Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.CCOC(C)=O.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:10])([CH3:8])[CH3:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(C)(C)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(CBr)cc1
Yield: 82 %

Procedure:
To a stirring solution of 2-p-tolylpropan-2-ol (500 mg, 3.3 mmol) in carbon tetrachloride at room temperature under argon was added N-bromosuccinimide (590 mg, 3.3 mmol), followed by benzoyl peroxide (16 mg, 0.06 mmol). The reaction mixture was stirred at reflux for 4 h. The reaction mixture was concentrated under reduced pressure to obtain a colorless gum. EtOAc (20 mL) and water (20 mL) were added and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under vacuum to obtain crude product, which was purified by flash chromatography (silica gel column eluted with 30% EtOAc/hexanes) to isolate 620 mg of the title compound as a colorless gum. HPLC/MS: retention time=2.908 min, [M+H—H2O]+=211.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]#[N:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[S:10][CH:11]=[CH:12][C:13]=3[C:14]([NH2:15])=[N:16][C:4]=2[CH:3]=1
Reactant: N#Cc1ccsc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: NC1=Nc2cc(Cl)ccc2Nc2sccc21
Yield: 142.2 %

Procedure:
Suspend 2-(4-chloro-2-nitro-phenylamino)-thiophene-3-carbonitrile (4.85 g, 17.35 mmol) in ethanol (40.0 ml). Dissolve tin(II) chloride dihydrate (11.75 g, 52.06 mmol) in 5N HCl (40.0 ml) and then add it to the suspension. Heat the reaction at reflux for 48 hours. Cool the reaction to ambient temperature and then chill it in a refrigerator for 2 hours. Collect the resulting precipitate by vacuum filtration and then dry it under vacuum to give 3.53 g (71%) of the title compound: mass spectrum (ion spray): m/z=250.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:7][CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:11][N:10]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3([CH3:34])[CH2:33][CH2:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)N2CCC(C(=O)N3CC(N)C(c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of rac-(3S,4R)-{4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (5.747 g, 0.011 mol) in dichloromethane (55 mL) was added trifluoroacetic acid (8.39 mL, 0.110 mol) and the reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was basified by addition of aqueous sodium carbonate (1M, 10 mL). The organic layers were washed with water (8 mL) and the aqueous layers were extracted with dichloromethane (10 mL). The combined org. layers were dried over sodium sulfate and concentration afforded 4.30 g (92%) of the title compound as a light brown foam. ES-MS m/e: 524.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[C:36](Cl)[N:35]=[N:34][C:33]=2[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:36]2[N:35]=[N:34][C:33]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:31][CH:30]=3)[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.13 mmol, 240 mg) in THF (10 mL) at room temperature was added NaH (100 mg, 4.5 mmol). Stirring continued for 10 min then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.56 mmol, 200 mg) was added. The resulting mixture was stirred at 50-55° C. over night, then was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by flash silica gel column chromatography using 30% ethyl acetate in hexanes to provide 4-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:31]([NH:38][C:39]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:28]([CH3:30])[CH3:29])=[CH:4][C:3]([C:1]#[N:2])=[CH:27][C:7]=4[N:8]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)NCc5ccccc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (30 mg, 0.075 mmol, INTERMEDIATE 15) in dichloromethane (1 ml) was added benzyl isocyanate (10 μl 0.081 mmol). The mixture was stirred for 2 h at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting mixture was repurified by reverse-phase HPLC: Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (7.9 mg, 0.015 mmol, 19.79% yield). Mass spectrum (ESI) 536.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=7.0 Hz, 2H), 7.94 (d, J=7.0 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H), 7.52 (s, 1H), 7.27-7.35 (m, 4H), 6.55 (br s, 1H), 4.43 (s, 2H), 3.99 (br d, J=11.0 Hz, 2H), 3.47 (septet, J=5.5 Hz, 1H), 3.42 (t, J=5.5 Hz, 2H), 2.86 (br t, J=10.5 Hz, 2H), 2.73 (s, 3H), 1.90 (m, 1H), 1.81 (br d, J=10.0 Hz, 2H), 1.46 (d, J=5.5 Hz, 6H), 1.31 (m, 2H).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH2:12]([O:14][C:15](=[O:23])[N:16]([CH2:20][CH2:21]Br)[CH2:17][CH2:18]Br)[CH3:13].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:10]=[C:9]1[C:11]2([CH2:21][CH2:20][N:16]([C:15]([O:14][CH2:12][CH3:13])=[O:23])[CH2:17][CH2:18]2)[CH2:1][CH2:2][C:3]2[C:8]1=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCOC(=O)N(CCBr)CCBr
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a stirred solution of α-tetralone (289 mg, 1.98 mmol) and bis-(2-bromo-ethyl)-carbamic acid ethyl ester (600 mg, 1.98 mmol) in DMF (2 mL) at 50° C. was added NaH (119 mg, 4.95 mmol) by small portions. After being stirred at 50° C. for 12 h, the reaction was cooled to 25° C. The reaction mixture was diluted with 15 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated. The crude product was purified via flash chromatography (gradient of 85:15 to 60:40 heptane/ethyl acetate over 20 min) to give the title compound (85 mg, 0.296 mmol) as a white solid. MS calculated for C17H22NO3 288.4. found (ESI) m/z 288.7 (M+H)+, retention time 1.58 min.
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])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([CH3:19])([OH:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:11]=2[N:12]=1)[CH3:23]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3ccccc3c2n1CC(C)(C)O
Yield: 83.6 %

Procedure:
4-Amino-2-(ethoxymethyl)-α,α-dimethyl-1H-Imidazo[4,5-c]quinoline-1-ethanol (CAN 144875-48-9, 1.6 g, 5.09 mmol) was combined with acetonitrile (60 mL) to give a white suspension. Then triethylamine (1.77 mL, 12.7 mmol) and trityl chloride (1.7 g, 6.11 mmol) were added under Argon with stirring. The reaction mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. Upon stirring the mixture the product precipitated and was isolated by filtration at 0° C., washed with cold acetonitrile and dried to yield the title compound (2.37 g, 83%) as white solid; MS (ESI): 557.5 (MH+).
Reaction SMILES: [C:1]([C@H:5]1[CH2:9]OS(=O)(=O)[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:12]([NH:6][C@@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][F:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)N1Cc1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4S)-4-(tert-butyl)-3-(phenylmethyl)-1,2,3-oxathiazolidine-2,2-dioxide (6.22 g, 23.09 mmol) in THF (100 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (46.2 ml, 46.2 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Solvent was evaporated, and ether (50 mL) and 20% H2SO4 aqueous solution (20 mL) were added. The reaction mixture was stirred for 2 h at room temperature, diluted with water, neutralized with solid NaHCO3 slowly then extracted with ethyl acetate. The combined organics were dried over anhydrous Na2SO4, filtered, then concentrated. The residue was purified by column chromatography to give the title compound (4.13 g) as a light yellow oil. LCMS m/z=210.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.96 (s, 9H), 2.41 (dt, J=24.7 and 4.3 Hz, 1H), 3.76 (d, J=13.1 Hz, 1H), 4.01 (d, J=13.1 Hz, 1H), 4.39-4.72 (m, 2H), 7.23-7.38 (m, 5H).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([Cl:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[Cl:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-(5'-bromo-4'-chloro-2'-nitrophenyl)glycine sodium salt (0.255 g, 0.824 mmol, as prepared above) and tin (II) chloride dihydrate (0.560 g, 2.48 mmol, Aldrich, used as received) in ethanol (6 mL) was refluxed for 3 h. It was then cooled to room temperature and allowed to stand overnight at room temperature. The white solid was filtered and dried to yield 0.038 g (18%) of the pure (1H NMR) title compound as white flakes; m.p. 230-232° C.; 1H NMR (DMSO-d6): δ 3.732 (s, 2H), 6.371 (s, 1H), 6.830 (s, 1H), 6.912 (s, 1H), 10.437 (s, 1H). Extraction of the filtrate with ethyl acetate (30 mL) gave 0.136 g (68%) more product for a combined yield of 86%. The product was used as such for the next reaction.
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H](CC1N=CNC=1)C(N[C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18](O)[C@@H:19]([OH:23])[CH:20]([CH3:22])[CH3:21])=O)=O)(=O)=O)(C)(C)C.[C:45]1(=[O:51])[O:50][C:48](=[O:49])[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:45]([O:23][CH:19]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH2:17][CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)(=[O:51])[CH2:46][CH2:47][C:48]([OH:50])=[O:49]
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(CCCC1CCCCC1)OC(=O)CCC(=O)O

Procedure:
100 mg of (S)-α-[(S)-α[(t-butylsulphonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide, 200 mg of succinic anhydride and 200 mg of sodium carbonate in 10 ml of dimethylformamide are stirred at 50° overnight. Thereafter, the reaction mixture is taken up in ethyl acetate and the organic phase is washed with saturated ammonium chloride solution and water, dried and evaporated. Chromatography of the resiude on 20 g of silica gel with a 90:10:1:0.5 mixture of methylene chloride, methanol, water and acetic acid yields (1S,2R,3S)-3-[(S)-α-[(t-butylsulphonyl)methyl]-hydrocinnamamido]imidazole-4-propionamido]-4-cyclohexyl-1-isopropylbutyl hydrogen succinate as a foam, MS: 733 (M+H)+, and (1R,2S)-1-[(S)-1-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide]-2-cyclohexylethyl]-2-isopropylethylene bis(hydrogen succinate) in the form of a foam, MS: 833 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:9])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1ccsc1N
Solvent: O
Product: O=c1[nH]cnc2sccc12
Temperature: 190 °C
Yield: 23 %

Procedure:
Methyl 2-aminothiophene-3-carboxylate (10 g, 64 mmol) was charged with formamide (50 mL). The reaction was heated at 190° C. under nitrogen for 3 hours. The solution was cooled to room temperature. The slurry was poured into 125 mL of water and extracted with chloroform:isopropyl alcohol mixture (2 times). The solution was concentrated and triturated to afford the title compound (2.25 g, 23%).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].S(=O)(=O)(O)O.[CH3:17]O>>[C:1]([O:11][CH3:17])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CO
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of D-(-)-mandelic acid (20 g) in methanol (100 ml) was added concentrated sulfuric acid (6 g) and the mixture was refluxed for 2.5 hours. After cooling to room temperature it was concentrated to about 50 ml and the residue was dissolved in methylene chloride (about 300 ml). The solution was the washed with water, saturated sodium bicarbonte and water, dried (magnesium sulfate) and evaporated to give a clear oil, which crystallized upon cooling to give 21.7 g of methyl D-(-)-mandelate, a compound of Formula 6, wherein R5 is phenyl.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:30])([F:31])[F:32])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CC2)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)C1(CC2CC2)CCNC1
Reaction time: 4 h

Procedure:
The title compound was prepared according to general procedure D described in connection with Scheme 5. tert-Butyl 3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidine-1-carboxylate was dissolved in 8 mL of CH2Cl2 and 2 mL of TFA was then added to the solution at RT. The reaction mixture was stirred for 4 h and the solvent was evaporated. The desired product was obtained as TFA salt without further application for next step. 1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 7.82-7.78 (m, 1H), 6.86 (br s, 1H), 4.88 (dd, 2H), 3.98 (m, 3H), 3.42 (d, 1H), 3.33 (m, 1H), 3.22 (br s, 2H), 2.63 (m, 1H), 2.20 (m, 1H), 2.01-1.73 (m, 3H), 0.68 (s, 1H), 0.53 (br s, 2H), 0.066 (m, 2H); MS (ESI) m/z: Calculated for C18H22F3N3O: 353.2. found 354.1 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:15]([O:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:16])([CH3:14])([CH3:13])[CH3:12].C1C[O:35][CH2:34][CH2:33]1>>[C:25]1([CH:24]([CH:21]2[CH2:22][CH2:23][N:18]([O:17][C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16])[CH2:19][CH2:20]2)[CH2:33][CH:34]=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)ON1CCC(C(=O)c2ccccc2)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)(C)C(=O)ON1CCC(C(CC=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of triethylphosphonoacetate (6.2 g, 27 mmol) in THF (100 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (32.5 mL, 1M, 32.5 mmol). The resulting mixture was stirred at 0° C. for 20 min. 1-tert-Butylcarbonyloxy-4-benzoylpiperidine (7 g, 25 mmol) was added and the resulting mixture was stirred at room temperature for 48 h. The mixture was evaporated and the residue dissolved in ethyl acetate (200 mL). The solution was washed with 2M hydrochloric acid (2×100 mL), dried and evaporated giving the sub-titled compound.
Reaction SMILES: [C:1]([C:4]1(C)[CH2:8][C:7]([CH3:9])=[C:6]([OH:10])[C:5]1=[O:11])(O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:1][C:4]1[CH2:8][CH:7]([CH3:9])[C:6](=[O:10])[C:5]=1[OH:11]
Reactant: CC1=C(O)C(=O)C(C)(C(=O)O)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(O)C(=O)C(C)C1
Yield: 91 %

Procedure:
85.1 g (0.5 mol) of the acid obtained according to paragraph (c), namely 2-carboxy-2,4-dimethylcyclopent-4-en-5-olone, are treated with 851 ml of 10% sulphuric acid and the mixture is refluxed for 45 minutes. For the working-up, the mixture is adjusted to pH 7 with 2N sodium hydroxide solution and then extracted three times with methylene chloride. The combined organic phases are dried over sodium sulphate and dried in a high vacuum for 1 hour. There are obtained 57.4 g (91%) of crystalline 3,5-dimethylcyclopent-2-en-2-olone of melting point 93°-94° C. The product is identical with the product obtained according to paragraph (c) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(OCC)(=O)C>C(O)CCC.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)[N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCO
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine and 8.05 g (50 mmol) of 3-trifluoromethyl-aniline (Fluka, Buchs, Switzerland) in 60 ml of n-butanol and 3 ml of DMF are stirred at 60° C. for 6 h. 50 ml of ethyl acetate are added to the cooled reaction solution and the precipitate is filtered off and further stirred in 40 ml of isopropanol at 40° C. for 60 min. After filtration with suction and drying, 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine is obtained; m.p. 248–250° C.; FAB-MS: (M+H)+=314; Rf=0.45 (methylene chloride:methanol=95:5).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](Cl)=[O:13].CCN(CC)CC>C1COCC1>[CH3:7][O:6][C:4]([C:3]1[N:1]=[CH:2][O:13][C:12]=1[C:11]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:9]([Cl:8])[CH:10]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: [C-]#[N+]CC(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(Cl)c(Cl)c1
Yield: 64 %

Procedure:
A solution of methyl isocyanoacetate (5.0 g, 50.0 mmol), 3,4-dichlorobenzoyl chloride (10.6 g, 50.0 mmol), and Et3N (20.9 mL, 150 mmol) was stirred in THF (20 mL) for 48 h at rt. The solution was concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated to afford a solid. The solid was washed with hexanes and collected by filtration to provide 8.7 g (64%) of the desired product. HPLC: RT=9.68 min. MS (ESI+): mass calcd. for C11H7Cl2NO3, 270.98; m/z found, 272/274 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.29 (d, J=2.1, 1H), 8.03 (dd, J=8.5, 2.1, 1H), 7.94 (s, 1H), 7.56 (d, J=8.5, 1H), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][NH:7][C:8](=[O:19])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])=[O:5])[CH3:2].[OH-].[Na+].CS(O[CH2:27][CH2:28][N:29]([O:37][CH3:38])[CH2:30][CH2:31]OS(C)(=O)=O)(=O)=O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:31][CH2:30][N:29]([O:37][CH3:38])[CH2:28][CH2:27][N:7]1[C:8](=[O:19])[CH2:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)NNC(=O)Cc1c(C)cc(C)cc1C
Reactant: CON(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(OC)CCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 65 °C

Procedure:
To a vigorously stirred suspension of N′-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazinecarboxylic acid ethyl ester (4.22 g, 15.96 mmol) in toluene (80 ml) was added aqueous sodium hydroxide (12 ml, 30% NaOH w/w in water) and tetra-butyl ammonium bromide (160 mg, 0.48 mmol) at room temperature, followed by methanesulfonic acid 2-[(2-methanesulfonyloxy-ethyl)-methoxy-amino]-ethyl ester (4.66 g, 16.00 mmol) dropwise over 15 minutes at 65° C. The reaction mixture was heated at 65° C. for 6.5 hours. After cooling, the layers were separated, the organic phase evaporated, the residue dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate/dichloromethane 5:4:1). Yield: 2.6 g of 5-methoxy-2-[2-(2,4,6-trimethyl-phenyl)-acetyl]-[1,2,5]triazepane-1-carboxylic acid ethyl ester (compound P3.1) as a colorless oil.