Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([C:24](=[O:27])[CH2:25][F:26])[CH2:20][C:21]([OH:23])=O)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:28][NH:29][CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH3:28][N:29]([CH3:30])[C:21](=[O:23])[CH2:20][CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:24](=[O:27])[CH2:25][F:26]
Reactant: CNC
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)O)C(=O)CF
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)N(C)C)C(=O)CF
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 3-(CBz-Val-amido)-5-fluoro-4-oxo-pentanoic acid (150 mg, 0.39 mmol) in THF (5 ml) was added a solution of 2.0 M dimethylamine in THF (0.2 ml, 0.4 mmol), EDCI (82.2 mg, 0.42 mmol) and HOBT (106 mg, 0.78 mmol) at 0° C. The resulting mixture was stirred for 2 h at 0° C., then was stirred at room temperature overnight. The solution was diluted with ethyl acetate (20 ml), washed with water (4×20 ml), and the organic layer was dried and evaporated. The residue was purified by chromatography over silica gel (hexane-EtOAc, 1:1 to pure EtOAc) to give 10 mg (6%) of the titled compound as a white solid. 1H NMR (DMSO-d6): 8.36-8.30 (m, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.33-7.29 (m, 5H), 5.45-5.09 (m, 2H), 5.03 (bs, 2H), 4.59-4.57 (m, 1H), 3.90-3.82 (m, 1H), 2.94 (bs, 3H), 2.84-2.73 (m, 4H), 1.97-1.93 (m, 1H), 1.25 (bs, 1H), 0.86-0.82 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[S:36]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:36]([C:39]3[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=3)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)c3cccc(C(=O)O)c3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 3-(chlorosulfonyl)benzoic acid.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)([OH:8])=[O:7].[CH3:20]O>>[CH3:20][O:7][C:6]([CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: CO
Reactant: O=C(O)CC1COc2ccccc2C1
Agent: O=S(=O)(O)O
Product: COC(=O)CC1COc2ccccc2C1
Yield: 98 %

Procedure:
1.5 ml of sulphuric acid (100% strength) are added to a solution of 7.69 g (40 mmol) of 3-carboxymethylchroman in 150 ml of methanol and the whole is boiled under reflux for 3 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in diethyl ether and washed, while cold, with water, sodium hydrogen carbonate and again with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.08 g (98%) of 3-methoxycarbonylmethylchroman are obtained in the form of a pale yellow oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][C:8](O)=[O:9])C(=O)C2=CC=CC=C12.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:32]([O:39][NH:40][CH2:41][CH2:42][N:43]1C(=O)C2=CC=CC=C2C1=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][N:40]([CH2:41][CH2:42][NH2:43])[C:8](=[O:9])[CH2:7][CH2:6][NH2:5])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2C(=O)N1CCNOCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NCCC(=O)N(CCN)OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
3-Phtalimido-propanoic acid (IV.1) (0.74 g, 3.375 mmol) was dissolved in tetrahydrofuran (15 ml, dried over potassium and distilled) under nitrogen, Triethylamine (0.494 ml, 3.54 mmol, 5% excess) was added to this solution and the mixture was cooled to -15° C. iso-Butyl chloroformate (0.46 ml, 3.54 mmol in 5 ml dry tetrahydrofuran) was added dropwise while maintaining the temperature at -15° C. After 15 minutes, N-benzyloxy-2-phtalimidoethylamine (IV.5) (1 g, 3.375 mmol in 10 ml dry tetrahydrofuran) was added dropwise at -15° C. and under nitrogen. The mixture was stirred during 3 hours at -15° C. and at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate (25 ml). The solution was extracted with water (25 ml), saturated sodium carbonate (25 ml), water (25 ml), 1M hydrochloric acid (25 ml), water (25 ml) and brine (25 ml). The organic solution was dried over magnesium sulfate, filtered and evaporated. The remaining white residue was recrystallized in hexane/ethyl acetate. The title compound was isolated as white crystals that were dried under vacuum. Yield: 53%
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[N:3]1.[Li]CCCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH3:1][N:2]1[C:6]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH3:7])[N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cn(C)nn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)nnn1C
Temperature: -70 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of 1,4-dimethyl-1,2,3-triazole (0.56 g, 5.77 mmol) in THF (5 mL) was added dropwise to a solution of BuLi (2.77 ml, 6.92 mmol, 2.5 M in hexane) in 30 mL of THF at −78° C. under N2. The resulting cloudy mixture was stirred at −70° C. for 1 h. Then tributyltinchloride (1.711 ml, 6.34 mmol) was added. The reaction mixture became clear and was stirred at this temperature for 30 min, and gradually warmed to rt. To the reaction mixture was added 10 ml of NH4Cl and 10 ml of water. The reaction mixture was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified on FCC (20% EA/Hexane) to give 1.7 g of a clear liquid (73%). LC-MS (ES) m/z=388 (M+H)+, 1H NMR (CDCl3, 400 MHz) δ 4.05 (s, 3H), 2.38 (s, 3H), 1.5-0.9 (m, 27H)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[C:9](OC)(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:9]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1N
Yield: 63.8 %

Procedure:
(S,S)-1,2-Diaminocyclohexane (1.14 g) and 2.96 g of methyl oleate were reacted in the same manner as in Reference Example 26 to obtain 2.41 g of the objective compound (yield: 65%)
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[C:19]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:27])=[CH:23][CH:24]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(biphenyl-4-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (d, J=7.9 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.56-7.69 (m, 4H), 7.47-7.50 (m, 4H), 7.38 (t, J=7.4 Hz, 1H), 3.78-3.84 (m, 4H), 3.72 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI+) M/Z 441 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]([OH:25])(=O)[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=5)[NH:4][N:3]=4)=[O:25])=[CH:23][CH:22]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: Cc1ccc(-c2cc(NC(=O)c3ccc(C(=O)Nc4cc(-c5ccc(C)cc5)[nH]n4)cc3)n[nH]2)cc1

Procedure:
Compound 472 was prepared from 3-amino-5-(4-methylphenyl)pyrazole and terephthalic acid. [M+H]+ calcd for C28H25N6O2: 477.20; found: 476.92.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1>C(#N)C.[Pd]>[N:19]1([CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:2]3[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCN(CCC2CCNCC2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Pd]
Solvent: CC#N
Product: Nc1cccnc1N1CCC(CCN2CCCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 0.317 g (2.00 mmol) of 2-chloro-3-nitro-pyridine in acetonitrile (10 mL) is added 0.393 g (2.00 mmol) of 1-(2-piperdin-4-yl-ethyl)-piperidine. The mixture is heated to 80° C. and stirred overnight. The mixture is cooled to room temperature and concentrated under reduced pressure. The crude residue is dissolved in ethanol (10 mL) and treated with 0.050 g (0.05 mmol) of 10% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is concentrated under reduced pressure to provide 0.577 g (quant.) of 4-(2-piperidin-1-yl-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([O:42]CC4C=CC=CC=4)=[C:37]([CH3:50])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:50])[CH:36]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(Cc3ccccc3)CC2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCNCC2)cc(C)c1O

Procedure:
1.62 g (2.22 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL MeOH were combined with 150 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 85:13.5:1.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([OH:21])=O)[S:8][C@H:7]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:32]=1.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH2:35])=[O:21])[S:8][C@H:7]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:6]=2[CH:32]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
A solution of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetic acid (200 mg, 426 μmol), 1,1'-carbonyidiimidazole (143 mg, 853 μmol) and tetrahydrofuran (5 mL) was heated at reflux for 1.5 hours. The resulting reaction mixture was cooled to 0° C. and a solution of tetrahydrofuran saturated with anhydrous ammonia (5 mL) was added. After 0.5 hours the reaction mixture was warmed to ambient temperature, concentrated under reduced pressure and purified by flash column chromatography (1:1 hexanes/ethyl acetate) to provide 200 mg (quantitative) of the title compound as a white powder.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=[O:15]>>[N+:1]([C:17]1[C:18]([F:21])=[C:19]([F:20])[C:11]([F:10])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5.0 mL of conc. HNO3 at 0° C. was slowly treated with 10.0 mL of conc. H2SO4, then 3.52 g (20.0 mmol) of 3,4,5-trifluoro-benzoic acid. The reaction mixture was warmed up to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 3.4 g (16.0 mmol, 80%) of 2-nitro-3,4,5-trifluoro-benzoic acid. LCMS: 222 (M+1)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[O:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)[C:19]([NH:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:25]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of the product from Example AJ ((S)-[2-(4-nitrophenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester) (2, 2.0 g, 5.25 mmol) was stirred in a solution of TFA/CH2Cl2 (15 mL/15 mL) for 30 minutes and concentrated to dryness. This crude reaction product was redissolved in CH2Cl2 (50 mL) then washed with NaHCO3 (aq) and brine. The EtOAc solution was further dried over NaHCO3 and concentrated to dryness to yield the title compound (1.34 g).
Reaction SMILES: [N+:1]1([O-:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3](N)[N:2]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].CCOCC>O>[N+:1]1([O-:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]([OH:14])[N:2]=1
Reactant: Nc1nc2ccccc2[n+]([O-])n1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [O-][n+]1nc(O)nc2ccccc21
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 7.5 g (46 mmol) 1,2,4-benzotriazine-3-amine 1-oxide (Chem. Ber. 46, 3522 (1913) in 75 ml water and 27 ml conc. sulphuric acid one adds dropwise at room temp. a solution of 13.3 g sodium nitrite in 25 ml water. One leaves to stand overnight, filters, takes up in soda solution, washes with ether, acidifies the aqueous phase, filters and recrystallises from glacial acetic acid. One isolates 4.7 g of title compound (63% of theory) of the m.p. 238-239° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:8]([CH3:22])[CH2:7]1.[N:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[N:34][CH:35]=1)=[C:28]=[O:29]>C1COCC1>[F:26][C:3]1[C:2]([NH:1][C:28]([NH:27][C:30]2[CH:35]=[N:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:29])=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:8]([CH3:22])[CH2:7]1
Reactant: C[C@@H]1CN(Cc2cccc(N)c2F)CCN1C(=O)OCc1ccccc1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OCc4ccccc4)[C@H](C)C3)c2F)cn1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a room temperature solution of (R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate (250 mg, 0.70 mmol, 1.0 equiv) in dry THF (3 mL) was added 5-isocyanato-2-methylpyridine (94 mg, 0.70 mmol, 1.0 equiv). After 1 h, the reaction was complete, as determined by LCMS. The reaction was washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (2%-10% MeOH/DCM) provided (R)-benzyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate (244 mg, 71%). LCMS m/z (APCI)=492.2 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH2:8][CH:9]1[S:13][C:12](=N)[NH:11][C:10]1=[O:15])[CH3:3].[OH2:22]>C(O)C>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH2:8][CH:9]1[S:13][C:12](=[O:22])[NH:11][C:10]1=[O:15])[CH3:3]
Reactant: O
Reactant: CCOc1ccc(CC2SC(=N)NC2=O)cc1OCC
Agent: Cl
Solvent: CCO
Product: CCOc1ccc(CC2SC(=O)NC2=O)cc1OCC
Yield: 86 %

Procedure:
In a mixture of 60 ml ethanol and 60 ml 1N-HCl is dissolved 5.0 g of the 5-(3,4-diethoxybenzyl)-2-iminothiazolidin-4-one prepared above and the solution is heated under reflux for 8 hours. The reaction solution is cooled, and water is added thereto. The aqueous mixture is subjected to extraction with chloroform to give 4.3 g (86.0%) of 5-(3,4-diethoxybenzyl)thiazolidine-2,4-dione as crystals. Recrystallization from ethyl acetate-n-hexane yields colorless prisms melting at 98°-99° C.
Reaction SMILES: O1CCOCC1.OS(O)(=O)=O.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19].[CH3:24][C:25](=[CH2:27])[CH3:26]>C(=O)=O.O>[CH3:24][C:25]([O:19][C:18](=[O:20])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:16][CH2:15][CH2:14][NH2:13])([CH3:27])[CH3:26]
Reactant: CCCC(CCCN)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
To a cooled solution of 7 mL of dioxane was added 0.7 mL of conc. H2SO4 dropwise. The solution turned purple in color. To this solution, 700 mg (3.5 mmol) of 5-amino-2-propylpentanoic acid monohydrochloride (7) was slowly added and the resulting solution was transferred into a pressure bottle. To this solution was added 12 mL of isobutylene and the resulting solution was slowly stirred magnetically under pressure at room temperature for 20 hours. The reaction vessel was cooled in dry ice, pressure was released, and the reaction vessel warmed up to room temperature to vaporize the excess isobutylene. The reaction mixture was poured into 100 mL of cold water. The aqueous part was extracted with 2×150 mL of ether, basified with 4N sodium hydroxide to pH 10, and extracted with 3×100 mL of ethyl acetate to yield 380 mg (1.76 mmol, 49%) of rac-5-amino-2-propylpentanoic acid 1,1-dimethylethyl ester (8) as an oil. NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [F:1][C:2](I)([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].S(S([O-])=O)([O-])=O.[Na+].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[CH3:42][S:43]SC>CN(C)C=O.O>[F:1][C:2]([S:43][CH3:42])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: CSSC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 20 %

Procedure:
Perfluorooctyl iodide (5.5 g), sodium dithionite (3 g), sodium hydrogen phosphate (3 g) and methyl disulphide (1 g) are stirred in dimethylformamide (10 cc) and water (5 cc) for 6 hours. After the usual treatment, methyl perfluorooctyl sulphide is obtained in 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (2.03 g, 0.011 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (6.38 g, 0.049 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 0.010 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.40 g, 35%) as a yellow oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[C:19](Br)[CH:20]=[C:21](Br)[C:16]4=[N:15][C:14]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[C:19]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH:20]=[C:21]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:16]4=[N:15][C:14]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(-c2nc3c(Br)cc(Br)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C1COCCN1
Product: Fc1ccc(-c2nc3c(N4CCOCC4)cc(N4CCOCC4)cn3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 24 %

Procedure:
In a similar manner as described in Example 3 from N-cyclopentyl-4-[6,8-dibromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (100 mg, 0.19 mmol) and morpholine at 100° C. for 3 days was obtained N-cyclopentyl-4-[2-(4-fluorophenyl)-6,8-di(4-morpholinyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinamine (25 mg, 24%) as a yellowish solid. 1H NMR (CDCl3) δ 8.66 (s, 1H), 8.11 (d, 1H), 7.66 (q, 2H), 7.10 (t, 2H), 6.49 (d, 1H), 6.43 (d, 1H), 5.24 (d, 1H), 4.45 (m, 1H), 4.03 (m, 4H), 3.94 (m, 4H), 3.60 (m, 4H), 3.13 (m, 4H), 2.0–2.1 (m, 2H), 1.4–1.9 (m, 6H); 19F NMR (CDCl3) δ −114.1; MS m/z 545 (M+1).