crop) 1.10 g (27%) of colorless solid; mp 101.5°-104° C., [α]D22 -6.35° (C=1 in methanol).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].BrC1C=CC2C3N(CCCOC(C)C)C(COCC)=NC=3C(N)=NC=2C=1.N1CCCC1=O>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1NCCO1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: O=C1CCCN1
Product: CCOCc1nc2c(N)nc3cc(N4CCOC4=O)ccc3c2n1CC(C)(C)O

Procedure:
The general method described in Part E of Example 1 was followed using 1-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol and 2-oxazolidinone as reactants in lieu of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-pyrrolidinone. The product, 3-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxazolidin-2-one, was isolated as a flocculent white solid, mp >250° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)=[CH:12][CH:11]=1.S(C1NC=CN=1)(C1NC=CN=1)=O>C(#N)C>[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:11]=[CH:12][C:13]([CH:16]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: O=S(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Reaction time: 15 h

Procedure:
13.6 g (0.2 mol) of imidazole are dissolved in 150 ml of acetonitrile and 3.5 ml of thionyl chloride are added at 10° C. 13 g (0.05 mol) of (biphenyl-4-yl)-phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After standing for 15 hours at room temperature, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the solution is washed with water. The organic phase is collected, dried over sodium sulfate and filtered and the solvent is distiller off in vacuo. The oily residue is dissolved in ethyl acetate and freed from insoluble, resinous constituents by filtration. The solvent is again distilled off in vacuo and the residue is purified by recrystallization from acetonitrile. 8.7 g (56% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane [alternatively named as diphenyl-imidazolyl-(1)-phenyl-methane or as 1-(α-biphenyl-4-ylbenzyl)imidazole] of melting point 142° C. are obtained.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1COCC1>[N:14]1([C:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:9](=[O:10])[O:8][CH2:7]3)=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C(=O)N3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-chlorocarbonylphthalid (39 g, 0.2 mole) in THF (400 ml) is added to a solution of morpholine (22 g. 0.25 mole) and triethylamine (26 g, 0.25 mole) in THF (200 ml) at 0° C. The mixture is stirred for 1 hour and is allowed to warm to room temperature. The reaction mixture is then poured into ice water ( 500 ml). THF is evaporated off in vacuo and the pH of the solution is adjusted to pH=2. The solution is cooled to 5° C. and the precipitated crystals are filtred off and washed with water (100 ml).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1
Reactant: BrBr
Reactant: Oc1ccccc1OC1CCCC1
Solvent: ClCCl
Product: Oc1ccc(Br)cc1OC1CCCC1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A solution of 2-(cyclopentyloxy)phenol intermediate (5.6 g, 31 mmol) in CH2Cl2 (40 mL) at −78° C. was treated dropwise with a solution of bromine (4.9 g, 31 mmol) in CH2Cl2 (10 mL) via addition funnel over a 1 h period. After warming up to room temperature gradually over 3 h, the reaction was quenched by addition of a saturated aqueous solution of Na2S2O4. The isolated organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude mixture was then purified by ISCO (0-10% EtOAc in hexanes) to afford intermediate 4-bromo-2-(cyclopentyloxy)phenol (2.6 g, 32%) as colorless oil. 1H NMR (300 MHz, CDCl3) 6.97-6.93 (m, 2H), 6.78 (d, J=9.3, 1H), 5.54 (s, 1H), 4.78 (m, 1H), 1.95-1.63 (m, 8H).