Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]([P:28](=[O:33])([OH:32])[O:29][CH2:30][CH3:31])#[C:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:34]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)#[CH:35]>[Au].ClC(Cl)C>[CH2:30]([O:29][P:28]1(=[O:32])[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:35]=[C:34]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[O:33]1)[CH3:31]
Reactant: CCCCC#CP(=O)(O)OCC
Reactant: C#CC1CCCCC1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(C2CCCCC2)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]|SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen hex-1-ynylphosphonate (57.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, ethynylcyclohexane (64.9 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-cyclohexyl-1,2-oxaphosphorin 2-oxide (42.1 mg, 47%) which is a title compound.
Reaction SMILES: [N:1]1[C:2]([CH2:10][C:11](OCC)=[O:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[CH:3]=1
Reactant: CCOC(=O)Cc1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cn2ccccc2n1

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 2.65 g of ethyl imidazo-[1,2-a]pyridin-2-ylacetate (prepared as described in Preparation 25), 0.5 of lithium aluminum hydride and 100 ml of tetrahydrofuran were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 20:1 to 4:1 by volume as the eluent, to give 1.32 g of the title compound, melting at 120.3°-126.9° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Temperature: 140 °C
Yield: 47.6 %

Procedure:
A mixture of 2-[1-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)-piperidin-4-yl]propan-2-ol (50 mg, 0.12 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (47 mg, 0.18 mmol), tetrakis(triphenylphosphine) palladium (14 mg, 0.01 mmol) and Cs2CO3 (80 mg, 0.24 mmol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-90%) to afford 210 as a white solid (29 mg, 48%). LCMS (Method G): RT 10.16 min, [M+H]+ 508.4. 1H NMR (CDCl3, 400 MHz): δ 8.40-8.37 (m, 1 H); 7.45-7.40 (m, 1 H); 7.32-7.24 (m, 2 H); 4.40 (m, 4 H); 3.94-3.84 (m, 6 H); 3.11 (m, 2 H); 2.92 (s, 3 H); 2.21 (m, 2 H); 1.78 (m, 2 H); 1.48 (m, 2 H) and 1.21 (m, 7 H)
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:22][C:23]#[N:24])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.CC(O)C.Cl.C(OC(C)C)(C)C>CO>[ClH:21].[NH2:8][CH:9]([CH2:22][C:23]#[N:24])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(CC#N)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Product: N#CCC(N)COc1noc2ccc(Cl)cc12

Procedure:
To a suspension of 1.0 g of 3-(2-tert-butoxycarbonylamino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole in 15 ml of methanol is added 7.8 ml of a 2-propanol solution (6.5M) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for seven hours. Thereafter, the solvent is removed by distillation under reduced pressure. To the residue obtained is added diisopropyl ether, and the crystals precipitated are collected by filtration, to obtain 0.78 g of colorless, crystalline 3-(2-amino-3-cyanopropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 188.8°-190.9° C. (decomp.).
Reaction SMILES: Cl.CN.CC(C)(C)C[CH2:7][NH2:8].[O:11]=[C:12]1[C:20]2([C:24]3=[CH:25][C:26]4[O:30][CH2:29][O:28][C:27]=4[CH:31]=[C:23]3[O:22][CH2:21]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:32][C:33]1[O:37][C:36]([C:38]([F:41])([F:40])[F:39])=[C:35]([C:42]([OH:44])=O)[CH:34]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>>[CH3:7][NH:8][C:42]([C:35]1[CH:34]=[C:33]([CH2:32][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3([C:24]4=[CH:25][C:26]5[O:30][CH2:29][O:28][C:27]=5[CH:31]=[C:23]4[O:22][CH2:21]3)[C:12]2=[O:11])[O:37][C:36]=1[C:38]([F:40])([F:41])[F:39])=[O:44]
Reactant: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Reactant: CC(C)(C)CCN
Agent: CN
Agent: Cl
Agent: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Product: CNC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using methylamine hydrochloride to replace 3,3-dimethylbutylamine, 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid, N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (96%) as a colorless solid: mp 202-203° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.19-7.17 (m, 1H), 7.10-7.05 (m, 1H), 6.95-6.92 (m, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.94 (br s, 1H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H), 2.92 (d, J=3.0 Hz, 3H); MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:21][CH:22]1[CH2:26][NH:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23]1.Cl>CCOCC.O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:25]1[CH2:26][CH:22]([OH:21])[CH2:23][C@H:24]1[C:27]([OH:29])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.8 %

Procedure:
24.05 g (0.121 mol) of o-acetoxybenzoyl chloride in 50 ml of anhydrous ether, and 17 ml (0.121 mol) of pure triethylamine in 18 ml of iced water, were added simultaneously over the course of 0.5 hr, at -2° C. ± 1° C., whilst stirring so as to produce emulsification, to a solution of 15.9 g (0.121 mol) of 4-hydroxy-L-proline in 42 ml of water and 17 ml (0.121 mol) of pure triethylamine. Stirring was continued for 0.75 hr at the same temperature and then for 25 minutes at ambient temperature. The pH was reduced from 7 to 3 by adding 9.8 ml of 12.35 N HCl (0.121 mol). The milky cloudiness was extracted with a total of 900 ml of pure ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4 and then concentrated in vacuo to give, in 2 to 3 successive crops, 23 g of the desired product (65% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[C:19]2[S:20][CH:21]=[C:22]([CH2:24][C:25]([O:27]CC)=[O:26])[N:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=[CH:10][C:9]=2[C:19]2[S:20][CH:21]=[C:22]([CH2:24][C:25]([OH:27])=[O:26])[N:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1csc(-c2cnn(-c3ccccc3)c2-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(-c2cnn(-c3ccccc3)c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of the compound (220 mg, 0.540 mmol) obtained in step 5 and 1N aqueous sodium hydroxide solution (1.08 mmol, 1.08 mL) in ethanol (5.0 mL) was heated under reflux for 1 hr. The reaction mixture was cooled to room temperature, and concentrated hydrochloric acid was added until the mixture became pH 6. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; 33% ethyl acetate/hexane) to give {2-[5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetic acid (140 mg, 68%) as a yellow powder.
Reaction SMILES: [N:1]1[NH:2][C:3](=O)[C:4](=O)[CH:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.P(Cl)(Cl)(Cl)=O>>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=c1cc2ccccc2n[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: C1=Cc2ccccc2NN=C1

Procedure:
The title compound was prepared according to the procedures shown in the scheme below. Compound 5-chloroisatoic anhydride (A) was reacted with (R)-2-chlorophenylalanine to provide benzodiazepine-dione B based on procedures described in, for instance, Example 2. Reaction of benzodiazepine-dione B with para-methoxybenzyl chloride in the presence of base, according to procedures described in, for instance, Example 3, provided PMB-protected benzodiazepine-dione C. Conversion of benzodiazepine-dione C to imidoyl chloride D was accomplished using phosphorous oxychloride, based on procedures described in, for instance, Example 4. The substituted phenyl group was installed using Suzuki coupling, based on procedures described in, for instance, Example 7, to provide benzodiazepine E. The PMB protecting group was removed by reacting benzodiazepine E with AlCl3, based on procedures described in, for instance, Example 8, to provide benzodiazepine F. Methyl phenyl ether F was converted to phenol G using boron tribromide, based on procedures described in, for instance, Example 16.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:38]=1)[CH:36]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35](/[CH:36]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:38]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCCCn3ccnc3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
Ex-50A: A solution of 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312 mg, 1.02 mmol) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287 mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted with (3:1) ethyl acetate/THF (3×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxy-phenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (309 mg, 53%) as a yellow oil. 1H-NMR (3.00 MHz, DMSO-d6) 8.28 (d, 2H, J=7.80), 8.20 (s, 1H), 8.01 (d, 1H, J=15.0 Hz), 7.86 (m, 5 H), 7.51 (s, 1H), 7.16 (d, 1H, J=7.5 Hz), 7.23 (m, 2H), 6.79 (d, 2H, J=10.8 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.45 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.92 (m, 4H), 1.77 (quintet, 2H, J=6.6 Hz).
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([O:27][CH3:28])[C:22]([F:26])=[CH:23][CH:24]=3)[C:19]([NH:29][S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:11]=1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl.CO.CS(C)=O>[NH2:5][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([O:27][CH3:28])[C:22]([F:26])=[CH:23][CH:24]=3)[C:19]([NH:29][S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN(C(=O)[O-])C(C)(C)C)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reaction time: 1 h
Yield: 45 %

Procedure:
1,1-Dimethylethyl[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 60) (2.7 g, 4.65 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (5.00 mL) was added to the reaction and stirred for 1 h. The reaction mixture was concentrated in vacuo to leave a purple residue. The residue was dissolved in methanol and loaded onto a methanol pre-conditioned SCX-2 ion-exchange cartridge (70 g). The cartridge was washed well with methanol, followed by HCl in methanol, then methanol and finally ammonia in methanol. Fractions were combined and evaporated in vacuo to give an off white solid, which was dissolved in DMSO, filtered and loaded onto a methanol pre-conditioned SCX-2 ion-exchange cartridge (70 g). The cartridge was washed well with Methanol followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (1 g, 45%) as a white solid: LCMS (System A) RT=0.84 min, ES+ve m/z 481/483 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O)=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH2:4][CH2:5][O:6][CH2:7][C:8]([Cl:13])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCC(=O)O
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NCCOCC(=O)Cl
Yield: 94.4 %

Procedure:
A solution of 2-azidoethoxyacetic acid (2.09 g, 14.4 mmol) in thionyl chloride (5 ml) was stirred at room temperature for 4 h. The excess thionyl chloride was removed under the vacuum of the water aspirator and the residue dissolved in benzene (10 ml, dried over molecular sieves) was evaporated in vacuo. The oil so obtained was dried in vacuo (water pump) over NaOH for 1 h yielding 2.23 g (13.6 mmol, 94.4%) of 2-azidoethoxyacetyl chloride as a colourless oil: 1Hmr (CDCl3) δ: 3.43 (2H, br. t, J=5 Hz, --CH2O--) 3.78 (2H, br. t, J=5 Hz, --CH2N3) and 4.50 ppm (2H, s, --COCH2O--); ir (neat) νmax : 2100 (azide) and 1800 cm-1 (--COCl). This material was used in the next reaction without any purification.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:27].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:27])[C:12]=2[N:11]=[C:10]1[CH2:23][O:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (0.99 g, 2.84 mmol) in 50 mL of CH2Cl2 was treated with 25 mL of concentrated NH4OH solution. To the rapidly stirred solution was added p-toluenesulfonyl chloride (569 mg, 2.98 mmol). After stirring for 30 min, the reaction was treated with CH2Cl2 (50 mL) and H2O (25 mL). The layers were separated and the organic portion was washed 2% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give a tan solid. Chromatography (SiO2, 2% MeOH/CHCl3 containing 0.5% concentrated NH4OH) followed by crystallization from propyl acetate gave N1-benzyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (148 mg) as white needles. mp 152–155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.61 (dd, J=8.2, 1.2 Hz, 1H), 7.85–7.77 (m, 1H), 7.59–7.52 (m, 1H), 7.42–7.34 (m, 4H), 7.33–7.24 (m, 2H), 6.02 (t, J=6.6 Hz, 1H), 5.39 (s, 2H), 4.43 (s, 2H), 4.40 (d, J=6.7 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 147.9, 144.9, 135.7, 129.2, 129.1, 128.6, 127.8, 126.7, 122.4, 120.7, 66.7, 65.3, 56.7, 15.0; MS m/z 348 (M+H)+; Anal. Calcd for C2OH21N5O.0.36H2O: C, 68.90; H, 6.11; N, 20.09; Found: C, 68.50; H, 6.07; N, 20.11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:26][N:22]1[CH2:23][CH2:24][CH2:25][C@@H:21]1[CH2:20][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[N:7]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(O)cc12
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(Oc3ccccc3)cc12
Yield: 6.5 %

Procedure:
A solution of (R)-5-hydroxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (Example 10, 74 mg, 0.20 mmol) and iodobenzene (61.2 mg, 0.3 mmol) with K2CO3 (41.4 mg 0.30 mmol), CuBr (17.2 0.12 mmol) and Cu powder (10 mg, 0.15 mmol) in NMP (0.7 mL) was heated at 170° C. Aqueous workup and flash chromatography (silica gel) yielded (R)-3-(1-methyl-2-pyrrolidinylmethyl)5-phenoxy-1-phenylsulfonylindole (5.8 mg, 8%, HRMS-FAB+ : C26H26N2O3S, calculated MH+ :447.17422; found MH+ : 447.17240).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:16][CH2:17][O:18][CH3:19])[C:6]1[C:7]([C:14]#[N:15])=[N:8][C:9]([Cl:13])=[C:10](Br)[N:11]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:16][CH2:17][O:18][CH3:19])[C:6]1[C:7]([C:14]#[N:15])=[N:8][C:9]([Cl:13])=[C:10]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)[N:11]=1
Reactant: OB(O)c1ccco1
Reactant: COCCN(CCOC)c1nc(Br)c(Cl)nc1C#N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COCCN(CCOC)c1nc(-c2ccco2)c(Cl)nc1C#N
Temperature: 75 °C
Yield: 78.3 %

Procedure:
A mixture of the product from step 4 (1.0 g, 2.87 mmol), 2-furanboronic acid (643 mg, 5.75 mmol), Cs2CO3 (3.31 g, 10.2 mmol), TFP (35 mol %, 236 mg, 1.02 mmol), and Pd2 dba3-CHCl3 (5 mol %, 10 mol % Pd, 150 mg) was subjected to 3 vacuum/Argon cycles and placed under a positive pressure of Argon. Anhydrous dioxane (50 mL) was added and the reaction mixture was heated to 75° C. for 16 h thereafter. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and filtered through a medium frit. Concentration and purification of the residue by flash chromatography (SiO2, 50/1 CHCl3-MeOH) afforded the 757 mg of the furan adduct (78% yield) as a tan powder: LCMS (5-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time=6.41 min on 250 mm column, (M+H)+=337.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:7]23[C:13]([O:14][C@H:5]([CH2:6]2)[CH2:4][C@@H:3]1[C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][O:23][C:21]=2[CH:22]=1)=[CH:12][C:10](=[O:11])[C:9]([O:15]C)=[CH:8]3.S(=O)(=O)(O)O>O>[O:25]1[C:20]2[CH:19]=[CH:18][C:17]([CH:3]3[CH:2]([CH3:1])[C:7]45[CH2:6][CH:5]([O:14][C:13]4=[CH:12][C:10](=[O:11])[C:9]([OH:15])=[CH:8]5)[CH2:4]3)=[CH:22][C:21]=2[O:23][CH2:24]1
Reactant: COC1=C[C@]23C[C@H](C[C@H](c4ccc5c(c4)OCO5)[C@H]2C)OC3=CC1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1C(c2ccc3c(c2)OCO3)CC2CC13C=C(O)C(=O)C=C3O2

Procedure:
Futoenone (50 mg, 0.15 mmol) and 30% sulfuric acid (7.5 ml) are added to a 25 ml round bottom flask. This mixture is heated with a heating mantle to reflux for approximately six hours. The reaction mixture is diluted with distilled water and crystals begin to precipitate. The flask is placed in a refrigerator to aid in precipitation. The crystals are collected by filtration, 300 mg (80%). M+(CI)=327. 1H NMR ppm: 0.59 (3H, d), 1.25 (1H, s), 1.72 (1H, t), 2.03 (1H, m), 2.17 (1h, d), 2.35 (2H, m), 2.53 (1H, m), 5.06 (1H, t), 5.72 (1H, s), 5.83 (1H, s), 5.93 (2H, s), 6.69 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[C:19]([F:32])=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([F:25])=[CH:22][C:23]=1[F:24].CN(C)C=O>C1(C)C=CC=CC=1>[F:32][C:19]1[C:18]([CH2:17][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[C:23]([F:24])[CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(-c2ccccc2)c(F)c1CO/N=C(/c1ccc(Cl)cc1)C1CC1
Yield: 40.1 %

Procedure:
In a manner similar to Example 6 of U.S. Pat. No. 4,079,149, the reaction of 0.59 g (0.003 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime with 0.072 g (0.003 mole) of sodium hydride and 0.77 g (0.003 mole) of 3-chloromethyl-2,4,6-trifluoro[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced 0.5 g of (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2,4,6-trifluoro[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.