Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12])[CH3:6].CO.[Li+].[OH-].O>C1COCC1>[F:30][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])=[CH:21][N:20]=2)[CH:17]=1)[C:11]([OH:13])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Yield: 89.7 %

Procedure:
Methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (19.8 g, 46.6 mmol) was dissolved in THF (300 mL) and methanol (100 mL) and LiOH (1N, 51.3 mL) was added followed by water dropwise till it went cloudy. The resultant solution was stirred for 16 hours at room temperature. The organics were removed by evaporation under reduced pressure. The aqueous slurry was diluted with water (100 mL), washed with ethyl acetate (200 mL), then acidified by addition of hydrochloric acid (2N) until a solid precipitated. The resulting suspension was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the product (17.2 g, 90%). 1H NMR δ (CDCl3): 1.39 (d, 3H), 3.17 (s, 3H), 3.19 (s, 3H), 3.93-4.05 (m, 2H), 4.60-4.69 (m, 1H), 6.26 (t, 1H), 6.99 (t, 1H), 7.50-7.55 (m, 2H), 8.38 (d, 1H), 8.55 (d, 1H), 10.17 (s, 1H); m/z 412 (M+H)+
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C:7](=[N:8][C:9]([CH3:10])([CH2:43][C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[C:11]([O:13][CH3:14])=[O:12])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate from Step A (9.78 g, 36.6 mmol) in 60 ml DMF at 0° C. was added a 1M solution of sodium bis(trimethylsilyl)amide in THF (45.72 ml, 45.72 mmol) over a 20 min period. After 30 min, a solution of 4-picolyl chloride hydrochloride (3.00 g, 18.29 mmol) in 40 ml DMF was added to the reaction via cannula over a 25 min period. The reaction was warmed to rt and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 3M LiCl (2×) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc/hexanes) afforded methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate as a white solid (5.28 g, 81%). LCMS [M+H]=359.2. 1H NMR (d4-MeOH) δ 8.51 (dd, J=4.5, 1.5 Hz, 2H), 7.56 (dd, J=8.4, 1.4 Hz, 2H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.10-7.07 (m, 2H), 3.33 (A of AB, d, J=13.0 Hz, 1H), 3.27 (s, 3H), 3.18 (B of AB, d, J=12.9 Hz, 1H), 1.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1.ON1C2C=CC=CC=2N=N1.[CH2:31]([CH2:33][NH2:34])[OH:32].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:33][NH:34][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])[CH:7]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC(=O)NCCO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (Step C, 6.0 g, 22.2 mmol), 1-Hydroxybenzotriazole (7.19 g, 53.2 mmol), and Ethanolamine (2.70 g, 44.2 mmol) in methylene chloride (30 ml) and DMF (5 ml) was added EDCI (7.66 g, 40 mmol) at 0° C., the resulting reaction mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was dissolved in methylene chloride (10 ml) and washed with NaHCO3, 0.1M HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 9:1) to provide the title compound.
Reaction SMILES: [CH2:1]([S:6](Cl)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:10](N)[CH2:11][CH3:12].C([N:16](C(C)C)C(C)C)C>C(Cl)Cl>[CH2:10]([CH:1]([S:6]([NH2:16])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH3:12]
Reactant: CCCCCS(=O)(=O)Cl
Reactant: CCCN
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(CCC)S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL CH2Cl2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 mmol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH2Cl2 under a nitrogen atmosphere. The reaction was stirred at 0° C. for 30 min, then at 25° C. for 4 h. The solution was partitioned between 20 mL of 1.0 M aqeous NaHSO4 and 25 mL CH2Cl2. The organic phase was washed sequentially with 25 mL H2O and 25 mL brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide 739 mg (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) Rf 0.23; 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J=7 Hz, 3H), 0.97 (t, J=7 Hz, 3H), 1.28-1.50 (br m, 4H), 1.52-1.68 (m, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (m, 2H), 3.08 (q, J=6 Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCl/NH3) m/e 211 (M+NH4)+.
Reaction SMILES: C1(=O)CCCCC1.O=[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.[NH2:23]O>>[CH2:21]1[C:16]2[CH:17]([NH:23][CH:9]3[C:10]([CH:15]=2)=[CH:11][CH:12]=[CH:13][CH2:14]3)[CH2:18][CH2:19][CH2:20]1
Reactant: O=C1CCCCC1CC1CCCCC1=O
Reactant: NO
Solvent: O=C1CCCCC1
Product: C1=CCC2NC3CCCCC3=CC2=C1

Procedure:
Sym. octahydroacridine was prepared by converting cyclohexanone to di-(2-oxo-cyclohex-1-yl)-methane and further reacting with hydroxylamine according to the method of Gill et al. (JACS 1952, 74, 4923) and was isolated as a colourless oil b.p. 110°-15°/0.5 mm. in 40% overall yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]=[C:32]=[O:33])=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]3)=[O:33])=[CH:28][CH:29]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene (0.201 g, 0.95 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 415 (M+H)+; MS (ESI−) m/z 413 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.95 (s, 3H), 4.36 (d, J 5.6, 2H), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m, 2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, 1H); Anal. Calcd for C19H6BrN3O3: C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N, 9.84.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([CH3:13])[CH:3]=1.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[CH:3][C:4]=1[CH3:13])[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCN(CC)c1ccc(Br)cc1C
Agent: [Li]CCCC
Product: CCN(CC)c1ccc(B(O)O)cc1C
Yield: 111.2 %

Procedure:
In a manner similar to that of Example 1c, by reacting 8 g of (4-bromo-2-methylphenyl)diethylamine (33 mmol) with 16 mL of a 2.5 M solution of n-butyllithium and 11.5 mL (50 mmol) of triisopropyl borate, 7.6 g of 4-diethylamino-3-methylphenylboronic acid (yield=100%) are obtained in the form of a thick oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[N:20]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:26]([N:20]1[CH2:25][CH2:24][N:23]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22][CH2:21]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCN(C(C)=O)CC3)s2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (100 mg; 0.3 mmol; 1 eq) is dissolved in anhydrous DCM (5 ml). The reaction is put under nitrogen. 1-Piperazin-1-yl-ethanone (76.1 mg; 0.59 mmol; 2 eq), diisopropylethylamine (0.3 ml; 1.78 mmol; 6 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. The solvents are evaporated and the crude product is purified by preparative HPLC. Compound (2) is isolated as a pale yellow powder (35 mg; 27%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[N:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCNC1
Solvent: Cc1ccccc1
Product: C(=NC1CCNC1)c1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Benzaldehyde (21.2 g; 0.20 mol) was added, dropwise, to a solution of 3-aminopyrrolidine (17.2 g; 0.20 mol) in toluene (80 ml). The solution thus obtained was stirred at room temperature. After 3 h the solvent was removed by evaporation at reduced pressure and the residue was taken up twice with toluene. 21 g N-(phenylmethylene)pyrrolidine-3-amine was thus obtained, and was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(Br)cn1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyridine (10.0 g, 62.1 mmol) in chloroform (200 mL) was added N-bromosuccinimide (12.0 g, 67.4 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2Cl2 (200 mL) and 1N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (0-5% EtOAc/CH2Cl2) yielding 12.0 g (80%) of 5-bromo-4-(trifluoromethyl)-2-pyridylamine LCMS (m/z): 241/243 (MH+). 1H NMR (CDCl3): δ 8.28 (s, 1H), 6.77 (s, 1H), 4.78 (bs, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.CC[N:14](C(C)C)C(C)C.C[O:22][C:23](=O)[CH2:24][CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])=O.[NH4+]>C1COCC1.[Pd].C(#N)C>[NH2:14][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:23](=[O:22])[CH2:24][CH2:25][N:26]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)CCNC1CCCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Nc1ncc2c(n1)N(C1CCCCC1)CCC(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
2,4-dichloro-5-nitropyrimidine (Aldrich; 10 g, 0.052 mol) was dissolved in THF (250 mL). To this was added DIPEA (11 mL, 0.062 mol) and the reaction cooled to 0° C. Methyl3-(cyclohexylamino)propanoate (9.5 g, 0.052 mol) in THF (30 mL) was slowly added. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. To the reaction mixture was added saturated NH4OH(aq) (100 mL), and the reaction heated at 55° C. for 4 hours using a dry ice condenser. The reaction mixture was extracted with DCM (3×100 ml), and combined organic extracts dried and evaporated. The residue was dissolved in methanol (200 mL). Ammonium formate (33 g, 0.52 mol) and 10% palladium (1.5 g) were added. The reaction was heated at reflux for 5 hours, filtered and the methanol evaporated to yield a dark orange solid, which was quenched with 2.0 N NaOH(aq) (100 mL), extracted with DCM (3×150 mL), and combined extracts dried and evaporated to yield an orange solid. Hot acetonitrile was added, this was stirred and then sonicated to give a precipitate that was filtered and dried to yield the title compound as a yellow solid (7.5 g, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:46]=[CH:45][C:19]([O:20][C:21]2[N:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:22]=2[C:23]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:24])=[CH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:23]([C:22]2[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:46][CH:45]=3)=[N:35][C:34]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[O:24])[CH2:27][CH2:28]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 81 %

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (0.177 g, 0.91 mmol) and 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide (0.4 g, 0.91 mmol) and other reagents as described in Example 9(e) were used to afford 0.45 g of the required product. Percentage purity (LCMS): 82.8%, (M+1)=610.1+1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[C:9]([CH3:29])[O:8][N:7]=1)=O)C.O.[NH2:31][NH2:32]>C(O)C>[CH3:29][C:9]1[O:8][N:7]=[C:6]2[C:10]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=1)=[N:32][NH:31][C:4]2=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OCCCN2CCCCC2)cc1
Solvent: CCO
Solvent: O
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(OCCCN4CCCCC4)cc3)c12
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To 291.3 mg of 5-methyl-4-[4-(3-piperidin-1-ylpropoxy)benzoyl] isoxazole-3-carboxylic acid ethyl ester (0.7057 mmol) in 1.54 mL of ethanol at room temperature was added 49.4 μL of hydrazine monohydrate (0.988 mmol). After 21 h, the heterogeneous reaction was cooled to 0° C. and filtered. The white solid was washed with cold ethanol then diethyl ether and dried at 65° C. under high vacuum. Yield 120 mg (46%) of a white solid Mp 178-9; MS m/z 369 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N+:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: O=C1CCC(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Reactant: C1CNCCN1
Product: O=C1CCC(c2ccc(N3CCNCC3)c([N+](=O)[O-])c2)=NN1

Procedure:
10.0 g (39.4 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 10.2 g (118.2 mmol) of piperazine for 5 hours.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1)[CH3:2].[CH3:10][C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[N:4][CH:5]=2)[C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCc1ccc(N)cn1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1ccc(-n2c(C)ccc2C)cn1
Yield: 45.7 %

Procedure:
A mixture of 2-ethylpyridin-5-amine (3.2 g, 26 mmol), 2,5-hexanedione (3.0 g, 26 mmol) and acetic acid (1 ml) in toluene (50 ml) was heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (20 ml). The aqueous phase was basified with aqueous sodium hydroxide (2M) and then extracted with dichloromethane (50 ml). The extract was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica by elution with dichloromethane/methanol (95:5) to give the title compound (2.38 g, 46%) as a colourless oil, which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.Br[C:14]1C=C(C)C=CC=1OC.[Li]CCCC.COB(OC)OC>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:14])=[CH:7][C:6]=1[B:8]([OH:10])[OH:9]
Reactant: COc1ccc(C)cc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(C)cc1B(O)O
Yield: 96 %

Procedure:
This compound was prepared in a manner similar to that of 5-fluoro-2-methoxyphenylboronic acid (EXAMPLE 107) from 2-bromo-4-methylanisole (2.00 g, 9.94 mmol), n-BuLi (2.5M in hexanes; 4.00 mL, 10 mmol), and trimethylborate (3.4 mL, 30 mmol) to afford 1.60 g (96%) of 2-methoxy-5-methylphenylboronic acid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: OCC1CCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCC4CCCC4)cc3C)c2cc1OC
Yield: 89.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopentylmethanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 85%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:31][CH2:30][C:27]([CH2:32][C:33]([O:35]C)=[O:34])([CH2:28][CH2:29]4)[CH2:26][O:25]5)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[OH-].[Li+].O1CCCC1.C(O)C>O>[CH2:1]([C:3]1[O:4][C:5]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]45[CH2:29][CH2:28][C:27]([CH2:32][C:33]([OH:35])=[O:34])([CH2:30][CH2:31]4)[CH2:26][O:25]5)=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)OC)(CC4)CO5)cc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1nc(C)c(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)CO5)cc3)cc2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A flask was charged with methyl 2-(1-(4′-(2-ethyl-4-methyloxazole-5-carboxamido)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-4-yl)acetate (0.025 g, 0.020 mmol), lithium hydroxide monohydrate (0.030 g, 0.716 mmol), tetrahydrofuran (1 ml), ethanol (0.3 ml) and water (0.3 ml), and stirred at 50° C. for 2 hours. The mixture was purified by HPLC (0.1% NH4OH, 10-60% acetonitrile/water, 20 minutes run, retention time ˜7 minutes) to afford (1-{4′-[(2-ethyl-4-methyl-oxazole-5-carbonyl)-amino]-biphenyl-4-yl}-2-oxa-bicyclo[2.2.2]oct-4-yl)-acetic acid (4 mg, 41%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.58 Hz, 3H) 1.68-1.90 (m, 6H) 2.02-2.16 (m, 4H) 2.40 (s, 3H) 2.84 (q, J=7.58 Hz, 1H) 3.87 (s, 2H) 7.44 (d, J=8.46 Hz, 2H) 7.58 (d, J=8.59 Hz, 2H) 7.63 (d, J=8.72 Hz, 2H) 7.83 (d, J=8.72 Hz, 2H) 10.13 (s, 1H). LC/MS, [MS+] 474.22, RT: 2.65 (Condition M).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH:57]=O)[CH:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(CC)CC)C>[CH:19]12[O:22][CH:15]([CH2:21][CH2:20]1)[CH2:16][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:57][C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)[CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:24]=1)[CH2:18]2
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(Cc4cccnc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (150 mg) in dichloromethane (4 mL) and triethylamine (0.12 mL) was treated with 3-pyridinecarboxaldehyde (0.1 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its tri-TFA salt; MS (ES+) 579.3 (M+H)+