Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]([C:46]#[N:47])([CH3:49])[CH3:48])=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: CC(C)(N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)NC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 2-amino-2-methylpropionitrile (22 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H19ClN6O2, 351.13; found 351.2.
Reaction SMILES: [CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8](Cl)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.N1C=CC=CC=1.O>CC(C)=O>[CH2:1]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCCCCC)C(=O)Cl
Reactant: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCC(CCCCCC)C(=O)n1cncn1
Yield: 118 %

Procedure:
2-Hexyldecanoyl chloride (25 g) was added during 10 minutes to a stirred solution of 1,2,4-triazole (14 g) and pyridine (10 ml) in acetone (50 ml). During addition the temperature rose from 20° to 38°. The mixture was drowned into water and extracted with toluene, and the toluene solution was washed with water and then distilled yielding 1-(2'-hexyldecanoyl)-1,2,4-triazole (33 g), b.p. 156°-160° at 0.15 mm of mercury. This compound was evaluated as an extractant for copper using the procedure of Example 1 and the results are presented in Table 1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]>CN(C)C=O.C(OCC)C>[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
313 mg of sodium azide was added to 1.63 g of (1R, 2R, 3S, 5R, 6R)-2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 16.3 mL of N,N-dimethylformamide, and the mixture was stirred for 1 hour at room temperature, and then for 20 hours at 35° C. 104 mg of sodium azide was further added thereto, and the mixture was stirred for 18 hours at 35° C. After being diluted with 50 mL of diethyl ether, the mixture was washed twice with water and then with a saturated aqueous solution of sodium chloride. The organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 775 mg of (1R, 2R, 3R, 5R, 6R)-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([O:12][C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.2 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with benzyl bromide (0.655 ml, 5.5 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was treated with water (50 ml). The solid material was collected by suction filtration, rinsed with water (2×50 ml) and sucked dry under reduced pressure to afford methyl 4-benzyloxy-2-hydroxy-5-isopropylbenzoate (1.25 g, 83%) as colourless needles. 1H NMR (DMSO-d6) 10.68 (1H, br s), 7.57 (1H, s), 7.48-7.40 (4H, m), 7.34 (1H, m), 6.64 (1H, s), 5.20 (2H, s), 3.87 (3H, s), 3.18 (1H, m), 1.17 (6H, d). MS: [M+H]+ 301.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][CH:9]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:10](O)=[O:11])(=[O:7])[CH3:6]>CN(C)C=O>[C:5]([O:8][CH:9]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:10]([Cl:3])=[O:11])(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC(OC(C)=O)C(=O)O
Solvent: CN(C)C=O
Product: CC(=O)OCC(OC(C)=O)C(=O)Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (62 ml, 0.86 mole) was added dropwise to 2,3-diacetoxypropanoic acid (14) in a flask to which a drop of N,N-dimethylformamide had been added. The mixture was then stirred at ambient temperature over night and then evaporated to a syrup at a temperature ≦40° C. The syrup was taken up in diethyl ether (60 ml) and activated charcoal (0.3 g) added. The mixture was then filtered through a tight glass filter and evaporated in vacuo (10 torr). The oily residue was distilled in a Kugelrohr apparatus to give 24.6 g (68%). Identity and purity checked by 1HNMR in CDCl3.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25]>C1COCC1>[CH2:24]([O:26][CH2:27][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:25]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCn1ccc2c(C(=O)OC)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Under nitrogen, to a solution of methyl 1H-indole-4-carboxylate (80 g, 0.46 mol) in THF (700 mL) is added potassium hexamethyldisilazide (1 M in THF, 550 mL, 0.55 mol) in drops at 0° C. The mixture is stirred at 0° C. for 30 minutes (min) and chloromethyl ethyl ether (51 mL, 0.55 mol) is then added at 0-5° C. After the addition, the reaction mixture is stirred at ambient temperature for another 3 hours (h), quenched carefully with 300 mL of water and extracted with ethyl acetate (EA, 3×300 mL). The combined extracts are washed with aqueous saturated sodium chloride (2×400 mL), then dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (80 g, 75%). MS (m/z): 234 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:45]([O:47]C)=O)[CH:40]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:50]>O1CCOCC1>[C:45]([C:41]1[CH:40]=[C:39]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([CH:32]=2)[CH2:30][N:15]([C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH:12]2[CH2:11][CH2:10][CH:9]([N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:14][CH2:13]2)[CH:44]=[CH:43][N:42]=1)(=[O:47])[NH2:50]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(-c2ccnc(C(N)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of methyl ester 148 (50 mg, 0.07 mmol) in 1,4-dioxane (2 mL) is treated with conc. ammonia (1 mL) and the reaction stirred at RT 6 h. LC/MS at this juncture showed some residual starting material so more conc. ammonia (1 mL) is added and the reaction mixture heated 2 h at 40° C. LC/MS at this juncture showed the reaction is complete. The solvents are removed in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C@H:16]3[C@@:25]45[CH2:35][CH2:36][C@:22]6([CH2:23][C@@H:24]4[C@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[O:28][CH2:27][O:26]5)[C@@:17]43[CH2:18][CH2:19][N:20]([CH2:38][CH:39]3[CH2:41][CH2:40]3)[C@@H:21]6[CH2:37][C:12]([C:13]=24)=[CH:11][CH:10]=1)C1C=CC=CC=1.CI>>[C:31]([C@:29]1([CH3:30])[C@@H:24]2[C@@:25]3([CH2:35][CH2:36][C@:22]4([CH2:23]2)[C@@:17]25[C:13]6[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH3:1])[C:14]=6[O:15][C@@H:16]32)[CH2:37][C@H:21]4[N:20]([CH2:38][CH:39]2[CH2:40][CH2:41]2)[CH2:19][CH2:18]5)[O:26][CH2:27][O:28]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Solvent: CI
Product: COc1ccc2c3c1O[C@H]1[C@@]45CC[C@@]6(C[C@@H]4[C@@](C)(C(C)(C)C)OCO5)[C@@H](C2)N(CC2CC2)CC[C@]316
Yield: 49.4 %

Procedure:
The title compound 8 was synthesized similar to the procedure described in Example 5 for compound 7 using methyl iodide instead of benzyl bromide. After column chromatography, 418 mg (49.4% yield) of compound 8 was isolated in a purity of 98.8% as an white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:32]=[CH:31][C:30]([CH:33]([CH3:37])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C(=O)O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1

Procedure:
(4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-phenyl)-propionic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 4-bromo phenyl propionic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H34N4O3 (m/e) 486, obsd 487 (M+H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([CH3:24])=[N:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:20]1=[CH2:24])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc2c(c1)CCN=C2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C1c2ccc(OC)cc2CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl chloroformate (0.30 mL) was added to an ice-cold solution of 6-methoxy-1-methyl-3,4-dihydroisoquinoline (0.36 g) and triethylamine (0.58 mL) in 10 mL dichloromethane. After 0.5 h, the volatile material was evaporated to furnish 0.66 g of 6-methoxy-1-methylene-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13](I)=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([CH:20]=[CH2:21])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(I)cc1Cl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(Cl)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a solution of N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (3.0 g, 6.4 mmol) in THF (40 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.0 g, 12.8 mmol), 2M Na2CO3 (12 ml) and Pd2(PPh3)4 (222 mg, 0.19 mmol). The solution was degrassed with N2, and heated at 80° C. overnight. Then the reaction mixture was cooled to room temperature, poured into water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=10:1 to 3:1) to give N-(2-bromopyridin-4-yl)-2,6-dichloro-4-vinylbenzamide (2.2 g, yield: 92%). 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.51 (d, J=3.5 Hz, 1H), 7.35 (s, 2H), 6.61 (m, 1H), 5.86 (d, J=17.5 Hz, 1H), 5.48 (d, J=11.0 Hz, 1H). LCMS (ESI) m/z: 371.0 [M+H+].
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH:9]C(=O)OC(C)(C)C)[CH2:4]1)#[CH:2].[ClH:17]>O1CCOCC1>[C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([NH2:9])[CH2:4]1)#[CH:2].[ClH:17]
Reactant: C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: C#C[C@@H]1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl ((1S,3R)-3-ethynylcyclohexyl)carbamate (P0, 1.4 g), a 4.0 mol/L solution of hydrochloric acid in 1,4-dioxane (30 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain (1S,3R)-3-ethynylcyclohexaneamine (U1) hydrochloride as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:28]([C:35]([NH:37][OH:38])=O)C1C=CC=CC=1>C1COCC1>[OH:38][NH:37][C:35]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCNCC2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)NO)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.7 %

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine (118 mg, 0.327 mmol) in anhydrous THF (3.5 mL) was added N-(phenoxycarbonyl)hydroxylamine (57.5 mg, 0.344 mmol). The mixture was warmed to reflux and stirred for 17 h, then cooled to ambient temperature and concentrated to a yellow solid. Purification by column chromatography on silica gel (eluted with CH2Cl2/MeOH/NH4OH) follow by purification by radial chromatography (eluted with CH2Cl2/MeOH/NH4OH 94:5:1) afforded 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-piperidine-1-carboxylic acid hydroxyamide (86 mg, 61%) as a yellow solid. 1H NMR (CDCl3) δ 1.69-1.79 (m, 2H), 1.96 (d, 1H, J=11.1 Hz), 2.04 (s, 3H), 2.27 (s, 3H), 2.63-2.77 (m, 3H), 3.85 (s, 2H), 4.05 (d, 2H, J=12.7 Hz), 4.25 (s, 2H), 6.88 (s, 1H), 7.22 (s, 1H), 7.35 (t, 1H, J=7.7 Hz), 7.54 (d, 1H, J=5.9 Hz), 7.59 (t, 1H, J=7.5 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.5 Hz), 8.18 (s, 1H), 8.39 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 17.9, 18.1, 26.9, 43.8, 53.4, 54.6, 57.7, 120.6, 126.3, 126.9, 127.7, 129.8, 132.0, 132.9, 136.3, 138.9, 141.3, 146.4, 153.8, 158.9, 160.7; ES-MS m/z 420 (M+H). Anal Calcd. For C24H29N5O2.0.1(CH2Cl2): C, 67.63; H, 6.88; N, 16.36. Found: C, 67.59; H, 6.99; N, 16.02.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]3[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13][C:11]3=[CH:12][C:4]=2[O:3]1.CO.[CH:22]1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]3[CH2:15][CH:14]([C:16]([O:18][CH3:22])=[O:17])[CH2:13][C:11]3=[CH:12][C:4]=2[O:3]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1(C)CC(=O)c2cc3c(cc2O1)CC(C(=O)O)C3
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2cc3c(cc2C1)C(=O)CC(C)(C)O3
Temperature: 20 °C
Reaction time: 2 h

Procedure:
4.98 g (19.2 mmol) of the compound from Example 15 are dissolved in 38 ml of CH2Cl2 and 19 ml of absolute MeOH and 4.35 g (21.1 mmol) of dicyclohexylcarbodiimide and 20 ml of dimethylaminopyridine are added at 0° C. The mixture is allowed to come to room temperature and is stirred at 20° C. for 2 h. Precipitated dicyclohexylurea is filtered off and washed well with CH2Cl2, and the combined CH2Cl2 phases are washed twice with 1N NaOH solution, once with 1N hydrochloric acid and once with NaCl solution. After drying over Na2SO4, the solution is evaporated and the residue is flash chromatographed on silica gel (eluent: methylene chloride)
Reaction SMILES: C1N2CN3CN(C2)CN1C3.N12CCCN=C1CCCCC2.[F:22][CH:23]([F:33])[C:24]1[O:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1>C(Cl)Cl.[Cu](Br)Br>[F:33][CH:23]([F:22])[C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1
Reactant: COC(=O)C1COC(C(F)F)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(C(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a cooled (0° C.) suspension of copper(II) bromide (5.95 g, 26.6 mmol) in DCM (50 ml) was added hexamethylenetetramine (3.73 g, 26.6 mmol, Aldrich) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (4.0 ml, 26.8 mmol, Aldrich). After 20 min a solution of methyl 2-(difluoromethyl)-4,5-dihydrooxazole-4-carboxylate (1.59 g, 8.88 mmol) in DCM (5 mL) was added and the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was partitioned between EtOAc and 1:1 satd NH4Cl-conc NH4OH. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed consecutively with 1:1 satd NH4Cl-conc NH4OH (1×), 10% citric acid (1×), satd NaHCO3 (1×) and brine (1×). The organic layer was dried over MgSO4. The filtrate was purified by silica gel flash chromatography, eluting with 25% EtOH/EtOAc:hexanes (0:1→1:0) to give 708 mg (45%) of a white crystalline solid. MS m/z=178 [M+H]+. Calculated for C6H5F2NO3:177.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(NCc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccncc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A 3.3 g. portion of 4-(4-chlorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for several days, adding another 0.5 ml. of methanesulfonyl chloride in the process. The mixture was then diluted with dichloromethane, extracted with aqueous sodium bicarbonate and with water, dried over magnesium sulfate and evaporated. The residue was taken up in dichloromethane and chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were combined and evaporated, and the residue was triturated with petroleum ether and diethyl ether to obtain 2.1 g. of the desired product.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1>CO.[Pd]>[O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(C=C2CCCS2(=O)=O)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)O)c1ccc(CC2CCCS2(=O)=O)cc1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
2-[4-(1,1-Dioxotetrahydro-1λ6-thiophen-2-ylidenemethyl)phenyl]propionic acid (90 mg) obtained in Example 41 was dissolved in methanol (2.0 ml), and to the solution was added 5% palladium/activated carbon (20 mg), and the mixture was stirred for 1 hour under hydrogen flow. The reaction mixture was filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate=1/2) to give the title compound (63 mg, 70%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]([N:40]=[C:41]=[O:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCCCCC>C(Cl)Cl>[C:32]([NH:40][C:41]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)=[O:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
To a solution of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenylamine (110 mg, 0.27 mmol) in methylene chloride (3 ml) was added benzoylisocyanate (0.038 ml, 0.27 mmol) at 5° C., and the mixture was stirred at room temperature for 16 hours. To the mixture was added hexane (9 ml), and the resulting precipitate was collected, washed with hexane to give (±)-1-benzoyl-3-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}urea (114.9 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]3[S:30][CH:31]=[C:32]([CH:34]([CH3:36])[CH3:35])[N:33]=3)[CH:24]=[CH:23][N:5]2[C:6](=[O:22])[C:7]=1[C:8]1[N:9]=[N:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:12]=1.[CH2:37](N(CC)CC)C.S(OC)(OC)(=O)=O.O>CN(C)C=O>[CH:34]([C:32]1[N:33]=[C:29]([CH2:28][CH2:27][C:25]2[CH:24]=[CH:23][N:5]3[C:6](=[O:22])[C:7]([C:8]4[N:9]=[N:10][N:11]([CH2:13][C:14]5[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=5)[N:12]=4)=[C:2]([O:1][CH3:37])[N:3]=[C:4]3[CH:26]=2)[S:30][CH:31]=1)([CH3:36])[CH3:35]
Reactant: CCN(CC)CC
Reactant: COc1ccc(Cn2nnc(-c3c(O)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Cn2nnc(-c3c(OC)nc4cc(CCc5nc(C(C)C)cs5)ccn4c3=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-3-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one (24 mg) was dissolved in dimethylformamide (1.5 ml), added with triethylamine (1.6 ml) and dimethyl sulfate (22 ml) and stirred overnight at room temperature. The reaction mixture was further added with dimethyl sulfate (5 ml), stirred for 4 hours, and then added with water and extracted with ethyl acetate. After the organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5 mg).