Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:12]=[N:13][C:8]=2[C:7](=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:36]>>[C:1]([C:5]1[N:6]=[C:7]([Cl:36])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(=O)c2nnn(Cc3ccccc3Cl)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
A mixture of 5-tert-butyl-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (12.3 mg, 38.7 μmol) and N,N-diethylaniline (12.3 μL, 77.4 μmol) in POCl3 (250 μL, 2.73 mmol) was refluxed for 3 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1.[Cl-].O>O1CCCC1>[CH3:7][C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11]([N:14]([C:2](=[O:4])[CH3:1])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([S:21][CH3:22])=[N:9]1
Reactant: CC(C)(C)[O-]
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1N(C(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.25 g (3.5 mmol) of acetyle chloride is then added and the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is washed with water to neutrality. The solution is dried over magnesium sulfate and then concentrated. A honey-like product is obtained which is purified by chromatography on a silica column. The purified product crystallizes from diisopropyl ether. 0.25 g of Compound 23 is obtained in the form of a white powder melting at 132° C.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Br[CH2:35][CH2:36][OH:37]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([O:23][CH2:35][CH2:36][OH:37])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Reactant: OCCBr
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCO)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol (0.32 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) was obtained.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50].Cl[C:52]1[CH:53]=[C:54]([NH:67][C:68]2[CH:77]=[C:71]3[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]3[N:69]=2)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[N:57]=1>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.O>[CH3:13][C:14]1[C:19]([C:52]2[CH:53]=[C:54]([NH:67][C:68]3[CH:77]=[C:71]4[CH2:72][N:73]([CH3:76])[CH2:74][CH2:75][N:70]4[N:69]=3)[C:55](=[O:66])[N:56]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:63])([CH3:65])[CH3:64])[N:57]=2)=[CH:18][CH:17]=[CH:16][C:15]=1[N:29]1[CH2:41][CH2:40][C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:31]=2[C:30]1=[O:50]
Reactant: CN1CCn2nc(Nc3cc(Cl)nn(COCC[Si](C)(C)C)c3=O)cc2C1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1CCc2c(n(COCC[Si](C)(C)C)c3ccccc23)C1=O
Temperature: 100 °C
Yield: 89.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (5 mL), water (1 mL) and sodium carbonate (143 mg, 1.35 mmol). After bubbling nitrogen through the resulting mixture for 30 min, 117c (240 mg, 0.451 mmol), 117e (185 mg, 0.451 mmol) and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) were added, and the reaction mixture was heated at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and partitioned between water (25 mL) and methylene chloride (50 mL). The organic layer was separated, washed with brine (75 mL) and dried over sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to a dark oil, which was purified by flash chromatography to afford an 89% yield (315 mg) of 117f as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.88 (s, 1H), 7.66 (d, 1H, J=8.0 Hz), 7.45 (m, 3H), 7.39 (t, 1H, J=8.0 Hz), 7.34 (d, 1H, J=8.0 Hz), 7.24 (t, 2H, J=8.0 Hz), 6.12 (d, 1H, J=10.5 Hz), 6.05 (d, 1H, J=10.5 Hz), 5.69 (s, 1H), 5.63 (d, 1H, J=10.5 Hz), 5.52 (d, 1H, J=10.5 Hz), 4.09 (m, 2H), 3.88 (m, 2H), 3.75 (m, 2H), 3.68 (s, 3H), 3.59 (m, 2H), 3.26-3.17 (m, 4H), 2.61 (m, 2H), 2.29 (s, 3H), 0.98 (t, 2H, J=8.0 Hz), 0.85 (t, 2H, J=8.0 Hz), −0.01 (s, 9H), −0.07 (s, 9H); MS (ESI+) m/z 781.4 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH:20]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[CH:20]1([C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)[OH:7])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Br[Mg]C1CCCC1
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C3CCCC3)ccc2c1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with cyclopentylmagnesium bromide in THF (1.0 M, 10 ml) was carried out to give the titled compound (0.80 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.B(F)(F)F.O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: FB(F)F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 6 h
Yield: 90 %

Procedure:
A solution of 140 parts of o-xylyl chloride and 500 parts of benzene is added to a mixture of 162 parts of boron fluoride dihydrate and 16 parts of sulfuric acid monohydrate at from 75° to 78° C, whilst stirring vigorously. After a further 6 hours, the organic phase is separated off and 162 parts (90% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH2:11][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][C:15]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22]C(Cl)Cl>C(Cl)Cl.O>[CH:21]([C:6]1[C:7]2[C:15]3[CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)cccc23)C1
Reactant: COC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C=O)c23)C1
Yield: 97 %

Procedure:
To a solution of ethyl 8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (from step 5) (0.264 g, 0.96 mmol), in methylene chloride, was added stannic chloride (0.424 g, 1.6 mmol) and 1,1-dichloromethyl methyl ether (0.1655 g, 1.4 mmol) at −10° C. Reaction mass was diluted with dichloromethane, water was added to it and organic layer was thoroughly washed with water after separation. It was concentrated and purified to yield Ethyl 5-formyl-8-methoxy-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.N>C(O)C.[Pd]>[CH3:17][C:4]1[C:5]2[N:6]([C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:9][N:10]=2)[N:7]=[CH:2][CH:3]=1
Reactant: Cc1cc(Cl)nn2c(-c3ccccc3)nnc12
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1ccnn2c(-c3ccccc3)nnc12
Yield: 85 %

Procedure:
6-chloro-8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x240 is dissolved in ethanol (300 ml), and 10% Pd/C (0.9 g) and 25% aqueous ammonia (60 ml) are added. The mixture is hydrogenated in the Parr apparatus under hydrogen pressure 2.5 atm at room temperature for 1 h10. The reaction mixture is filtered through a Celite layer, which is washed with ethanol. The combined filtrates are evaporated, and the residue is dissolved in dichloromethane. The solution is washed with brine and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure to afford 2.9 g of 8-methyl-3-phenyl[1,2,4]triazolo[4,3-b]pyridazine x241.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7].[Br:9][CH2:10][C:11](Br)=[O:12]>>[Br:9][CH2:10][C:11]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:8])[O:6][CH3:7])=[O:12]
Reactant: O=C(Br)CBr
Reactant: COC(=O)NCCO
Product: COC(=O)NCCOC(=O)CBr

Procedure:
by using methyl 2-hydroxyethylcarbamate and bromoacetyl bromide there is obtained methyl 2-bromoacetoxyethylcarbamate, nD20 1.4891;
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>[Cl-].C[N+](C)(C)C.C1(C)C=CC=CC=1>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: CS(=O)(=O)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 104.4 %

Procedure:
A 250-mL, three neck round bottomed flask was equipped with a mechanical stirrer, heating mantel, thermometer, pressure equalizing addition funnel and reflux condenser. A nitrogen purge was established across the top of the condenser with all gases exiting through a caustic scrubber. The flask was charged with 53.9 g (0.143 mole, 82% assay) of 2-(5-amino-2,4-dichlorophenyl)-4-(difluoromethyl)-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one, 1.7 g (0.015 mole) of tetramethylammonium chloride (Aldrich, 97%) and 24 g of toluene. The mixture was heated to reflux and 15.6 ml (23 g, 0.20 mole) of methanesulfonyl chloride (Aldrich, 99.5%) added dropwise over 36 minutes. Ninety minutes after the completion of the addition, a further 3.9 mL (5.75 g, 0.05 mole) of methanesulfonyl chloride was added. After an additional 1.5 hours at reflux, the reaction mixture was diluted with 75 mL of toluene, transferred to a 1-L round bottomed flask equipped with a mechanical stirrer, and rinsed in with 100 mL of toluene. The mixture was allowed to cool to room temperature and stirred overnight (15.5 hours). The resulting slurry was cooled using an ice bath for three hours, the product collected by filtration, and the filter cake washed with a total of 155 ml of cold toluene and dried in a vacuum oven to provide 57.8 g (83% yield) of 80.3% assay N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide as a tan solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[O:3]
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: CN(C)CCCN
Product: CCO[Si](CCCNC(=O)NCCCN(C)C)(OCC)OCC

Procedure:
To a stirred solution of 3-isocyanatopropyltriethoxysilane (74 g; 0.31 mole) was slowly added 30 g (0.30 mole) of N,N-dimethyl-1,3-propanediamine. There was a significant exotherm. The product was purified by strip distillation at 205° C. (0.1 torr). NMR (CDCl3) 0.40-0.9 (m; 2H), 1.22 (t; 9H), 1.4-1.9 (m; 4H), 2.21 (s; 6H), 2.33 (t; 2H), 2.9-3.4 (m; 4H), 3.81 (q; 6H), 5.8 (b, 2H) ppm. IR (neat film) 3340, 2980, 2940, 1635, 1575, 1105, 1080, 960, 780 cm-1.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([OH:22])=[O:21].[Cl-].[NH4+]>CS(C)=O>[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([O:22][CH2:2][C:3]#[N:4])=[O:21]
Reactant: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2-Bromoacetonitrile (3.60 ml, 52.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.297 ml, 2.86 mmol) were added to a solution of (S)-5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoic acid (Compound 1f-IIA) (673 mg, 2.60 mmol) in DMSO (5.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→30/70) to afford (S)-cyanomethyl 5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoate (Compound 1g-IIA) (772 mg, 100%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[OH:8][CH2:9][CH2:10][N:11]1[C:15]([NH2:16])=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=[N:12]1
Reactant: Nc1ccnn1CCO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: O=CNc1ccnn1CCO
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at ambient temperature for an hour. To this mixture was added 1-(2-hydroxyethyl)-5-aminopyrazole (30 g) at 0°-10° C., and the mixture was stirred under ice-cooling for 30 minutes. The mixture was poured into ice-cold water, adjusted to pH 10.5 with 40% aqueous potassium carbonate, and stirred under ice-cooling for 30 minutes. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 1-(2-hydroxyethyl)-5-formamidopyrazole (30.8 g).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=2[O:31]1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:29][C:30]1([CH3:40])[CH2:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])[C:32]=2[O:31]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cccc3c2OC(C)(C)C3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-ol (0.25 g), 8 M potassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 39%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:4](=[O:3])[CH2:5][C@@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: CNC
Product: CC(C)[C@@H](CC(=O)N(C)C)NC(=O)OCc1ccccc1

Procedure:
2.23 g of 3(R)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 30% dimethylamine (in methanol) are stirred for 6 days at 75° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is purified by FC (dichloromethane/methanol=97:3). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.40.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])=[C:15]([F:29])[CH:14]=2)[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC[N:43]([CH:47]([CH3:49])[CH3:48])C(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH:47]1([NH:43][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][C:16]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])=[C:15]([F:29])[CH:14]=3)[N:3]=2)[CH2:49][CH2:48]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)c(F)cc1Nc1ncc(C(F)(F)F)c(NC2CC2)n1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
To a solution of (4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)-(morpholino)methanone (120 mg, 0.28 mmol) in dioxane (2 mL) was added pTSA (52 mg, 0.28 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol). The mixture was heated to 100° C. for 2 hours. LSMS of crude sample indicated only 10% of desired material. DIPEA (100 μL, 0.56 mmol) and D4-cyclopropylamine (17 mg, 0.28 mmol) were added and the mixture was heated to 100° C. for one hour. After return to room temperature, DCM (20 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were added. The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by reversed phase HPLC to give (4-(4-(cyclopropylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)-methanone (42 mg, 33%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=460 at 3.41 min. 1H NMR (400 MHz, CDCl3): δ 8.77 (d, J=12.8 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.91 (d, J=5.6 Hz, 1H), 5.48 (s, 1H), 3.92 (s, 3H), 3.80-3.74 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.43 (m, 2H).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH2:9][C:8]=1[CH2:20][S:21][C:22]1[N:26]([CH3:27])[N:25]=[N:24][N:23]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[Br:28][CH:9]1[C:8]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10]1(=[O:19])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)CS(=O)(=O)[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Br)S(=O)(=O)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem 1,1 dioxide (350 mg) in dichloromethane (30 ml), N-bromosuccinimide (200 mg) and triethylamine (0.13 ml) were added sequentially. The mixture was stirred for 15 min at room temperature. Following dilution with dichloromethane, the organic phase was sequentially washed with 4% aqueous NaHSO3, saturated NaHCO3 and water. After drying over Na2SO4 and removal of the solvent, the residue was purified by flash chromatography (eluting with hexane-EtOAc mixtures) affording 2-bromo-4-tert-butylcarbonyl-7α-methoxy-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem 1,1-dioxide as a waxy solid (200 mg), IR (KBr) νmax 1800, 1700 cm-1. A portion of this material (180 mg) was dissolved in acetonitrile (10 ml) and treated with silver benzoate (95 mg). The mixture was stirred for 30 min at room temperature, then filtered and rotoevaporated. Following flash chromatography (eluting with gradient of EtOAc in hexane) the title product was obtained as a light yellow solid (80 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24].CN(C=O)C.Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Si:36]([O:35][CH2:34][CH2:33][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CN(Cc1nc2ccccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1nc2ccccc2n1CCO[Si](C)(C)C(C)(C)C)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-(1H-benzimidazol-2-ylmethyl)-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (500 mg) and DMF (15 mL) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (555 μL) and K2CO3 (358 mg), followed by heating and stirring at 95° C. for 24 hours. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. To the resulting solid was added EtOAc, followed by suspending. An equivalent amount of Hex was added thereto, followed by collecting by filtration and washing with a Hex-EtOAc mixed solvent to obtain N-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-benzimidazol-2-yl]methyl}-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (523 mg).