Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(S(CC)(=O)=O)C=CC=2OC)=NC=1)C)=O.[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45](S(C)(=O)=O)=[N:44][CH:43]=1)[CH3:41])=[O:38].[Cl:55][C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][C:62]=1[N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)[NH2:59].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45]([NH:59][C:58]2[CH:60]=[CH:61][C:62]([N:63]3[CH2:64][CH2:65][O:66][CH2:67][CH2:68]3)=[C:56]([Cl:55])[CH:57]=2)=[N:44][CH:43]=1)[CH3:41])=[O:38]
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)c1cccc(Br)c1)c1cnc(Nc2ccc(N3CCOCC3)c(Cl)c2)nn1
Yield: 16.7 %

Procedure:
In a similar manner as described for Intermediate 23, 3-bromo-N{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (200 mg, 0.52 mmol), 3-chloro-4-morpholin-4-ylaniline (200 mg, 0.94 mmol) and 4-toluenesulfonic acid monohydrate (20 mg) in tetrahydrofuran (10 mL) gave 3-bromo-N-(1-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.045 g) as a white solid. MS m/z 517, 519 (M+1, M+3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.ClCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([F:1])=[CH:3][C:4]=3[OH:10])([OH:32])[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: COc1ccc(O)cc1F
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 3-fluoro-4-methoxyphenol (Niemann, M. B. J. Am. Chem. Soc. (1941), 63:609) (4.60 g, 32.4 mmol) in tetrahydrofuran (60 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (18.0 mL, 36.0 mmol). Tetrahydrofuran was removed under reduced pressure and dichloromethane (60 mL) was added. To the solution was added a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (8.00 g, 25.5 mmol) in dichloromethane (60 mL) at 5° C. and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL). The reaction mixture was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography with 40% to 90% gradient of ethyl acetate in hexanes to afford 1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (6.60 g, 57%) as a pink solid: MS (ES+) m/z 438.3 (M−17).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=1.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
The 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solution was stirred (80° C., 18 h) and then concentrated. The residue was dissolved in ethyl acetate and washed with water, brine and dried over MgSO4. Solvent evaporation afforded 1.0 g of ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate. Mass calculated for C15H12F2O3=278.25. found: [M+H]+=279.1.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH3:39][C:40]1[N:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=3)[C:25]([NH:46][C:43]3[CH:42]=[N:41][C:40]([CH3:39])=[CH:45][N:44]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)N3CCC3)nc2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (2.4 mL, 18 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-phenylmethoxy-benzoic acid (Intermediate 3) (6.19 g, 15 mmol) in DCM (100 mL) and stirred at ambient temperature for 30 minutes. Further 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.24 mL, 1.8 mmol) was added and stirring continued for 20 minutes. 5-Methylpyrazin-2-amine (CAS no. 5521-58-4) (3.34 g, 31 mmol) and pyridine (2.5 mL, 31 mmol) were added and the reaction stirred for a further 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (350 mL), washed with water (2×100 mL) and brine (100 mL), dried (MgSO4), and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of 50-75% ethyl acetate in isohexane, to afford the product (4.01 g, 53%). 1H NMR δ (400 MHz, CDCl3) 2.28 (quintet, 2H), 2.49 (s, 3H), 4.18 (t, 2H), 4.63 (t, 2H), 5.05 (s, 2H), 6.78 (s, 1H), 7.10 (s, 1H), 7.25-7.37 (m, 7H), 8.04 (d, 1H), 8.07 (s, 1H), 8.25 (s, 2H), 9.46 (s, 1H); m/z 496 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1COCC1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[Na+]>O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
Under ice cooling, a mixture of 515 g of p-toluenesulfonyl chloride and 500 ml of THF was added dropwise to a mixture of 295 g of 2-(2-methoxyethoxy)ethanol, 589 g of 25 wt % NaOH aqueous solution, and 2,500 ml of THF. The reaction solution was aged for 1.5 hours, after which 1,500 ml of water was added to quench the reaction. The organic layer was separated and concentrated in vacuum. The concentrate was dissolved in a mixture of 660 ml toluene and 330 ml hexane, and washed with water. The organic layer was concentrated in vacuum, obtaining 684.74 g of the target compound, 2-(2-methoxyethoxy)ethyl p-toluenesulfonate as oily matter. Yield 97%.
Reaction SMILES: [Cl:1]C1C=CC(OCC2C=CC=CC=2)=CC=1.C1(C=NC2C=CC=CC=2)C=CC=CC=1.[CH2:30]([N:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:47]1[CH:48]=[CH:49][C:44]([N:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:45][CH:46]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(OCc2ccccc2)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Product: Clc1ccc(N(Cc2ccccc2)c2ccccc2)cc1

Procedure:
Chloro-4-(phenylmethoxy)benzene (2.18 g, 0.010 mol) and N-(phenylmethylene)benzenamine (1.81 g, 0.010 mol) were reated in Na/DMF (1 g: 50 mL) at 50° C. for 7 hrs. The reaction was followed by HPLC to about 90% conversion. This technique indicated among other thigs the presence of the title compound, benzyldiphenylamine, and some unknown material in a ratio 65:18:17. Similar aqueous workup as for the preparation of benzyldiphenylamine and chromatography on silica gave 0.50 g of the title compound mp 94°-5° C. from methanol (lit8 mp 97°-7.5° C. 70% yield). This material is contaminated with a small amount of diphenylbenzylamine. 1H NMR (200 MHz, CDCl3) δ (assignment): 5.03 (s, 2H, Ph2NCH2Ph), 6.96-7.38 (m, 14H, aromatic). MS [m/e (70 eV, % of base peak)] C19H16ClN 293 (M+., 52.8), 295 (M+. +2, 28.8), 202 (M+. -C7H7+, 22), 167(C6H4NPh)+., 48.3), 91 (C7H7+, 100). FTIR (CDCl3): 3066, 3033, 1589, 1494, 1454 cm-1.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=O)[CH2:3][CH2:4][S:5][CH3:6].NCC(O)=O.N[C@H](C(O)=O)CCSC.[NH2:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27]>O>[NH2:1][C@H:2]([C:7]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:9])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CSCCC(N)C(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: NCC(=O)O
Solvent: O
Product: CSCC[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1A and B above by replacing DL-methionine and glycine respectively with L-methionine and L-valine (Aldrich Chemical Co., Beil 4,427). The title compound had a melting point of 227° to 229° C (d). The title compound was found to be water soluble. The product thus obtained was subjected to amino acid analysis and found to contain 49.44 mole percent valine and 50.56 mole percent methionine.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1C#N.OS(O)(=O)=O.[C:18](=[O:21])([O-])[O-:19].[Na+].[Na+]>O>[Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:18]([OH:19])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
2-Bromo-4-nitro-benzonitrile (0.5 g, 2.34 mmol) was hydrolysed using H2SO4 (2.2 mL) in water (2.7 mL) at 80° C. for 8 h. After completion of reaction, the solution was poured over crushed ice, basified with sodium carbonate and extracted with EtOAc. Aqueous layer was separated, acidified with 1:1 HCl and extracted with EtOAc (3×100 mL). The combined organic layers were concentrated to obtained compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:33])[C:9]2[CH:32]=[CH:31][C:12]3[N:13]([CH3:30])[C:14]([N:16]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccccc1)n2C)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Tert-butyl 5-[(2-chloropyrimidin-4-yl)amino]-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (0.97 g, 2.2 mmol) was dissolved in DMF (10 ml) and cesium carbonate (2.15 g, 6.6 mmol) was added. After 15 min, iodomethane (0.20 ml, 3.3 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified through silica gel to give the title compound as a white solid (0.80 g. 78% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.90 (d, J=6.3 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.38 (m, 4H), 7.25-7.29 (m, 2H), 6.17 (d, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.41 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=465 [M+H]+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1.Cl>N1C=CC=CC=1>[C:8]([C:12]1[CH:19]=[CH:18][C:15](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48051.9 %

Procedure:
19.20 g (0.185 mol) of malonic acid were dissolved in pyridine (33 ml) and stirred for 15 minutes at RT. 25.00 g (0.154 mmol) of para-tert.-butylbenzaldehyde and 1.50 ml (0.020 mol) of piperidine were then added. The reaction mixture was heated for 8 hours at 100° C., with stirring. After pouring the reaction solution into a mixture of concentrated hydrochloric acid and ice, stirring was continued for a further two hours at room temperature. The resulting precipitate was filtered out with suction. Recrystallisation of the precipitate from methanol yielded 15.20 g (0.074 mol, 48% of theory) of para-tert.-butyl-trans-cinnamic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(#N)C.O>[CH:34]([NH:37][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:36])[CH3:35]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: CC#N
Solvent: O
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 885 μL (10.4 mmol) of isopropylamine. The reaction mixture is stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 4:6) affords 60 mg (10% over two steps) of the product as a white solid; LC/MS:536/538 (M+H)+, m.p.: 247-250° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]#[N:12])[CH2:3][CH2:2]1.[CH2:13](N)[CH2:14][NH2:15]>>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]2[NH:12][CH2:13][CH2:14][N:15]=2)[CH2:3][CH2:2]1
Reactant: N#CCc1ccccc1C1CC1
Reactant: NCCN
Product: c1ccc(C2CC2)c(CC2=NCCN2)c1

Procedure:
2-(2-Cyclopropyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-cyclopropyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light brown powder; MS (ISP): 201.4 ((M+H)+.).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:25](OCC)([O:28]CC)[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11].O>C(C(C)=O)C(C)C>[CH3:6][O:7][N:8]=[C:9]([C:25](=[O:28])[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
70% Perchloric acid (0.54 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1 g) in methyl isobutyl ketone (4 ml) under ice-cooling, and stirred at the same temperature for 20 minutes. Water (4 ml) was added to the resultant mixture and stirred for 5 minutes. The precipiates were collected by filtration, washed with water and dried over phosphorus pentachloride in vacuo to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 502 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])[C:3]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(C#CC(C)(C)O)c2c(N)ncnc21
Yield: 68.1 %

Procedure:
To a solution of Example 57b (0.500 g, 0.981 mmoles) in THF (14 ml), 2-Methyl-3-butyn-2-ol (0.1 ml, 1.178 mmoles) diisopropylamine (0.70 ml, 4.90 mmoles), copper(I) iodide (18.6 mg, 0.098 mmoles) and) Tetrakistriphenylphosphine Palladium (0.113 g, 0.098 mmoles) were added and the system is degassed for 30 min. and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.311 g, 68% yield). MP: 109-113° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05 (m, 3H), 7.83 (dt, J=8.6, 1.5 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.30-7.11 (m, 4H), 5.84 (q, J=7.1 z, 1H) 5.74 (s, 1H), 1.82 (d, J=7.0 Hz, 3H), 1.46 (s, 6H). Mass: 466.09 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[C:21]([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:29]2)[N:20]=1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(F)cc4)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 74 mg (0.28 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 47 mg (48% of theory) of the product were obtained in solid form.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol), and Et3N (0.43 mL, 3.0 mmol) in CH2Cl2 (150 mL) was added 4-chlorobenzenesulfonyl chloride (380 mg, 1.8 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with CH2Cl2 (200 mL) and washed with H2O, 0.5 N HCl, brine, and dried over MgSO4, to afford the titled compound (410 mg) as a white solid in 90% yield. MS (ESI), (M+H)+ 305.2; 1H NMR (DMSO-d6) δ 7.77 (d, 2H, J=8.7), 7.62 (d, 2H, J=8.7), 6.90 (br s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=1)[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:31]=[CH:30][CH:29]=[C:22]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH:21]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)c1cccc(N)c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.1 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (2.54 g, 9.3 mM), allyl 3-aminobenzoate (1.5 g, 8.5 mM), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.72 g, 11 mM) were dissolved in toluene (50 ml) and stirred for 18 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M HCl (3 by 30 ml), water, saturated NaHCO3, and brine. Drying over MgSO4 and evaporation gave (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine as a gum (3.7 g, 100% ) in a state sufficiently pure for further work. Nmr (CDCl3): δ 2.32 (s, 3H); 2.60 (br, 2H); 3.40 (dd, 1H); 4.03 (quintet, 1H); 4.13 (dd, 1H); 4.57 (t, 1H); 4.66 (dm, 2H); 4.82 (dt, 2H); 5.23-5.46 (m, 4H); 5.86-6.12 (m, 2H); 7.41 (t, 1H); 7.82 (d, 1H); 7.91 (d, 1H); 8.07 (t, 1H); 9.18 (br, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CS(C2C=CC=C([Cl:49])C=2)(=O)=O)=CC=1)C(OC)=O.O1C=CC(B(O)O)=C1>>[Cl:49][C:3]1[CH:2]=[C:1]([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-chlorobenzenesulphonylmethyl)-2-hydroxy-benzoate (Intermediate 54) and furan-3-yl boronic acid.