Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([OH:24])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39][C:40](=[O:44])[C@@H:41](Br)[CH3:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:23]=[C:22]([O:24][C@@H:41]([C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:44])[CH3:42])[N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](Br)C(=O)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.75 g 4-{2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 10 ml DMF were added 990 mg (S)-2-bromo-propionic acid benzyl ester (prepared by standard benzylation procedure using (S)-2-bromopropionic acid and benzyl alcohol/p-TsOH) and 2.67 g cesium carbonate. After stirring at room temperature for 12 h the solution was diluted with 100 ml ethyl acetate and extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The crude product obtained after evaporation of the solvent was pure enough for the following reactions. Yield: 2.1 g
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH3:4].[Cl:5]([O-:8])(=[O:7])=[O:6].[Na+:9]>>[C:1](=[O:6])([OH:3])[O-:2].[Na+:9].[Cl:5]([O-:8])(=[O:7])=[O:6].[NH4+:4]
Reactant: N
Reactant: O=C=O
Agent: [Na+]
Agent: [O-][Cl+2]([O-])[O-]
Product: O=C([O-])O
Product: [NH4+]

Procedure:
mixing carbon dioxide, ammonia, and sodium chlorate with an aqueous solution to form a sodium bicarbonate precipitate and aqueous ammonium chlorate; and
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:31])([CH3:30])[CH2:22][NH:23][S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:29][N:27]([CH3:28])[S:24]([NH:23][CH2:22][C:21]([F:31])([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH:10]=2)=[CH:20][CH:19]=1)[CH3:30])(=[O:25])=[O:26]
Reactant: CN(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1cccc(-c2ccc(C(C)(F)CNS(=O)(=O)N(C)C)cc2)c1
Temperature: 0 °C

Procedure:
In a 250 mL 3 neck flask fitted with a stirrer and thermometer, 356 mg of 2-propanesulfonyl chloride is added dropwise to 350 mg of {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(dimethylamino)sulfonyl]amine (prepared in example 38) and 380 mg of DBU in THF (125 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and then stirred overnight at this temperature. In the morning, the reaction is concentrated under reduced vacuum. The resulting material is taken into ethyl acetate and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum. This crude material is purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor with hexane/ethyl acetate eluent to provide the title compound.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]N1C(=O)N(O)C(=O)N(O)[C:10]1=[O:19].[O:20]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:10]([OH:19])(=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7](=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: O=O
Reactant: Cc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1
Product: O=Cc1ccccc1

Procedure:
A mixture of 0.276 g of toluene, 0.005 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1% by mole relative to toluene), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4H2O was stirred at 60° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 6 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield benzoic acid and benzaldehyde in 49% and 3% yields, respectively, at 53% conversion of toluene.
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH2:4][CH2:3]1)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:24].CC([NH3+])(C)CO.[NH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O-:38])=[O:37])=[C:34]([F:41])[CH:33]=1.C(=O)([O-])[O-].[Ca+2].CS(C)=O>O>[F:41][C:34]1[CH:33]=[C:32]([NH:31][CH:2]2[C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][C:5]=3[CH2:4][CH2:3]2)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]4=[O:24])[CH:40]=[CH:39][C:35]=1[C:36]([OH:38])=[O:37]
Reactant: Nc1ccc(C(=O)[O-])c(F)c1
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Agent: CC(C)([NH3+])CO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)O)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (26 g), p-amino-o-fluorobenzoic acid 1,1-dimethyl-2-hydroxyethylammonium salt (42 g), calcium carbonate (21.4 g) and DMSO (200 ml) was stirred at ambient temperature for 72 hours. The mixture was poured onto a mixture of ice and water (1 liter). The precipitate was isolated, washed with water and dried under vacuum. The product was purified by column chromatography using initially a 9:1 mixture of methylene chloride and methanol and then a 9:1:0.1 mixture of methylene chloride, methanol and acetic acid as eluant. There was thus obtained o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoic acid as a gum (20 g).
Reaction SMILES: C=O.F[C:4](F)(F)C(O)=O.[N:10]1([C:16]2[N:21]=[CH:20][C:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH3:4][N:13]1[CH2:12][CH2:11][N:10]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)[CH2:15][CH2:14]1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C)CC4)nc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Formaldehyde (37% aq., 0.212 mL, 2.61 mmol) was added to a suspension of ethyl 2-(6-piperazin-1-ylpyridin-3-yl)-1,3-benzothiazole-6-carboxylate trifluoroacetate (0.315 g, 0.65 mmol) in methanol (10 mL). Sodium cyanoborohydride (74 mg, 1.17 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The r.m. was then kept at −10° C. o.n. The formed solid was collected, washed with cold methanol and dried to give the title compound. The mother liquor was evaporated in vacuo and the residue was partitioned between DCM and sat. sodium hydrogencarbonate. The aqueous layer was extracted twice with DCM, dried (Na2SO4), filtered, and evaporated in vacuo, giving together with the filtrated solid the title compound (0.20 g) as a yellow solid. 1H NMR δ ppm 8.83 (d, 1 H) 8.73 (s, 1 H) 8.17 (dd, 1 H) 8.05 (s, 2 H) 7.01 (d, 1 H) 4.36 (q, 2 H) 3.70 (br. s., 4 H) 3.32 (s, 4 H) 2.29 (s, 3 H) 1.36 (t, 3 H); MS m/z (M+H) 383.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]C(=O)C)[CH2:3][CH2:2]1.[OH-].[K+].Br[C:14]1([CH3:20])[CH2:19][CH2:18][O:17][C:15]1=[O:16].C(Cl)(=O)C>CC(O)C>[CH3:20][C:14]1([S:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:19][CH2:18][O:17][C:15]1=[O:16]
Reactant: CC1(Br)CCOC1=O
Reactant: CC(=O)SC1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CC(C)O
Product: CC1(SC2CCOCC2)CCOC1=O
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To thioacetic acid S-(tetrahydro-pyran-4-yl)ester (4.25 g; 26.5 mmol) in 2-proponal (20 mL) was added KOH (36.4 mL of a 0.8 M solution in 2-propanol; 29.2 mmol). The mixture was stirred 30 minutes and α-bromo-α-methyl-γ-butyrolactone (3.00 mL; 26.5 mmol) was added dropwise. The mixture was stirred 2 hours, quenched with acetyl chloride (0.62 mL; 8.75 mmol) and the volatiles removed in vacuo. The residue was diluted with ether and filtered. Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide 2.65 g of the desired product. 1H NMR (CDCl3) δ 4.45 (m, 1H), 4.29 (dt, 1H), 3.89 (m, 2H), 3.48 (dq, 2H), 3.20 (m, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.88 (m, 1H), 1.86 (m, 2H), 1.65 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[N:6][C:5]([CH2:8][NH2:9])=[N:4]1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][C@@H:18]([CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[CH2:17]1.C(N(CC)C(C)C)(C)C.CO>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][C@@H:18]([CH2:22][NH:23][C:24]([NH:9][CH2:8][C:5]2[N:6]=[N:7][N:3]([CH3:2])[N:4]=2)=[O:25])[CH2:17]1
Reactant: Cn1nnc(CN)n1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1nnc(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reaction time: 20 h
Yield: 86.6 %

Procedure:
Intermediate 30 (0.041 g) was added to a stirred solution of Intermediate 29 (0.110 g) in N,N-dimethylformamide (2 ml) at 22° C., and N,N-diisopropylethylamine (0.052 ml) was added. After stirring for 20 h, the mixture was applied in two equal portions to ion exchange cartridges (10 g Isolute SCX pre conditioned with methanol). Elution with methanol (3 column volumes) followed by 10% 0.880 ammonia in methanol (2 column volumes) and evaporation of the first basic fractions in vacuo gave the crude product. Purification by Biotage flash chromatography on silica gel (8 g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia, gave the title compound as a white solid, (0.0828 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([OH:42])=O)[C:33]=2[CH:43]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:42])[C:33]=2[CH:43]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reactant: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)NC)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Ethyl 4′-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate (59.7 mg, 0.16 mmol) was dissolved in 10 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (63.8 mg, 0.18 mmol, with 23 wt % LiCl) followed by triethylamine (32.4 mg, 0.32 mmol) and BOP (78.7 mg, 0.18 mmol), and then the reaction mixture was maintained at room temperature for 16 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed by brine, dried over MgSO4, filtered and then concentrated. The residue was dissolved in 2 mL of DMSO and purified by preparative HPLC (Xterra Prep RP, 30×100 mm, 25 mL/min, A: acetonitrile with 0.1% TFA, B: water with 0.1% TFA, A: 15% to 90% during 20 min, UV detection at 214 nm) to give 44 mg (37% yield) of the title compound as a yellow solid. MS (ES) m/e 626 [M+H]+.
Reaction SMILES: C1(C2(C3C=CC=CC=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16]([N:19]4[CH2:24][CH:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH2:23][CH2:24][N:19]([S:16]([C:14]3[CH:15]=[C:9]([OH:8])[C:10]([OH:11])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:20][CH:21]=2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)c(O)c1)N1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
1-(2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl)-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (3.2 g, 6.2 mmol) was dissolved in methylene chloride (100 ml). Trifluoroacetic acid (50 ml) was added dropwise and the reaction was stirred for 5 hours at room temperature. The solvent was evaporated and the residue was purified by column chromatography on silica gel (100 g, methylene chloride then ethyl acetate as eluant). The product was crystallized from ether/hexane to give a white solid (2.1 g, 96%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[N:14]=[C:15]([NH:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:16][CH:17]=1)\[C:10]([O-:12])=O.[Na+].[NH2:39][C@@H:40]1[C:60](=[O:61])[N:42]2[C:43]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[C:44]([C@H:47]3[O:51][C:50](=[O:52])[CH2:49][CH2:48]3)[CH2:45][S:46][C@H:41]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:6][O:7]/[N:8]=[C:9](/[C:13]1[N:14]=[C:15]([NH:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:16][CH:17]=1)\[C:10]([NH:39][C@@H:40]1[C:60](=[O:61])[N:42]2[C:43]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[C:44]([C@H:47]3[O:51][C:50](=[O:52])[CH2:49][CH2:48]3)[CH2:45][S:46][C@H:41]12)=[O:12]
Reactant: CC(C)(C)OC(=O)C1=C([C@@H]2CCC(=O)O2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: CO/N=C(\C(=O)[O-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C([C@@H]3CCC(=O)O3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Methanesulphonyl chloride (23 μl, 0.3 mmol) was added to sodium 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (0.12 g,0.25 mmol) in DMF (0.5 ml) at -40° C. The mixture was allowed to warm to -10° C. over 0.5 h then cooled to -30° C. and t-butyl (6R,7R)-7-amino-3-[(5S)-2-oxotetrahydrofuran-5-yl]ceph-3-em-4-carboxylate (68 mg, 0.2 mmol) in DMF (1 ml) and pyridine (24 μl, 0.3 mmol) was added. The reaction was stirred for 1 h without cooling, then diluted with ethyl acetate, washed twice with water and brine, dried, concentrated and flash chromatographed, eluting with 40,50% ethyl acetate in hexane, to give the title compound (92 mg,60%), δH (CDCl3) 1.53 (9H,m), 1.9-2.1 (1H,m), 2.5-2.8 3H,m), 3.27 and 3.57 (2H,ABq,J18.7 Hz), 4.07 (3H,s), 5.06 (1H,d,J5Hz), 5.6-5.8 (1H,m), 5.98 (1H,dd,J5,9 Hz), 6.72 (1H,d,J9 Hz), 6.74 (1H,s), 7.02 (1H,s), 7.2-7.4 (15H,m); [mass spectrum: +ve ion (thioglycerol)MH+, 766].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:70])[CH2:68][OH:69]>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([O:69][CH2:68][CH2:67][OH:70])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: OCCO
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(OCCO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
To 150 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine, 187 mg of tripotassium phosphate, 84 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 46 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added 3 ml of ethylene glycol and 1.5 ml of 1,4-dioxane, and the mixture was degassed, and substituted by argon gas, and the mixture was stirred at 100° C. for 13 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol as pale brown powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 52 mg of the objective compound as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]2[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1.[Cl:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:20]([O:22][CH3:23])=[O:21])=[C:10]([CH3:19])[NH:11][C:12]([CH3:18])=[C:13]2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: O=C(Cl)CCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(=O)CCCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester (0.8 g, 2.53 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 3-Chloropropionyl chloride (0.32 g, 2.53 mmol) was dissolved in THF (15 mL) and added dropwise to the mixture over 10 min. The mixture was stirred at 0° C. for 1 h., concentrated in vacuo, and the residue extracted with CH2Cl2 /brine. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (1:1 to 1:0 EtOAc:hexane gradient) gave the title compound (1.05 g, 100%) as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:11][CH2:10][C:9]([O:12][C:17](=[O:18])[NH:16][CH2:15][CH2:14][Cl:13])=[N:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C=NCCCl
Reactant: CCCCCCONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCCCCCON=C(CCl)OC(=O)NCCCl
Temperature: 25 °C

Procedure:
N-Hexyloxychloroacetamide (19 grams; 0.1 mole), benzene (100 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. β-Chloroethylisocyanate (12.6 grams; 0.12 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-β-chloroethylcarbamoyloxy)-2-hexyloxyiminoethane.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][OH:40].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([O:40][CH2:39][C:38]([F:42])([F:41])[F:37])[C:11]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(OCC(F)(F)F)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl) pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.47 mmol) were combined in a round bottom flask under an N2 atmosphere. The reaction solution was heated to reflux and refluxed overnight. Analysis showed the reaction had only progressed a moderate amount, so additional reagents were added, 2,2,2-trifluoroethanol (14.0 μL, 0.19 mmol) and sodium hydride (60% dispersion in mineral oil, 6 mg, 0.19 mmol) and contents were heated at reflux for an additional 48 hours. The contents were cooled to room temperature then transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H19ClF6N4O2, 592.1; m/z found, 593.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.80 (d, J=2.1 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 8.17 (s, 1H), 8.05 (dd, J=8.2, 2.0 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.3, 0.4 Hz, 1H), 7.75 (dd, J=8.8, 2.2 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.34 (m, 2H), 6.60 (s, 1H), 5.00 (q, J=8.6 Hz, 2H), 3.56 (s, 3H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(OC)C[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C=O.NCCC[C:30](O)=[O:31].ClC1C=C(C=CC=1Cl)[CH2:37][N:38](OC)[C:39]([C:41]1[CH2:45][N:44]([CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C:43](=[O:52])[C:42]=1[OH:53])=[O:40]>>[OH:53][C:42]1[C:43](=[O:52])[N:44]([CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[CH2:45][C:41]=1[C:39](=[O:40])[N:38]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH2:37][O:31][CH3:30]
Reactant: NCCCC(=O)O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1cccc2ccccc12)OC
Reactant: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Agent: C=O
Product: COCN(C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1)c1cccc2ccccc12
Yield: 45 %

Procedure:
2-Hydroxy-3-(methoxy-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester, paraformaldehyde and 4-amino-butyric acid were reacted using the method described for the synthesis of Compound 810 to give the title compound as an orange powder (0.0217 g, 45% yield). 1HNMR (300 MHz, CDCl3) δ: 8.09 (1H, d, J=8.05 Hz), 7.87 (2H, t, J=768 Hz), 7.57–7.41 (4H, m), 5.35 (2H, s), 4.16 (2H, s), 3.56 (3H, s), 3.54 (2H, t, J=6.33 Hz), 2.38 (2H, t, J=6.58 Hz) 1.91 (2H, t, J=6.22 Hz).