Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S(=O)(=O)(O)O>O>[C:1]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: CCCCCCCCO
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCOC(=O)c1cc(O)c(O)c(O)c1
Yield: 75 %

Procedure:
A mixture of 30 g of tara (about 0.1 mole of bound gallic acid), 120 g (0.95 mole) of n-octanol and 3 g of anhydrous sulfuric acid was heated at 140° C. for 7 hours with continuous removal of the water of reaction, after which the mixture was washed neutral with water and then evaporated down to give the crude n-octyl gallate in the form of an oil. The purity of the product was 65% and the yield was 75%, calculated as pure ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-methoxyphenyl)-piperazine hydrochloride (5.0 g, 20 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (200 mL). The crude solid product was collected by filtration, air dried, and purified by trituration with CHCl3 (1.3 g, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cc1

Procedure:
In analogy to example 19, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 4-methoxycarbonylphenylboronic acid was prepared the title compound as yellow oil, MS (ESI+): m/z=437.2 ([M+H]+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][C@@H:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1CCCO1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.6 [(M+H)+], mp 183.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (S)-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1.[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH:30]=O)[C:24]=2[NH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:30][N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:16][CH2:17]3)[C:24]=2[NH:23][CH:22]=1
Reactant: O=Cc1cccc2nc[nH]c12
Reactant: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc2c(OCCN3CCN(Cc4cccc5nc[nH]c45)CC3)cccc2n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
A mixture of 2-methyl-5-(2-piperazin-1-ylethoxy)quinoline (0.04 g, 0.15 mmol) and 3H-benzimidazole-4-carboxaldehyde (0.024 g, 0.15 mmol) in 1,2-dichloroethane (5 mL) was treated with sodium triacetoxyborohydride (47 mg, 0.22 mmol) and stirred at 20° C. under an atmosphere of argon for 24 h. The mixture was then treated with saturated aqueous NaHCO3 (20 mL) and the organic layer separated and purified directly by chromatography on silica (ethyl acetate to 10% methanol/ethyl acetate), to afford the title compound (0.013 g, 22%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34]([OH:36])=O)[N:33]=[C:21]4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C1C=CC2N(O)N=[N:45][C:43]=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][N:22]4[N:31]=[C:32]([C:34](=[O:36])[NH:45][CH3:43])[N:33]=[C:21]4[N:20]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(C(=O)O)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Reaction time: 8 h

Procedure:
To a solution of 8-3 (243 mg, 0.5 mmol) in DMF (5 mL) was added Methanamine HC salt (50 mg, 0.75 mmol), HOBT (73 mg, 0.5 mmol), EDCI (192 mg, 1 mmol) and TEA (125 mg, 1.25 mmol) at room temperature and the mixture was stirred for overnight. The mixture was diluted with 15 mL of H2O, extracted with EA, the combined organic phase was washed with NaHCO3 aq. and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.HPLC to give 8-7.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[C:27]([OH:30])[CH:26]=2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][N:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[C:27](=[O:30])[CH:26]=2)=[CH:23][CH:24]=1)(=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Nc1ccc(-c2cc(O)no2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(=O)n(-c3ccc(C(F)(F)F)cc3[N+](=O)[O-])o2)cc1
Reaction time: 5 h
Yield: 76.1 %

Procedure:
After mixing 6.4 g of 4-chloro-3-nitrobenzotrifluoride, 7.0 g of 5-(4-acetylaminophenyl)-3-hydroxyisoxazole, 4.5 g of potassium carbonate, and 50 ml of dimethyl sulfoxide, the reaction was performed for 5 hours at 70° C. After the reaction was over, the reaction mixture obtained was poured into water and crystals thus formed were recovered by filtration and recrystallized from a mixture of dimethylformamide and methanol to provide 8.8 g of the desired product with a yield of 75.9%. The melting point thereof was 238° C. to 239° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:6]12[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][CH:4]([CH2:13]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18]([S:3][CH2:1][CH3:2])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:12]2
Reactant: CCS
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Ethanethiol (0.433 mL, 5.84 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (2 g, 6.15 mmol), and sodium carbonate (1.955 g, 18.45 mmol) in DMF (12 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×20 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was recrystallised from 15% ethyl acetate/hexane to give N-(2-adamantyl)-6-chloro-2-ethylsulfanyl-pyridine-3-carboxamide (1.489 g, 69%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]2[C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][C:15]=3[CH2:14][CH2:13]2)[N:22]=[C:21]([CH3:25])[N:20]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:19]4=[O:34])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]2[C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][C:15]=3[CH2:14][CH2:13]2)[N:22]=[C:21]([CH3:25])[N:20]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])[C:19]4=[O:34])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:41]1[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=1[F:35])=[O:5]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)O)c(F)c1)CC3
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoic acid (0.75 g), pentafluorophenol (1.77 g), N,N-dicyclohexylcarbodiimide (0.66 g), N-hydroxybenzotriazole (0.01 g) and methylene chloride (100 ml) was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained pentafluorophenyl o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate as a gum (0.72 g);
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][NH:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=1
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccc(C2CC2)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cccc(CCNCc2ccc(C3CC3)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.927 g of 2-chloro-4-cyclopropyl-benzaldehyde (5.37 mmol) and 1.52 g 2-(3-trifluoromethyl-phenyl)-ethylamine (8.05 mmol) were dissolved in 15 ml methanol and refluxed for 2 h. After cooling down to rt, the reaction mixture was treated in portions with 305 mg NaBH4, stirred at rt for 10 min and 12 h under reflux. The reaction mixture was then cooled to rt, treated with 1 ml 1N HCl and concentrated in vacuo. The resulting oil was then diluted with EtOAc, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (40 g silicagel, heltane/AcOEt 2:1) leading to 1.41 g (2-chloro-4-cyclopropyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine (74%) as a yellow oil. MS: 354 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH2:2]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH2:2]1
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCCOC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCCOC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
A mixture of (S)-1-[1-(tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethylamine from Example 18 (295 mg, 1.20 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (400 mg, 1.68 mmol) and DIPEA (0.38 mL, 2.16 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 16 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. Purification by Isolute® SCX-2 was repeated a second time and then the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 128 as a white solid (310 mg, 71%). LCMS: RT 2.42 and 2.46 min [M+H]+ 364.0. 1H NMR (DMSO, 400 MHz): δ 8.38-7.88 (3H, m), 7.80 (1H, t, J=8.38 Hz), 7.65-7.54 (1H, m), 7.21-7.09 (2H, m), 5.95 (1H, br), 4.71-4.57 (1H, m), 4.14-4.04 (1H, m), 4.00-3.86 (1H, m), 3.83-3.71 (1H, m), 3.55-3.43 (1H, m), 3.16 (0.5H, d, J=4.68 Hz), 2.56-2.43 (0.5H, m), 2.36-2.23 (0.5H, m), 2.02 (0.5H, br), 1.83-1.72 (4H, m), 1.56 (0.5H, bd, J=13.68 Hz), 1.24-1.08 (0.5H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]([CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(C2CCCCC2)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
5.81 g (33.0 mmol) of 4-cyclohexylphenol, 5.57 g (30.0 mmol) of 4-chloro-2,5-dimethyl-nitrobenzene and 6.22 g (45.0 mmol) of potassium carbonate are suspended in 30 ml of N,N-dimethylformamide and the suspension is stirred at 150° C. for 12 h. It is then poured into ice-water and the precipitate is isolated by filtration, washed repeatedly with hexane and dried under reduced pressure (12.1 g, purity 71.9%, yield 88.9%, log P (pH 2.3)=6.69).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[CH:1]1([NH:4][C:10]2[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1NC1CC1

Procedure:
The compound was prepared by reacting cyclopropylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product having a melting point of 86°-87° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[O:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][N:31]=1)=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][C:27]1[O:28][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:30][N:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)c1cnc(C=O)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cnc(C=C(Br)Br)o1
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a stirred solution of carbon tetrabromide (24.0 g, 72.4 mmole) in methylene chloride (200 mL) at 5-10 deg C. under argon atmosphere was added triphenylphosphine (37.0 g, 141 mmole) in portions. The reaction mixture was stirred for 5 min and treated with a solution of 2-formyl-5-t-butyloxazole in methylene chloride (60 mL). The reaction mixture was stirred at room temperature for 2 hours, while a white solid precipitated out of the solution. The solid was filtered off, the filtrate concentrated and purified (silica gel, EtOAc/hexane 1:4) to give 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene as a pale solid (9.13 g, 39 %).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[N:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[N:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)nc2c1=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2nc(CN3CCOCC3)sc21
Temperature: 190 °C

Procedure:
A mixture of ethyl 4-methyl-2-(morpholin-4-ylmethyl)-7-oxo-4,7-dihydro[1,3]-thiazolo[5,4-b]pyridine-6-carboxylate (Preparation 30, 105 mg) and 4-chlorobenzyl-amine (1 mL) is heated to 190° C. for 40 min. and then allowed to cool to ambient temperature. The solvent is removed in vacuo. The mixture is diluted with ether to precipitate 89 mg (66%) of the title compound as a tan solid. Physical characteristics: 1H NMR (DMSO-d6) δ2.59, 3.64, 3.91, 4.00, 4.56, 7.33-7.36, 8.75, 10.59; IR (diffuse reflectance) 2857, 2809, 1662, 1599, 1569, 1550, 1531, 1526, 1517, 1492, 1346, 1296, 1116, 797, 732 cm−1. Anal. Found: C, 55.50; H, 4.98; N, 12.00.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O1CCCC1>>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[OH:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1oc(C(C)(C)C)cc1C=O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1C(O)C1CCCCC1
Yield: 62 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-tert-butyl-2-methyl-3-furaldehyde (2.5 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (23 mL) to give the title compound (2.3 g, 62%) as an oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[CH2:31]Cl)C1C=CC=CC=1.[CH3:33][NH:34][CH3:35]>O1CCCC1>[CH2:20]([C@@H:18]1[CH2:19][N:14]2[C:15]([C:16]3[NH:8][C:9]([CH2:31][N:34]([CH3:35])[CH3:33])=[N:10][C:11]=3[N:12]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:27])=[N:17]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(CCl)n2Cc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(CN(C)C)nc21
Temperature: 70 °C
Yield: 14.3 %

Procedure:
Compound 42 (60 mg, 0.134 mmol) obtained in Example 42 was dissolved in tetrahydrofuran (3 mL), to the solution was added a 2 mol/L solution of dimethylamine (200 μL, 0.401 mmol, 3.1 equivalents) in tetrahydrofuran, and the mixture was stirred with heating at 70° C. for 5.5 hours. The reaction solution was concentrated and then directly purified by silica gel column chromatography (chloroform:methanol=99:1 to 97:3), and the title compound (7 mg, 19%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C1(=O)O[CH2:15][CH2:14][O:13]1>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:15][CH2:14][OH:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=C1OCCO1
Product: CC(=O)Nc1cccc(OCCO)c1
Yield: 99 %

Procedure:
The title product was prepared according to the procedure described in Example 114, Step 1, starting from 3-acetamidophenol (2.10 g, 13.9 mmol) and ethylene carbonate (0.88 g, 10 mmol). The crude product was purified by column chromatography on silica using toluene/EtOAc/MeOH (49:49:2). Oil; yield 99%. MS m/z 195 (M)+.
Reaction SMILES: [NH3:1].[CH:2]([N:15]1[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[CH:2]([N:15]1[CH2:18][CH:17]([NH2:1])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CO
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
Ammonia gas was bubbled through a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (952.4 mg, 3 mmol) in MeOH (15 mL). After 2 hours, TLC showed the reaction to be complete. The title compound was obtained as a white solid (643.5 mg, 90%) after removal of the solvent. MS: 239 (MH+); HPLC Rf: 3.54 min; HPLC purity: 98%.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]=[CH:21][CH2:22][Br:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:23][CH2:22][CH:21]=[CH:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCC=CCBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCOCCOCCOCC=CCBr
Yield: 98.8 %

Procedure:
At RT, a solution of 1 g of 3-(2-{2-[2-(4-bromo-but-2-enyloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid tert-butyl ester (commercially available), 6 ml of TFA and 3 ml of DCM is stirred during 3 hrs, and then concentrated to dryness under RP. The oily residue is diluted with toluene and concentrated to dryness under RP affording 853 mg of 3-(2-{2-[2-(4-bromo-but-2-enyloxy)-ethoxy]-ethoxy}-ethoxy)-propionic acid in the form of a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20]C)=[O:19])=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([OH:20])=[O:19])=[N:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1-c1nnc(-c2ccc(C(C)(C)C)cc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccccc3C(=O)O)o2)cc1
Yield: 87.7 %

Procedure:
A mixture of methyl 2-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1.50 g), 1 M aqueous sodium hydroxide solution (9.0 ml), tetrahydrofuran (18 ml) and methanol (9 ml) was heated under reflux for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (1.26 g, yield 87%) as a colorless amorphous solid. NMR (CDCl3) δ: 1.35 (9H, s), 7.52 (2H, d, J=8.8 Hz), 7.67–7.76 (4H, m), 7.96–8.04 (3H, m), 8.15–8.20 (1H, m).