Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:37][C:38](=O)[NH:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[N:19]([CH3:20])[C:14]2[CH2:15][N:16]([C:38]([NH:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: Cn1c(C(=O)Nc2ccccc2N)cc2c1CNCC2
Reactant: O=C(Nc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C(=O)Nc2ccccc2N)cc2c1CN(C(=O)Nc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by pyridin-3-yl-carbamic acid 4-nitro-phenyl ester (1.0 eq) and stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[C:23]([C:25](=[O:37])[NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH3:36])[CH:29]=4)[N:22]=[C:21]([CH3:38])[N:20]=3)[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+]>C(#N)C>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:25]([C:23]2[CH:24]=[C:19]([C:16]3[CH2:15][CH:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]4)[O:18][N:17]=3)[N:20]=[C:21]([CH3:38])[N:22]=2)=[O:37])=[CH:29][C:30]=1[O:35][CH3:36]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)COC(C)=O)CC4)C3)nc(C)n2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)CO)CC4)C3)nc(C)n2)ccc1F
Reaction time: 6 h
Yield: 38.3 %

Procedure:
2-(4-(3-(6-(4-Fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidin-1-yl)-2-oxoethyl acetate (1.8 g, 3.5 mmol) was dissolved in ACN (20 mL) and 2.5 N sodium hydroxide (20 mL) was added. The mixture was stirred for about 6 h and then ACN was removed under reduced pressure. The aqueous layer was adjusted to pH 6 with 10% aqueous hydrogen chloride and then extracted with EtOAc (2×15 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Table 2, Method a) to afford N-(4-fluoro-3-methoxybenzyl)-6-(5-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-2-methylpyrimidine-4-carboxamide 0.65 g (39%): 1H NMR (400 MHz, DMSO): δ 9.499-9.467 (t, J=6.4 Hz, 1H), 8.139 (s, 1H), 7.143-7.114 (m, 2H), 6.900-6.884 (m, 1H), 4.684-4.657 (m, 1H), 4.482-4.38 (m, 4H), 4.095-4.049 (m, 3H), 3.815 (s, 3H), 3.495-3.451 (m, 1H), 3.217-3.196 (m, 2H), 2.911-2.800 (m, 1H), 2.752 (s, 3H), 1.855-1.684 (m, 3H), 1.234-1.105 (m, 2H). LC/MS Rt=1.22 (Table 1, method c) min; MS m/z: 486.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (1R,2S,4R,5S)-5-(benzyloxy)bicyclo[2.2.1]heptan-2-ol (4.20 g, 19.2 mmol) in DMF (10 mL) was added tert-butylchlorodiphenylsilane (6.00 mL, 23.1 mmol) and imidazole (3.27 g, 48.1 mmol). The resulting mixture was stirred at ambient temp. overnight. The mixture was partitioned between diethyl ether and water. The organic portion was separated, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography (0 to 5% of EtOAc in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:24][N:25](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:35]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:35][NH:25][CH:24]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccccc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccccc2)ccn1
Yield: 86 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 18.4 g (50.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-phenyl-2-propen-1-one obtained in Example 20-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 14.5 g of the title compound as a white powder. (Yield: 86%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[N+:21]([O-])=O)=[O:4].[H][H]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])=[CH:7][C:6]=1[NH2:21])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Reaction time: 18 h

Procedure:
In a Parr apparatus, hydrogenate an ethanolic solution of 3-nitro-2′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (5.54 g, 0.0169 mol) under 55 psi of hydrogen using tetrakis(triphenylphosphine)palladium (0) (300 mg). After 18 hours, filter the mixture through celite and concentrate under reduced pressure to give 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
2,4,5-Trichloropyrimidine (250 mg, 1.36 mmol) and ferric acetylacetonate (24 mg, 0.07 mmol) were taken up in tetrahydrofuran (2.7 ml) and the reaction was cooled to −78° C. Methylmagnesium bromide (0.45 ml of 3 M in THF, 1.36 mmol) was added dropwise and the mixture was stirred at −78° C. for one hour. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by Combiflash (0-10% diethylether in hexanes) to provide 2,5-dichloro-4-methylpyrimidine (99 mg, 0.61 mmol, 45%) as a white solid. MS APCI: [M+H]+ m/z 163.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.O1CCC[CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>>[Cl:17][C:6]1[C:7]([N:8]([CH3:19])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: O=C(Nc1c(Cl)ncnc1Cl)c1ccccc1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: CN(C(=O)c1ccccc1)c1c(Cl)ncnc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of N-(4,6-dichloropyrimidin-5-yl)benzamide (3.0 g, 0.011 mol) in tetrahydrofuran (70 mL, 0.9 mol) was added cesium carbonate (9.8 g, 0.030 mol). The suspension was stirred for 5 minutes and to this was added methyl iodide (1.4 mL, 0.022 mol) (purified on aluminum oxide). After stirring for 1 hour, cesium carbonate (5.0 g, 0.015 mol) and methyl iodide (0.70 mL, 0.011 mol) (purified on alumina) were added. The reaction was stirred for 2 hours, quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered, concentrated and trituration in diethyl ether to obtain 2.54 g (80%).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[C:44]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([CH2:56][NH2:57])[CH2:53][C@H:52]1[C:58]([N:60]1[CH2:64][CH2:63][S:62][CH2:61]1)=[O:59])=[O:50])([CH3:47])([CH3:46])[CH3:45]>CN(C)C=O>[C:44]([O:48][C:49]([N:51]1[CH2:55][C@@H:54]([CH2:56][NH:57][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([O:12][CH3:13])=[O:11])[CH:3]=2)[CH2:53][C@H:52]1[C:58]([N:60]1[CH2:64][CH2:63][S:62][CH2:61]1)=[O:59])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)NC[C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of monomethyl isophthalate (226 mg, 1.26 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added 1-hydroxybenzotriazole monohydrate (204 mg, 1.51 mmol), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (288 mg, 1.51 mmol) and triethylamine (0.180 mL, 1.26 mmol). The mixture was stirred at room temperature for 30 minutes followed by the addition of a solution of Example 17D (380 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (2 mL). The mixture was allowed to stir at room temperature for 16 hours, concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and extracted with 1 M HCl (20 mL), saturated sodium bicarbonate (20 mL) and brine (20 mL) respectively. The organic layer was separated and dried (Na2SO4), filtered and concentrated to a light yellow oily solid which was chromatographed on a Biotage 40M with ethyl acetate to provide the titled compound. MS (APCI) m/e 478 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[C@@H:15]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C@H:14]([CH3:21])[O:13][C:12](=[O:22])[C@@H:11]([NH:23][C:24](=[O:34])[C:25]3[C:30]([OH:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:41]([O:46][CH2:47]Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>CC(C)=O>[C:41]([O:46][CH2:47][O:31][C:30]1[C:25]([C:24](=[O:34])[NH:23][C@H:11]2[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C@@H:15]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C@H:14]([CH3:21])[O:13][C:12]2=[O:22])=[N:26][CH:27]=[CH:28][C:29]=1[O:32][CH3:33])(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)OCCl
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CC3CCCC3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CC3CCCC3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1OCOC(=O)C(C)C
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a mixture of N-((3S,7R,8R,9S)-7-(cyclopentylmethyl)-8-(cyclopropylmethoxy)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (60 mg, 0.126 mmol) and K2CO3 (34.9 mg, 0.253 mmol) in acetone (1 mL) was added chloromethyl isobutyrate (34.5 mg, 0.253 mmol) and the reaction was heated to 60° C. After TLC analysis indicated full consumption of the picolinamide starting material, the mixture was concentrated under a stream of N2 and the residue purified by column chromatography on SiO2 (gradient, EtOAc/hexanes) to yield the title compound as a colorless semi-solid (60.4 mg, 83%): IR (thin film) 3381, 2942, 1745, 1678, 1506, 974 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 5.81-5.61 (m, 2H), 4.89 (dd, J=9.2, 6.3 Hz, 1H), 4.57 (dt, J=11.0, 7.5 Hz, 1H), 3.89 (s, 3H), 3.50 (dd, J=9.6, 7.0 Hz, 1H), 3.36 (dd, J=9.6, 6.9 Hz, 1H), 3.01 (t, J=9.0 Hz, 1H), 2.54 (p, J=7.0 Hz, 1H), 2.36 (dd, J=13.1, 6.8 Hz, 1H), 1.92-1.43 (m, 15H), 1.42 (d, J=6.5 Hz, 2H), 1.35-1.19 (m, 2H), 1.14 (d, J=7.0 Hz, 3H), 1.17-0.92 (m, 5H), 0.62-0.48 (m, 2H), 0.29-0.17 (m, 2H); HRMS-ESI (m/z) ([M]+) calcd for C31H46N2O8, 574.3254; found, 574.3262.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:23]([O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
To a solution of compound 30 (2.8 g, 10.83 mmol) and benzyl trichloroacetimidate (3.4 g, 14 mmol) in DCM (100 mL) was added trifluoromethanesulfonic acid (0.24 mL, 2.7 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 6 h and warmed to room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and the organic layer dried over Na2SO4. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (80 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 60 min, 60 mL/min) to give the product 31 (1.2 g, 32%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 3.70 (s, 3H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:38].CCN(C(C)C)C(C)C.[CH2:48](Cl)[O:49][CH3:50]>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH2:48][O:49][CH3:50])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:38]
Reactant: COCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Reaction time: 23 h
Yield: 80.7 %

Procedure:
A mixture of 6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (350 mg, 0.578 mmol), DIPEA (0.303 mL, 1.734 mmol) and MOM-Cl (0.110 mL, 1.445 mmol) in THF (3.0 mL) was stirred at 50° C. in a sealed tube. After 23 hours, the solution was concentrated and purified by silica gel chromatography (0-40% EtOAc in hexanes) to give 6-(N-(4-bromo-3-fluoro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (303 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59 (br. s., 1H), 0.74-0.94 (m, 2H), 0.94-1.10 (m, 1H), 1.99-2.12 (m, 1H), 3.00 (d, J=4.9 Hz, 3H), 3.27 (s, 3H), 3.37 (s, 3H), 4.61 (s, 2H), 4.71 (s, 2H), 5.85 (d, J=4.6 Hz, 1H), 7.13 (dd, J=10.0, 2.7 Hz, 1H), 7.17-7.25 (m, 2H), 7.33 (d, J=1.5 Hz, 1H), 7.48 (s, 1H), 7.58 (s, 1H), 7.83-7.92 (m, 2H). LCMS (m/z, ES+)=649, 651 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 30 °C
Yield: 71.9 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.2 g) in a mixture of tetrahydrofuran (15 ml) and ethyl alcohol (15 ml) was added thiourea (0.46 g). The mixture was stirred for an hour at 30° C., poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with 10% aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (0.83 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccc(F)cc3F)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][C:23]([NH2:25])=[O:24].[F:26][C:27]([F:35])([F:34])[C:28](=O)[CH2:29][C:30](=O)[CH3:31].[OH-].[Na+]>OS(O)(=O)=O.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[N:22]1[C:30]([CH3:31])=[CH:29][C:28]([C:27]([F:35])([F:34])[F:26])=[N:25][C:23]1=[O:24]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: NC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nc(=O)n1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 80 °C

Procedure:
To [2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-urea (38 mg, 0.1 mmol) in 13% (v/v) H2SO4 in EtOH was added 1,1,1-trifluoro-2,4-pentanedione (15 μL, 0.15 mmol). The mixture was heated at 80° C. for 6 hrs, followed by neutralization with 6N NaOH solution. Purification by prep. LCMS yielded 1-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-6-methyl-4-trifluoromethyl-1H-pyrimidin-2-one 13-1. MS: 497.7 (M+H)+; tR=8.14 min (method 2).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:10][CH:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)[C:12](OC)=[O:13])(=[O:9])[CH3:8].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[C:7]([NH:10][CH:11]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)[CH2:12][OH:13])(=[O:9])[CH3:8]
Reactant: CCCCCCCCc1ccc(CCC(NC(C)=O)C(=O)OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(CO)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a suspension of lithium aluminum hydride (1.2 g) in tetrahydrofuran (100 ml), a solution of methyl 2-acetamido-4-(4-octylphenyl)butyrate (11 g) in tetrahydrofuran (200 ml) was added and the suspension was stirred at room temperature for 30 minutes. An aqueous tetrahydrofuran (70%, 10 ml) was added to the solution and the mixture was left standing overnight. Magnesium sulfate was added to the mixture, the precipitate was filtered off and the solvent was distilled away under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order and dried over sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (6.6 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C@H:18]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH3:19])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:16])([C@H:18]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH3:19])[CH2:17][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
1H-1,2,4-Triazole (42.1 g) was added portionwise to a dispersion of 60% sodium hydride in oil (22.2 g) in dimethylformamide (300 ml) under ice-cooling, followed by stirring for 15 minutes. To the mixture was added a solution of the crude product of 2-(4-chlorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (52 g) in dimethylformamide (50 ml), followed by stirring for 4 hours at 80° C. After cooling, the reaction mixture was poured into ice water (400 ml) and extracted three times with ethyl acetate (200 ml). The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=3:2→ethyl acetate/acetone=4:1) to give (3R)-2-(4-chlorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (53 g) as a colorless amorphous substance.
Reaction SMILES: N1C=CC=CC=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
Copper acetate (91 mg, 0.5 mmol), pyridine (53 mg, 0.67 mmol) and active Molecular Sieve 4A (250 mg) were added to a solution of 4-formylphenylboronic acid (100 mg, 0.67 mmol) and pyrazole (16 mg, 0.33 mmol) in 1,4-dioxane (4 ml), and they were stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated and then purified by the silica gel TLC chromatography to obtain 1-(4-formylphenyl)pyrazole (yield: 38 mg, 66%) in the form of a white powder.