Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C1([SiH3])C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21]([CH3:25])=[CH:22]2)=[CH:17][CH:16]=1.[H][H]>C1COCC1>[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH:21]([CH3:25])[CH2:22]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C=C(C)CC2
Reactant: [H][H]
Agent: [Li]CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
In a dry sealable Schlenk flask under an argon atmosphere 0.0254 g (0.043 mmol) (S,S)-ethylene-1,2,-bis(η5 -4,5,6,7-tetrahydro-1-indenyl)titanium (S)-1,1'-binaphth-2,2'-diolate was dissolved in THF (5 mL). The vessel was degassed by exposure to vacuum (2 x ~10 sec), put under an atmosphere of hydrogen and subsequently cooled to 0° C. in an ice water bath. After equilibration, a solution of n-butyllithium (0.052 mL, 1.58M in hexanes, 0.083 mmol, 1.91 equiv) was added and the mixture was allowed to stir for 10 min. Phenylsilane (0.016 mL, 0.126 mmol, 2.9 equiv) and 0.130 g (0.756 mmol, 18 equiv) 7-methoxy-2-methyl-3,4-dihydronaphthalene were then added. The flask was sealed and the solution moved into a dry box and transferred to a Parr® high pressure reaction vessel containing a magnetic stir bar. The pressure vessel was sealed and moved to a fume hood where it was charged to 2150 psig with hydrogen and placed in an oil bath at 70° C. The reaction mixture was allowed to stir for 44 h. The vessel was cooled to room temperature, vented and opened to air. The reaction mixture was worked up by partitioning between diethyl ether/hexane (1/4) and water and separating the layers. The organic extract was distilled at reduced pressure to yield 0.097 g (0.557 mmol, 73%) of 7-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalene with an ee of 90.4%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:26][C:27](=[O:44])[C@@H:28]([NH:36]C(=O)OC(C)(C)C)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH:19]=2)=[CH:14][CH:13]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:36][C@@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([NH:26][C@H:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH:19]=2)=[CH:14][CH:13]=1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)c1nc2ccccc2[nH]1
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
Tert-butyl [(1S)-2-({1-(1H-benzimidazol-2-yl)-2-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}amino)-1-benzyl-2-oxoethyl]carbamate (10 mg, 0.016 mmol) was dissolved in a mixture of trifluoroacetic acid (1 mL) and methylene chloride (1 mL) and stirred for 45 minutes. The solvent was removed in vacuo. The diastereomers alpha to the benzimidazole were resolved through preparative LCMS purification to yield 5.5 mg (95%) of (2S)-2-amino-N-{(1R)-1-(1H-benzimidazol-2-yl)-2-[4-({1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}-3-phenylpropanamide (Peak A) and 5.5 mg (95%) of (2S)-2-amino-N-{(1S)-1-(1H-benzimidazol-2-yl)-2-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]ethyl}-3-phenylpropanamide (Peak B). Peak A: 1H NMR (500 MHz, CD3OD): δ 7.84 (d, J=8.4 Hz, 2H), 7.76–7.79 (m, 2H), 7.56–7.59 (m, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.28–7.31 (m, 3H), 7.10–7.13 (m, 2H), 6.93 (s, 1H), 5.59–5.63 (m, 1H), 4.19–4.22 (m, 1H), 3.50–3.55 (m, 1H), 3.32–3.41 (m, 1H), 3.08–3.13 (m, 1H), 2.86–2.91 (m, 1H); LCMS found for C27H25N5O4S (M+H)+: m/z=516.0 Peak B: 1H NMR (500 MHz, CD3OD): δ 7.77–7.82 (m, 4H), 7.62–7.64 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 6.88–7.01 (m, 6H), 5.61–5.65 (m, 1H), 4.14–4.18 (m, 1H), 3.48–3.53 (m, 2H), 2.97–3.25 (m, 2H); LCMS found for C27H26N5O4S (M+H)+: m/z=516.0
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12]Cl)[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[CH2:1]([O:8][CH:9]1[CH2:12][N:17]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: ClCC(CCl)OCc1ccccc1
Solvent: O
Product: CC(C)N1CC(OCc2ccccc2)C1
Temperature: 90 °C
Yield: 85 %

Procedure:
21.9 parts of 2-benzyloxy-1,3-dichloro-propane, 59.1 parts of iso-propylamine and 59.1 parts of water were added to an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 17.4 parts of 3-benzyloxy-1-(iso-propyl)azetidine boiling at 105° - 107° C. under 2 mm Hg were obtained. The yield was 85%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[N:17]=1>C(OCC)C.CCCCCC>[Cl:22][C:20]1[CH:19]=[C:18]([O:23][CH3:24])[N:17]=[C:16]([C:5]2[S:4][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][CH:6]=2)[N:21]=1
Reactant: COc1cc(Cl)nc(Cl)n1
Reactant: FC(F)(F)c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Cl)nc(-c2ccc(C(F)(F)F)s2)n1
Temperature: -40 °C

Procedure:
2.05 g 2-Trifluoromethylthiophene in 20 mL diethylether are treated with 8.2 mL of a 1.6 M solution of n-butyllithium in hexane at -70° C. After 30 minutes the mixture is warmed to -40° C. and added dropwise to a solution of 2,4-dichloro-6-methoxypyrimidine in 20 mL of ether, which is kept at 0° C. The mixture is allowed to reach room temperature, is washed with water and 0.24 g of the product are isolated as an oil after flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:27])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:19])=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH3:19])=[CH:4][CH:3]=1
Reactant: OCCCCO
Reactant: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Product: CC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1(OCCCCO)c1ccc(Cl)cc1
Yield: 37.6 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-2-[1-(4-chlorophenyl)-ethyl]-3-hydroxy-2,3-dihydroisoindol-1-one (498 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a pale yellow oil (242 mg, 51%). 1H NMR (300 MHz, CDCl3): 7.87-7.83 (m, 1H, C(O)═C═CH), 7.53-7.46 (m, 2H, Ar—H), 7.07-7.03 (m, 9H, Ar—H), 4.41 (q, J=7.2 Hz, 1H, N—CH), 3.70 (m, 2H, HO—CH2), 3.29-3.25 and 3.01-2.95 (m, 2H, OCH2), 1.86 (d, J=7.2 Hz, 3H, CH3), 1.77-1.68 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.31, 145.26, 141.47, 137.76, 134.79, 133.15, 133.06, 132.84, 130.20, 129.67, 128.75, 128.41, 128.27, 123.71, 123.27, 95.44, 63.35, 62.89, 52.49, 29.96, 26.48, 20.08. m/z (ES): 470 [M+H]+. HPLC: Rt=3.76 min. Anal.: calc. for C26H25Cl2NO3: C, 66.39; H, 5.36; N, 2.98. Found: C, 66.33; H, 5.25; N, 2.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:12][CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2=NCCN=C2c2ccncc2)cc1
Solvent: CCO
Product: Fc1ccc(-c2nccnc2-c2ccncc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
The product of example 1 a above (0.1 g, 0.4 mmol) was treated with a solution of ferric chloride (0.13 g, 0.8 mmol) in ethanol (1 mL) and stirred at 50° C. for 12 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was chromatographed on silica gel eluted with 1-3% methanol in methylene chloride. Recrystallization from methylene chloride hexane gave the title compound as an white crystalline solid. ES (+) MS m/e=252 (MH+)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][C:7]1([NH:13][S:14]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:1]([N:10]1[CH2:9][CH2:8][C:7]([NH:13][S:14]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)(=[O:15])=[O:16])([CH2:6][OH:5])[CH2:12][CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(NC1(CO)CCNCC1)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(CO)(NS(=O)(=O)c2ccc(Cl)s2)CC1
Temperature: 25 °C

Procedure:
Acetyl chloride (0.15 g, 1.894 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (1 mL) to a cold 0° C. solution of N-[4-(hydroxymethyl)piperidin-4-yl]-5-chloro-thiophene-2-sulfonamide (0.19 g, 0.61 mmol) in CH2Cl2 (5 mL) and triethylamine (0.44 mL, 3.18 mmol) The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted with CH2Cl2 (10 mL) and the organic layer was washed with 1N HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude oil (175 mg). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: starting with 1:4 EtOAc-hexane and ending with 1:1 EtOAc-hexane to afford N-[1-Acetyl-4-(hydroxymethyl)-piperidin-4-yl]-5-chlorothiophene-2-sulfonamide as yellowish color oil (62 mg, 28.9%). Mass Spectrum (+ESI): 353 (M+H)+. Anal. Calc'd for C12H17ClN2O4S2.1.62 H2O: C, 37.29; H, 5.70; N, 7.26. Found: C, 37.62; H, 5.36; N, 7.31.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[K+]>O.ClCCl>[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]2[CH:23]=[CH:24][C:25]3[S:26][C:27]4[C:18](=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=4)[C:19](=[O:30])[C:20]=3[CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=c1c2cc(Cl)ccc2sc2ccc([S+](c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
To 320 ml of dichloromethane were suspended 20.2 g (0.1 mol) of diphenylsulfoxide and 24.6 g (0.1 mol) of 2-chlorothioxanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 3 hours. After completion of the reaction, the obtained reaction solution was washed with water (320 ml×5 times) and 18.4 g (0.1 mol) of potassium hexafluorophosphate and 200 ml of water were added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then, 9.2 g (0.05 mol) of potassium hexafluorophosphate and 100 ml of water were further added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then the obtained dichloromethane layer was washed with 200 ml of water and concentrated to dryness under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.0 g of objective substance as pale yellow glassy substance (yield: 7%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:27])[C@H:9]([CH3:26])[NH:10][C:11](=[O:25])[C@H:12]([CH3:24])[NH:13]C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:28]>C(O)(=O)C>[BrH:28].[CH:1]1([NH:7][C:8](=[O:27])[C@H:9]([CH3:26])[NH:10][C:11](=[O:25])[C@H:12]([CH3:24])[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC1CCCCC1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N[C@@H](C)C(=O)NC1CCCCC1

Procedure:
3.0 g of N-benzyloxycarbonyl-L-alanyl-L-alanine cyclohexylamide were treated with hydrogen bromide in acetic acid in a manner analogous to that described in Example 1(B)(ii) to give L-alanyl-L-alanine cyclohexylamide hydrobromide in the form of an oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9](=[O:20])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1Br.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.[Na+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:7][O:8][C:9](=[O:20])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)COc1ccc(Cl)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(Cl)cc1-c1ccccc1
Yield: 26.1 %

Procedure:
An aqueous Na2CO3 solution (2M, 18.5 mL) is added to a stirred solution of (2-bromo-4-chloro-phenoxy)-acetic acid methyl ester (5.03 g, 18.0 mmol), phenylboronic acid (2.24 g, 18.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.04 g, 0.900 mmol) in 1,4-dioxane (50 mL) at ambient temperature under argon. The resultant mixture is heated at 95° C. for 24 hours. At ambient temperature, 5N HCl (18.5 mL) is added to the mixture, followed by the addition of EtOAc (70 mL) and saturated aqueous NaCl solution (50 mL). The organic layer is separated, dried over MgSO4, filtered and concentrated. After chromatography on silica gel (CH2Cl2 followed by 0.5% HOAc/1% MeOH/98.5% CH2Cl2), 1.30 g (4.70 mmol, 26% yield) of the title compound and 2.41 g of the corresponding acid are obtained. The acid is dissolved in MeOH (5 mL)/CH2Cl2 (20 mL), and the solution is treated dropwise with (trimethylsilyl)diazomethane (2M in hexane, 8.8 mL). After stirring for 1 hour, the mixture is concentrated and chromatographed on silica gel (1:1 CH2Cl2/hexane) to give another 2.68 g of the title compound (9.68 mmol, 80% total yield) as oil. 1H NMR (CDCl3): δ3.77 (s, 3H), 4.58 (s, 2H), 6.80 (d, J=8.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.33-7.37 (m, 2H), 7.42 (br t, J=7.4 Hz, 2H), 7.56 (d, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[C:8]1[CH2:20][CH2:21][CH3:22])[C:3]([NH2:5])=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:36][C:11]1[C:10]2[N:9]=[C:8]([CH2:20][CH2:21][CH3:22])[N:7]([CH2:6][C:2]([CH3:23])([CH3:1])[C:3]([NH2:5])=[O:4])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)C(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
2,2-Dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide was treated with mCPBA (3.24 g, 14.4 mmol) followed by ammonium hydroxide (75 mL) and p-toluenesulfonyl chloride (2.5 g, 13 mmol) according to a modification of the method described in Part F of Example 1. The reaction was cooled to 0° C. before the addition of mCPBA. After the addition, the reaction was stirred for 15 minutes at 0° C. and 1.75 hours at ambient temperature. The reaction was not washed prior to the addition of ammonium hydroxide. The amination reaction was stirred for one hour. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol), recrystallized from toluene:methanol, dried overnight in a vacuum oven at 80° C., recrystallized from acetonitrile:water, and dried overnight in a vacuum oven at 80° C. to provide 0.553 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as a yellow solid, mp 219-221° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:18]([O-])(O)=O.[Na+].C(=O)=O>CO>[CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([O:11][CH3:18])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCC(=O)O
Reactant: O=C([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)CCC(=O)OC
Temperature: 25 °C

Procedure:
A solution of 4-butylamino-4-oxobutanoic acid (20 mmol) and concentrated sulfuric acid (1 ml) in MeOH (40 ml) is heated at reflux for 8 hours. The reaction is cooled to room temperature and saturated NaHCO3 is carefully added until CO2 gas no longer evolves. Most of the MeOH is removed in vacuo and the residue is partitioned between Et2O (100 ml) and H2O (40 ml). The water layer is re-extracted with Et2O (50 ml). The combined Et2O layers are washed with H2O (20 ml×2) and dried. Filtration and evaporation of solvent gives the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:33])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:34])[CH3:6])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([CH3:33])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:34])([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Reaction time: 4 h

Procedure:
0.243 g (0.483 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 2.9 ml of THF/EtOH=1/1, treated with 1.45 ml (3 eq.) of 1N NaOH and kept at room temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane produced finally 0.221 g of the title compound as white solid of mp. 149–151° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 3-Trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.86 min; [M+H]+=505.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31](F)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:13]=1)=[O:6].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:32]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:29])=[C:12]([NH:14][C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=2)[CH:13]=1)=[O:6]
Reactant: C1CCNC1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(F)c3)ccc2C)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3cc(F)cc(N4CCCC4)c3)ccc2C)cc1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 67 except that the reaction mixture was heated to 100° C. for 16 hours rather than for 6 days, N-[5-(3,5-difluorobenzamido)-2-methylphenyl]-4-diethylaminomethylbenzamide was reacted with pyrrolidine. There was thus obtained the title compound in 81% yield; NMR Spectrum: (DMSOd6) 0.98 (t, 6H), 1.95-2.0 (m, 4H), 2.2 (s, 3H), 2.4-2.5 (m, 4H), 3.3. (m, 4H), 3.6 (s, 2H), 6.4-6.5 (m, 1H), 6.85-6.95 (m, 2H), 7.2 (d, 2H), 7.45 (d, 2H), 7.58 (m, 1H), 7.8 (m, 1H), 7.95 (d, 2H), 9.8 (s, 1H), 10.1 (broad s, 1H); Mass Spectrum: M+H+503.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
13.50 g (corresponding to 59.66 mmol) of 4′-benzoyloxyacetophenone was dissolved in 1100 ml of methanol, and 34.52 g (corresponding to 71.59 mmol) of tetra-n-butylammonium tribromide was added thereto. The mixture was stirred overnight at room temperature, and was distilled off under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate and washed twice with water and then washed with an aqueous saturated sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/methylene chloride=1/1), to obtain 13.38 g (corresponding to 43.84 mmol) of 4′-benzoyloxy-2-bromoacetophenone (FIG. 5, Step 4).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[N:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO.CCOC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH3:11])=[N:8][C:6]=2[N:7]=1
Reactant: Cc1nc2nc(Cl)nc(Cl)c2s1
Reactant: C1COCCN1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 5,7-dichloro-2-methyl-thiazolo[4,5-d]pyrimidine (92 mg, 0.42 mmol) in MeOH (3 mL) was added morpholine (81 μL, 0.93 mmol) and the mixture stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and H2O. The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a cream solid (102 mg, 90%).
Reaction SMILES: CO[C:3](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:13]([C:10]([C:11]#[N:12])=[C:3]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=C(C#N)C#N)c1cccn1C
Product: Cn1cccc1C(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N

Procedure:
N-(2-{[2,2-dicyano-1-(1-methylpyrrol-2-yl)vinyl]amino}ethyl)(tert-butoxy)carboxamide was synthesized in the same manner using [methoxy(1-methylpyrrol-2-yl)methylene]methane-1,1-dicarbonitrile and tert-butyl N-(2-aminoethyl)carbamate. The ESI/MS data for this compound are shown below.