Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[C:34]([CH2:35][C:36]([O-:38])=O)=[CH:33][N:32]=[CH:31][N:30]=4)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CCOC(C)=O.CO.CN(C=O)C>[NH2:45][C:36](=[O:38])[CH2:35][C:34]1[C:29]([CH2:28][CH2:27][C:25]2[C:24]([C:39]([F:41])([F:40])[F:42])=[CH:23][N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[N:26]=2)=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(=O)[O-])n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
Lithium 2-(4-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoro-methyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetate (I113) (0.092 g, 0.16 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.023 g, 0.17 mmol) and EDCI (0.033 g, 0.17 mmol) and N,N-diisopropylethylamine (0.109 mL, 0.624 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.075 g, 0.78 mmol) was added in one portion, and the reaction was stirred room temperature for 24 hours. More reagents were added, 1-hydroxybenzotriazole (0.011 g) and EDCI (0.016 g) and N,N-diisopropylethylamine (0.055 mL) and ammonium carbonate (0.035 g) and the reaction was stirred for another 20 hours at 35° C. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (70 mL) and sat. aq. NaHCO3 (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×70 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oily solid. The crude product was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-10% methanol in EtOAc) to give the title compound (I114) (0.076 g, 83% yield) as a pale yellow foam; 1H NMR (400 MHz, d6-DMSO) δ 10.03 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 7.64 (br s, 1H), 7.55 (d, J=7.6 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 7.11 (br s, 1H), 4.12-4.04 (m, 2H), 3.57 (s, 2H), 3.30-3.21 (m, 4H), 2.77 (br s, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.53-1.37 (m, 11H). LCMS Method C: rt 6.12 min; m/z 586.1 [M+H]+.
Reaction SMILES: [ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([OH:31])=[O:30])[CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([OH:31])=[O:30])[CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN(CCCOCC=C2c3ccccc3CCc3ccccc32)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(O)[C@@H]1CCCN(CCCOCCC2c3ccccc3CCc3ccccc32)C1

Procedure:
The acid prepared in Example 5 (0.5 g, 1.1 mmol) was dissolved in methanol (15 ml) and stirred under an atmosphere of hydrogen for 8 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue which was re-evaporated from acetone and then crystallised from a mixture of acetone and ethyl acetate. This afforded 0.3 g (60%) of the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.ClCCl>[C:9]12([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[OH:8])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: Oc1cccc(Br)c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
17 g (0.1 mol) of 3-bromophenol, 15.22 g (0.1 mol) of 1-adamantanol and 50 ml of dichloromethane are introduced into a round-bottomed flask. 5 ml of concentrated sulphuric acid are added dropwise and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water, the mixture is neutralized with sodium bicarbonate and extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (50:50). After evaporation of the solvents, 15.2 g (50%) of the expected phenol, melting point 112°-114° C., are collected.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3f (1.55 g, 1.0 equiv) and EtOH (30 mL) was added at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (132.1 mg, 0.8 equiv) in H2O (3.1 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (13 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (160 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4f. The diastereomeric ratio of crude 4f was determined to be 58/42 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4f (1.04 g, 78% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc(C(=O)O)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-2-fluoro-benzoic acid (5.61 g, 36.2 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) in 60 mL acetic acid was stirred at 60° C. overnight. The mixture was taken up in 250 mL water and stirred for 30 min. The precipitate was filtered and washed with water. The filtrate was washed with ethyl acetate. The organic phase was neutralized with sat. K2CO3 (aq) and concentrated i.vac. The precipitate was filtered and combined with the first isolated precipitate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:22])(=[O:34])[CH3:33]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CC(=O)Nc1cccc(CN)c1
Product: CC(=O)Nc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-(3-Acetylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminomethylphenyl)acetamide using method H. NMR; δH [2H6]—DMSO 9.92,(1H, s), 9.15,(1H, t), 8.01,(2H, d), 7.89,(1H, dd), 7.77,(1H, d), 7.52,(5H, m), 7.23,(1H, t), 6.99,(1H, d), 4.47,(2H, d), 2.56,(3H, s), 2.32,(3H, s), 2.01,(3H, s). LCMS; retention time 2.95 min, MH+ 441.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:14]S(C)(=O)=O)=[CH:8][C:7]=2[C:6]=1C(C1C=CC(OCCCN(CCCC)CCCC)=CC=1)=O.C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1)CCC.[H][H]>[Pt]=O>[CH2:4]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH2:14])=[CH:8][C:7]=2[CH:6]=1)[CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Agent: O=[Pt]
Agent: CCCCc1cc2cc([N+](=O)[O-])ccc2o1
Product: CCCCc1cc2cc(N)ccc2o1

Procedure:
Patent application WO0248132 describes a method for the synthesis of dronedarone using 2-n-butyl-5-nitro-benzofuran which is reduced, under pressure, with hydrogen in the presence of platinum oxide as catalyst in order to form 2-n-butyl-5-amino-benzofuran. This benzofuran derivative is then subjected to the action of methanesulfonyl chloride, which gives 2-n-butyl-5-methanesulfonamido-benzofuran which is treated with 4-[3-(di-n-butylamino)-propoxy]-benzoyl chloride to give dronedarone.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15](S(C3C=CC=CC=3)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:41]([C:44]1[CH:57]=[CH:56][C:47]([CH2:48][O:49][C:50]([NH:52][CH2:53][CH2:54][SH:55])=[O:51])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([S:55][CH2:54][CH2:53][NH:52][C:50]([O:49][CH2:48][C:47]3[CH:56]=[CH:57][C:44]([N+:41]([O-:43])=[O:42])=[CH:45][CH:46]=3)=[O:51])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 81 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R, 5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 81%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([SH:36])[NH:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>CN(C)C=O.[Cu]>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]2[N:26]=[C:25]([S:36][C:3]3[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=3[F:1])[NH:24][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(F)cc1F
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccc(F)cc3F)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 36.8 %

Procedure:
At 0° a diazonium salt solution prepared from 2.58 g of 2,4-difluoroaniline, 1.58 g of sodium nitrite, and 10 ml of 6N hydrochloric acid is added dropwise to a solution of 6.25 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in a mixture of 240 ml of dimethylformamide, 10 ml of 2N sodium hydroxide solution, and 1.45 g of powdered copper. The solution becomes reddish brown under nitrogen evolution. The mixture is stirred for another 3 hours, the solution is concentrated under vacuum, and the residue is distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is subjected to column chromatography on 500 g of neutral aluminum oxide (activity stage II). Elution with acetone/hexan 2:3 yields 3.12 g of 4,5-bis(4-methoxyphenyl)-2-(2,4-difluorophenylthio)imidazole, having a melting point of 174°-176° after crystallization from hexane/ether and a melting point of 186°-188° after another crystallization from ethanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[NH:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.C(N(CC)CC)C.[CH2:22]([O:24][C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:23].O>O1CCCC1.C(OCC)(=O)C>[CH2:22]([O:24][C:25](=[O:29])[C:26]([C:6]1[S:7][CH:8]=[CH:9][C:5]=1[NH:4][C:3]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:2]=1[Cl:1])=[O:27])[CH3:23]
Reactant: Clc1cccc(Cl)c1Nc1ccsc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)c1sccc1Nc1c(Cl)cccc1Cl

Procedure:
2.44 g (10 mmoles) of 3-(2,6-dichloroanilino)thiophen, 1.01 g of triethylamine and 1.37 g (10 mmoles) of chlorooxalic acid ethyl ester are stirred in 20 ml of tetrahydrofuran at room temperature for 10 hours. 100 ml each of water and ethyl acetate are added, and the organic phase is dried and concentrated. Recrystallization of the residue from ethanol gives 3-(2,6-dichloroanilino)-2-thiophenglyoxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:18])C.[NH4+]>C(O)=O.O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:18])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Clc1cc(OCc2ccccn2)ccn1
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: O=c1cc(OCc2ccccn2)cc[nH]1
Yield: 82.9 %

Procedure:
2-Chloro-4-(pyridin-2-ylmethoxy)pyridine (4.10 g, 18.5 mmol) and ammonium acetate (7.21 g, 92.3 mmol) were heated to 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The resulting solid was filtered off to provide the title compound (3.1 g, 83%) as a white solid: ESI MS m/z 203 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5](=[O:19])[CH2:4][CH2:3]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>O1CCCC1>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][C:5](=[O:19])[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]2=3)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: O=C(O)CCCN1C(=O)CCC(=O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)CCCN2C(=O)CCC(=O)c3ccccc32)CC1
Yield: 12.2 %

Procedure:
On the basis of the method described by M. K. Dhaon et al. in J. Org. Chem. 47 (1982) p. 1962, reaction of 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoic acid (0.06 g) from step b and 1-ethylpiperazine (0.25 mmol, 0.03 g) in the presence of EDC.HCl (N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) (0.36 mmol, 0.07 g), Et3N (0.48 mmol, 0.05 g) in tetrahydrofuran (5 ml) afforded 10.0 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[N-:17]=[N+:18]=[N-:19].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:17]([CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[N+:18]=[N-:19]
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(CN=[N+]=[N-])ccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 6chloromethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (10 g, 42.2 mmol, 1.00 mmol equiv.) in DMF (84 mL) is added sodium azide (13.7 g, 211.2 mmol, 5.00 mmol equiv.) at room temperature and the reaction contents are stirred overnight. The reaction is checked by TLC (5% ethyl acetate in hexanes). The reaction is terminated by pouring the reaction contents into water and extracting with ethyl acetate. The organic solvents are removed in vacuo and the crude product filtered through a plug of silica gel (ratio of 10:1) and eluted with hexanes. The solvent is removed in vacuo and stored under vacuo to afford 10 grams of the desired product 6-azidomethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (97% yield).
Reaction SMILES: [O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([O:20][CH3:21])([CH2:10][CH2:11][P:12]([O:17]CC)([O:14][CH2:15][CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC(C1C=CC=CC=1)C(=O)C1C=CC=CC=1.CCOP(OC=C)(OCC)=O.[OH-].[Na+]>CO>[O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([O:20][CH3:21])([CH2:10][CH2:11][P:12]([OH:17])([O:14][CH2:15][CH3:16])=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(CCC(OC)(C(=O)c1ccccc1)c1ccccc1)OCC
Agent: C=COP(=O)(OCC)OCC
Agent: COC(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(O)CCC(OC)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
1-Oxo-2-methoxy-2-(2-diethylphosphonoethyl)-1,2-diphenylethane (100 g, prepared from benzoin methyl ether and diethyl vinyl phosphonate as described in Example 1 of U.S. Pat. No. 4,082,821) is dissolved in methanol (400 ml). Sodium hydroxide (40 g) is added to the solution and the mixture is heated under reflux for 2 hours. The methanol is removed by rotary evaporation, water (300 ml) is added and the mixture is washed with diethyl ether (4×100 ml). The resulting aqueous mixture is cooled to 0° C., and concentrated hydrochloric acid is added until the pH is zero, when a solid is precipitated. This is washed with water and then stirred together with acetone (300 ml), when sodium chloride remains as undissolved solid. The sodium chloride is filtered off and acetone is removed by evaporation to give a solid which is recrystallised from a mixture of acetone and ether to give 90 g of product, a compound of formula XVIII where R1 is methoxy, R3 and Ar1 are each phenyl, R7 is --CH2CH2 -- and R8 is --CH2CH3.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=O.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:18][CH:19]([CH3:30])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:18]([CH:19]([CH3:30])[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:3]([CH2:2][Cl:1])=[N:17][C:12]=3[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: O=C(Cl)CCl
Reactant: CC(CCO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2cc(Br)ccc12
Solvent: ClC(Cl)Cl
Product: CC(CCO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.2 %

Procedure:
A solution of chloroacetyl chloride (16.1 g, 142 mmol) in chloroform (120 mL) was added dropwise to a solution of 7-bromo-N4-[3-(tert-butyldimethylsilanyloxy)-1-methylpropyl]quinoline-3,4-diamine (54.96 g, 129.5 mmol) in chloroform (500 mL), and the reaction was stirred for three days at room temperature. The solvent was removed under reduced pressure, and the intermediate amide was heated at reflux for two hours in glacial acetic acid (600 mL). The acetic acid was removed under reduced pressure, and the residue was passed through a plug of silica gel (eluting with dichloromethane) to provide 9.53 g of 7-bromo-1-[3-(tert-butyldimethylsilanyloxy)-1-methylpropyl]-2-chloromethyl-1H-imidazo[4,5-c]quinoline and a mixture of three other products. The mixture of products was dissolved in glacial acetic acid and heated at reflux for two days. The acetic acid was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 0% to 5% 2 M methanolic ammonia in dichloromethane) to provide 9.14 g of 3-{2-[(acetyloxy)methyl]-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl}butyl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(Oc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(Oc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 (440 mg) in 30 mL of methanol under a nitrogen atmosphere was added 10% Pd/C (30 mg). The solution was purged with H2 gas, then stirred at room temperature under a balloon atmosphere of H2. After 8 h, the reaction was flushed with nitrogen and filtered through celite to remove the catalyst, then concentrated in vacuo. The resulting brown oil was used without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:24]>>[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:19]1=[O:24]
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CN1CCCNC1=O
Product: CN1CCCN(Cc2ccc(C#Cc3ccccc3)cn2)C1=O

Procedure:
The title compound, light yellow oil, MS: m/e=306.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-methyl-tetrahydro-pyrimidin-2-one.