Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:6]
Reactant: Cc1ccc(-n2cnnn2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4C)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:39])[N:8]([CH2:9][C@H:10]2[CH2:15][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=2)[C:7](=[O:37])[NH:6][C:5]1=[O:38].I[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH3:3][C:4]1([CH3:39])[N:8]([CH2:9][C@H:10]2[CH2:15][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]2[C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:32])([F:33])[F:34])=[CH:28][CH:29]=2)[C:7](=[O:37])[N:6]([CH:41]([CH3:43])[CH3:42])[C:5]1=[O:38]
Reactant: CC1(C)C(=O)NC(=O)N1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)N(C[C@H]2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(C)(O)C(F)(F)F)cc2)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.6 %

Procedure:
To a stirred mixture of sodium hydride (0.0203 g, 0.508 mmol, Sigma-Aldrich, St. Louis, Mo.) in DMF (1 mL) in a 5 mL vial, 5,5-dimethyl-1-(((2s)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione (0.090 g, 0.161 mmol, Example 228) in DMF (total 1.5 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and 2-iodopropane (0.020 mL, 0.20 mmol, Sigma-Aldrich, St. Louis, Mo.) was added dropwise. The cold bath was removed and the mixture was stirred at room temperature for 12 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (20 mL). Saturated aqueous NaCl (20 mL) was added and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated aqueous NaCl (80 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (25 g of silica, 0 to 80% EtOAc in hexanes) to afford 5,5-dimethyl-3-(1-methylethyl)-1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-2,4-imidazolidinedione (0.021 g) as a mixture of two isomers.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([N:21]2[C:25]([OH:26])=[CH:24][CH:23]=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH3:27][C:28]1[C:36]([C:37]2[CH2:41][CH2:40][O:39][N:38]=2)=[C:35]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:27][C:28]1[C:36]([C:37]2[CH2:41][CH2:40][O:39][N:38]=2)=[C:35]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[CH:33][C:29]=1[C:30]([C:24]1[CH:23]=[N:22][N:21]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:25]=1[OH:26])=[O:31]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: Oc1ccnn1C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(C(=O)c2cnn(C3CCCC3)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.9 g (9.4 mmol) of dicyclohexylcarbodiimide and 1.3 g (8.8 mmol) of 1-cyclopentyl-5-hydroxy-1H-pyrazole were added to a solution of 2.5 g (8.8 mmol) of 2-methyl-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid in 100 ml of dioxane, and the mixture was stirred at room temperature for 12 hours. Solid components were then filtered off and the filtrate was admixed with 1.5 g (10 mmol) of potassium carbonate and refluxed for 4 hours. The solvent was removed, the residue was then taken up in water and the mixture was washed with ethyl acetate, and then adjusted to pH 3 using 10% strength hydrochloric acid and extracted with methylene chloride. The solvent of the resulting organic phase was distilled off, the residue was taken up in 300 ml of aqueous potassium carbonate solution, insoluble components were filtered off, the pH was adjusted to 3 using 10% strength hydrochloric acid and the resulting precipitate was separated off and dried. Yield: 1.5 g (42% of theory) of 4-[2-methyl-3-(4,5-dihydro-isoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-cyclopentyl-5-hydroxy-1H-pyrazole
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:36])([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37].CI.[CH3:41][Si](C)(C)N[Si](C)(C)C.[Li]>C1COCC1>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:27][CH2:28][C:29]([CH3:36])([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]4)=[N:22][CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:37])[CH3:41]
Reactant: COC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(Cc5ccccc5OC(F)F)n4c3)cn2)CC1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(C(C)c5ccccc5OC(F)F)n4c3)cn2)CC1
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A solution of Example 43 (1 g, 1.97 mmol) and methyl iodide (0.25 mL, 4.1 mmol) in THF (10 mL) was cooled under nitrogen to −78° C. and 1M lithium hexamethyldisilazane solution (8.0 mL, 8 mmol) was added dropwise. The mixture was left stirring overnight, allowing the temperature to rise slowly to ambient temperature. The reaction mixture was partitioned between EtOAc and brine. The organic layer was washed once with brine, dried over MgSO4, filtered and concentrated in vacuo, then purified by column chromatography on SiO2, eluting with EtOAc-hexane (4:1 v/v). The residue was crystallised from diethyl ether/hexane, filtered, and washed with diethyl ether/hexane, then dried, to give the title compound (0.26 g, 25%) as a white solid. δH (400 MHz, DMSO-d6) 8.63 (m, 2H), 8.35 (m, 1H), 7.56 (dd, J 7.6, 1.5 Hz, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.16 (d, J 7.9 Hz, 1H), 7.12 (t, J 72, 76 Hz, 1H), 4.96 (m, 1H), 4.25 (m, 2H), 3.66 (s, 3H), 3.34 (m, 2H), 2.27 (s, 3H), 2.03 (m, 2H), 1.72 (d, J 7.3 Hz, 3H), 1.44 (m, 2H), 1.23 (m, 3H). LCMS (pH 10): MH+ 536, RT 2.31 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:23][C@H:24]1[NH:29][C@@H:28]([CH3:30])[CH2:27][NH:26][CH2:25]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][C@H:24]([CH3:23])[NH:29][C@H:28]([CH3:30])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(N)c2c1=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3C[C@@H](C)N[C@@H](C)C3)c(F)c(N)c2c1=O

Procedure:
Ethyl 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate and cis-3,5-dimethylpiperazine were reacted in the same way as in Example 4 to give ethyl 5-amino-1-cyclopropyl-6-fluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate. It was recrystallized from ethyl acetate. m.p. 194°-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[I:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([I:10])=[C:6]([Cl:8])[N:5]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc(Cl)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.76 g (7.32 mmol) of N-Iodosuccinimide. The solution was stirred 18 h at room temperature and then poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.2 g (76%) of a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[OH:26][C@@H:25]([CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN1CCCCC1
Yield: 74.1 %

Procedure:
Using an analogous procedure to that described in Example 297, (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), was reacted with piperidine (70 mg, 0.83 mmol), to give (2S)-7-(2-hydroxy-3-piperidinopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (93 mg, 73%).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:8][NH:9][C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:12]=2[CH:11]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][N:9]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]([F:18])([F:19])[F:20])=[N:16][C:12]=2[CH:11]=1)[S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5]
Reactant: CNc1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(c1ccc2c(c1)nc(C(F)(F)F)n2CC1CCOCC1)S(=O)(=O)C1CC1
Yield: 97 %

Procedure:
Following the procedure in Example 5, using cyclopropanesulfonyl chloride (34 mg, 0.24 mmol), N-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazol-5-amine (63 mg, 0.20 mmol) (for preparation, see the step G in example 1), DIPEA (49 uL, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 mL) at 0° C. The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 81 mg (97%) of a white solid as the title compound. 1HNMR (400 MHz, METHANOL-D4): δ 0.85-0.92 (m, 2 H), 0.93-1.01 (m, 2 H), 1.37-1.52 (m, 4 H), 2.18-2.31 (m, 1 H), 2.55-2.65 (m, 1 H), 3.30-3.36 (m, 2 H), 3.38 (s, 3 H), 3.86-3.95 (m, 2 H), 4.32 (d, J=7.62 Hz, 2 H), 7.58 (dd, J=8.89, 2.05 Hz, 1 H), 7.76 (d, J=8.79 Hz, 1 H) 7.86 (d, J=1.95 Hz, 1 H). MS (ESI) (M+H)+=418.0. Anal. Calcd for C18H22F3N3O3S+0.10 H2O+0.20 CH3OH (425.66): C, 51.36; H, 5.45; N, 9.87. Found: C, 51.39; H, 5.49; N, 9.92.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:32]3[CH2:33][CH2:34][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][CH2:31]3)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 76.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 76.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].C[CH2:13][N:14](C(C)C)[CH:15](C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([N:14]([CH3:15])[CH3:13])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reaction time: 0.08 h

Procedure:
To a solution of 2-Chloro-6-methyl-isonicotinic acid (1 g) in DMF (200 ml) at 25° C. was added DIPEA (2.9 mL) and TBTU (1.8 ml). After 5 min, dimethylamine (0.75 g) was added dropwise. This was stirred overnight. The reaction was added to water and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash:chromatography (9:1 to 2:8 gradient cyclohexane:EtOAc) afforded the title compound (320 mg). Rf=0.56 (1:1 cyclohexane:EtOAc)
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:26][CH:27]=2)=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:26][CH:27]=3)=[CH:17][CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (255 mg), 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (475 mg), potassium carbonate (415 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (581 mg, yield 86%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 85–86° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:18][CH2:17]1)=[O:4].[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:21]([O-:23])=[O:22])[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:17][CH2:18]1)=[O:4]
Reactant: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)ccc21
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(1′-methyl-2′-oxo-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2 g) in acetic acid (20 ml) at 15° C. is added nitric acid (fuming, 0.8 ml) over a period of 3 min. The mixture is stirred at this temperature for 1 h and then diluted with water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated. The compound (2.25 g) is obtained as a brown semi-solid.
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][CH:18]1[O:20][CH2:19]1)#[N:13]>C(O)C>[C:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:11][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:13]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC(N)CCc1ccccc1
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccccc1C#N
Yield: 613.3 %

Procedure:
In this example, 1.5 g of 1-methyl-3-phenylpropylamine and 1.8 g of 1-(2-cyanophenoxy)-2,3-epoxypropane are refluxed for 1.5 hours in 50 ml of99.5% ethanol. After completion of the reaction, the reaction solution is concentrated under reduced pressure. The residue is then charged on a column packed with silica gel and the elution is carried out with methanol. The main fraction of the eluate is concentrated under reduced pressure. Then, the residue is recrystallized from 200 ml of n-hexane to obtain 20 g of 1-(2-cyanophenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol as crystals. (Yield: 62%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][NH2:11])=[C:4]([F:12])[CH:3]=1.[F:13][CH:14]([F:23])[C:15]([NH:17][C:18](=O)[O:19]CC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[NH:17][C:15]([CH:14]([F:23])[F:13])=[N:11]2)=[C:4]([F:12])[CH:3]=1
Reactant: CCOC(=O)NC(=O)C(F)F
Reactant: COc1cc(NN)c(F)cc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1cc(-n2nc(C(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 12.2 %

Procedure:
To a stirred mixture of 8.0 g (0.042 mole) of 4-chloro-2-fluoro-5-methoxyphenylhydrazine and 8.4 g (0.05 mole) of ethyl difluoroacetylcarbamate in 120 mL of xylene was added 2.1 g of phosphorus pentoxide. After complete addition the mixture was heated at reflux for one hour. While still hot, the reaction mixture was decanted from a dark residue into a clean flask. This residue was washed with xylene and the wash was combined with the decanted reaction mixture. The resultant mixture was stirred at room temperature for one hour. A precipitate formed and was removed by filtration and saved for later purification. The filtrate was extracted with three 150 mL portions of an aqueous 10% sodium hydroxide solution. The basic washes were combined and extracted with xylene. During the extraction an oil formed a third phase in the bottom of the separatory funnel and was removed from the other two phases. The basic aqueous phase was separated from the organic phase and filtered through a celite pad. The filtrate was washed with two portions of diethyl ether and acidified with concentrated hydrochloric acid. The acidified aqueous mixture was stirred at room temperature forming a brown precipitate. Collection of the precipitate by filtration yielded 1.5 g of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one. The precipitate which was previously saved for purification was stirred in 70 mL of an aqueous 10% sodium hydroxide solution. The basic mixture was filtered through a celite pad to remove insoluble materials. The filtrate was acidified with concentrated hydrochloric acid producing a white solid. This solid was collected by filtration to yield an additional 0.7 g of product (mp 188°-190° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=O)=[O:11].C(N(CCCC)CCCC)CCC.[Cl:27]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([Cl:27])(=[O:13])=[O:11]
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: Nc1c(I)cc(Br)cc1S(=O)(=O)Cl
Reaction time: 18 h

Procedure:
To a solution containing 7.6 g (20 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 4.8 ml (20 mmol) of tributylamine in 20 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, a solution of dichlorotriphenylphosphorane (9.7 g (37.5 mmol) in 45 ml of dichloromethane). The mixture is brought to room temperature, stirring is continued for 18 hours and the product is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (2:8).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24]=O)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:11][O:10][C:8]([C:7]1[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]=[N:27][OH:28])[NH:3][C:2]=1[CH3:1])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1C#N
Temperature: 25 °C
Reaction time: 0.92 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.4 g), hydroxylamine hydrochloride (539.3 mg) and sodium acetate (752.3 mg) in acetic acid (15 ml) was stirred at room temperature for 55 minutes to form dimethyl-2-methyl-4-(2cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5dicarboxylate. To the reaction mixture was added acetic anhydride (2.375 g), and the mixture was heated at 110° C. for 4 hours with stirring. The reaction mixture was concentrated and treated with water (30 ml). The resultant acidic solution was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, and evaporated to dryness under reduced pressure. The residue was kept overnight in a refrigerator for crystallization. The resultant crystals were collected by filtration and washed with small portion of cold methanol to give crystals of dimethyl 2methyl-4-(2-cyanophenyl)-6-cyano-1,4-dihydropyridine-3,5dicarboxylate (1.71 g). Additional crop (0.9 g) was recovered from the mother liquor. The combined crystals (2.61 g) were recrystallized from methanol to give pure crystals (1.2 g), m.p. 166°-166.5° C.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26]C)[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH:23]([CH3:26])[C@@H:24]([C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: c1cnc2ncoc2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)[C@H](O)c1nc2ncccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 mL THF and the reaction mixture was cooled to 0° C. under N2 atmosphere. Isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol ) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.