Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([Cl:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(Cl)c3)nc2-c2ccc(Cl)cc2)cc1
Yield: 52.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (35 mL), 3-chlorophenacyl bromide (1.05 g, 4.48 mmol) was added. After heating the reaction mixture at 80°-85° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was chromatographed (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (525 mg, 53%) as a pale yellow solid: mp 156°-159° C. Anal Calc'd. for C22H16N2SO2Cl2 : C, 59.60, H, 3.69, N, 6.32, S, 7.23. Found: C, 59.43, H, 3.59, N, 6.15, S, 7.16.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:15][OH:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)(=[O:26])=[O:25].CN(C=O)C>C(OCC)(=O)C.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][C@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:30]2[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH2:15][OH:16]
Reactant: OC[C@H](CCC(F)(F)F)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@H](CO)CCC(F)(F)F)C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A stream of nitrogen was passed through a suspension of (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]amino}-5,5,5-trifluoropentan-1-ol (0.55 g), 2-(4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.59 g) 2.5 M K2CO3 (2.75 mL) and DMF (0.91 mL) for 20 minutes. [1,1′-Bis(diphenyl-phosphino)ferrocene]-palladium (II) chloride (1:1 complex with dichloromethane, 34 mg) was then added, the vessel sealed, and the reaction was warmed to 85° C. and stirred under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (50 mL) and shaken vigorously. The ethyl acetate layer was separated and washed 3 times with water, dried with magnesium sulfate, and filtered. Removal of the solvent left a residue that was purified by chromatography on SiO2 using a gradient of 10-30% ethyl acetate in hexanes. Rotary evaporation of appropriate fractions yielded (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([NH2:22])[CH:3]=1.[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:23](=[O:24])[NH:22][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4,5-Dichloro-2-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D39) (140 mg, 0.4 mmol) was dissolved in 10 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 0.25 ml) and triethylamine (0.2 ml, 1.5 mmol) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous sodium bicarbonate, dried over MgSO4, filtered and evaporated The product was chromatographed on silica gel eluting with methanol-dichloromethane mixtures, and then further purified by MDAP to yield 5,6-dichloro-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 22 mg, which was converted into the hydrochloride salt using 4M HCl in dioxan.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:12]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2cccnc2c1N
Agent: CN(C)c1ccncc1
Product: COc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 33.3 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-methoxyquinolin-8-amine (Intermediate 64) (150 mg, 0.86 mmol), benzenesulfonyl chloride (130 μl, 1.03 mmol) and DMAP (cat.) gave the title compound (90 mg, 33%) after recrystallisation from DCM/n-pentane.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:4]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:5]=1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.N1C=CC=CC=1.[C:49](Cl)(=[O:51])[CH3:50]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1)[CH2:14][N:7]([CH2:6][C:5]1[CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:4]=1[CH:3]([O:2][CH3:1])[CH:37]1[CH2:38][CH2:39][N:40]([C:49](=[O:51])[CH3:50])[CH2:41][CH2:42]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CC(=O)Cl
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a solution of N-(2-(methoxy piperidin-4-ylmethyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (20.5 mg, 0.034 mmol) in methylene chloride (0.5 mL) at room temperature was added pyridine (10 μL, 0.1 mmol) followed by acetyl chloride (5 μL, 0.07 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 10-100% ethyl acetate in hexanes) to afford the title compound (14 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 1.17-1.34 (m, 3H) 1.69-1.78 (m, 1H) 1.87 (t, J=12.65 Hz, 1H) 2.04 (s, 1.5H) 2.06 (s, 1.5H) 2.27-2.41 (m, 1H) 2.82-2.93 (m, 1H) 3.04 (s, 3H) 3.72 (d, J=15.77 Hz, 0.5H) 3.81 (d, J=12.45 Hz, 0.5H) 4.18 (d, J=6.64 Hz, 1H) 4.21 (s, 3H) 4.54-4.65 (m, 1H) 4.65-4.73 (m, 3H) 4.87 (d, J=16.60 Hz, 1H) 7.37 (s, 1H) 7.50 (d, J=7.88 Hz, 1H) 7.59 (d, J=7.88 Hz, 1H) 7.64 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 652.2, Found: 653.5 (M+1)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.O.[NH2:12][NH2:13]>C(O)(=O)C>[CH:7]1([C:5]2[CH2:4][C:3](=[O:2])[NH:12][N:13]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(C2CC2)=NN1
Temperature: 100 °C
Yield: 147 %

Procedure:
To a solution of methyl-3-cyclopropyl-3-oxopropionate (10 g) and acetic acid (28 mL) in a round bottom flask under argon was added hydrazine hydrate (2.25 g). The mixture was immersed into an oil bath and heated to 100° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was added to 1 N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and cold ether to afford the desired 5-cyclopropyl-2,4-dihydro-pyrazol-3-one (8.2 g) as a beige solid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([O:16]C)=O)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][C:14]([C:12]1[N:13]=[C:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:16]
Reactant: COC(=O)c1nc(CC2CCCCC2)[nH]c(=O)c1O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nc(CC2CCCCC2)[nH]c(=O)c1O
Temperature: 140 °C
Yield: 36.7 %

Procedure:
A mixture of methyl 2-(cyclohexylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (30 mg, 113 μmol), methylamine (2M in THF) (1.5 ml, 3.00 mmol) and MeOH (10 ml) was heated in a microwave oven at 140° C. for 40 min. The cooled reaction mixture was concentrated in vacuo. The residue was heated in a mixture of MeOH and Amberlyst until all the product had dissolved. The resin was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to give the title compound as an off-white solid (0.011 g; 35% with 95% purity). LCMS: m/z=266 (MH+).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:11][C:12](=O)[CH:13]=[C:14](OCC)[O:15]CC)[CH3:10]>C(O)(=O)C>[CH2:9]([O:11][C:12]1[CH2:13][C:14](=[O:15])[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C=C(OCC)OCC
Solvent: CC(=O)O
Product: CCOC1=Nc2ccccc2NC(=O)C1
Temperature: 140 °C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
To a solution phenylenediamine (17.2 g, 159.2 mmol) and acetic acid (0.4 mL) in xylenes (225 mL) at 140° C. was added 3,3-diethoxyacrylic acid ethyl ester (30.0 g, 159.2 mmol) in xylenes (80 mL) dropwise over 50 minutes. The reaction was heated at 140° C. for 2 hours, was cooled to room temperature, and was stirred for 24 h. The resulting white precipitate was filtered, was washed with ether (100 mL), and was dried under vacuum to provide 18.37 g of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one as a white fluffy solid. MS 205 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.[N:33]1C=CC=CC=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH2:33])=[O:25])[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)noc1-c1nc2cc(OCC3CC3)ccc2o1
Reactant: c1ccncc1
Product: Cc1c(OC[C@H](C)NC(N)=O)noc1-c1nc2cc(OCC3CC3)ccc2o1

Procedure:
Using tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-4-methylisoxazol-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 22 (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]([O-])=O)=[C:5](O)[CH3:6].C(O)(=O)C>O.C(OCC)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[C:8]2[C:9](=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[NH:15][C:5]=1[CH3:6])=[O:18]
Reactant: COC(=O)C(=C(C)O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C)[nH]c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
A mixture of 2-(4-chloro-2-nitro-phenyl)-3-hydroxy-but-2-enoic acid methyl ester (4.66 g, 17.2 mmol), iron (5.76 g, 103 mmol) and glacial acetic acid (16 mL) is heated at 115° C. for 1 h and allowed to cool. The reaction mixture is diluted with water and ethyl acetate. The ethyl acetate layer is washed with brine and dried over MgSO4. The mixture of the title compound and a small amount of impurity is used in the next reaction without additional purification. ES/MS m/e 224.0 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C[O:36][C:37]([C:39]1[C:47]2[N:46]([CH2:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)[C:45]([C:57](=[O:68])[NH:58][CH:59]3[CH2:64][CH2:63][N:62]([CH:65]([CH3:67])[CH3:66])[CH2:61][CH2:60]3)=[N:44][C:43]=2[CH:42]=[CH:41][CH:40]=1)=[O:38].[Li+].[OH-].Cl>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=[C:11]2[C:14](=[O:25])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[CH:29][CH:30]=1.[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][CH2:48][N:46]2[C:47]3[C:39]([C:37]([OH:38])=[O:36])=[CH:40][CH:41]=[CH:42][C:43]=3[N:44]=[C:45]2[C:57](=[O:68])[NH:58][CH:59]2[CH2:64][CH2:63][N:62]([CH:65]([CH3:66])[CH3:67])[CH2:61][CH2:60]2)=[CH:51][CH:52]=1
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CCc1ccc(Cl)cc1
Reactant: COC(=O)c1cccc2nc(C(=O)NC3CCN(C(C)C)CC3)n(CCc3ccc(Cl)cc3)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CCc2ccc(Cl)cc2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3cccc(C(=O)O)c3n2CCc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.45 g (4.21 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 45 mL DMF. Subsequently 989.1 mg (7.16 mmol) K2CO3 and 1.11 g (6.32 mmol) 1-chloro-4-(2-chloro-ethyl)-benzene were added and the resulting mixture was stirred for 24 h at 80° C. The solvent was distilled off. The residue was taken up in 300 mL ethyl acetate and washed once with a saturated NaHCO3-solution and with brine. The organic layer was dried over anhydrous MgSO4, concentrated and purified by flash chromatography using an ethyl acetate-methanol mixture as eluent to give 1.30 g of a 3:1-mixture of 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid methyl ester. That mixture of isomers was dissolved in 100 mL MeOH. 16.2 mL (16.2 mmol) of a 1 M aqueous LiOH-solution were added and the resulting suspension was stirred for 3 h at 60° C. The mixture was acidified by the addition of a 1 M HCl-solution and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave both isomers a) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and b) 3-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid as white amorphous solids. Both isomers were isolated as their formiates.
Reaction SMILES: [NH2:1][C:2]1[NH:18][C:5]2=[CH:6][C:7]3[C:8]([CH3:17])([CH3:16])[C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH2:13]([N:10]1[C:11]2[CH:12]=[C:4]3[N:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:18][C:5]3=[CH:6][C:7]=2[C:8]([CH3:17])([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Solvent: c1ccncc1
Solvent: O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Yield: 67.9 %

Procedure:
A solution of D3 (500 mg) and benzoyl chloride (0.6 ml; 5.12 mmol) in pyridine (15 ml) is stirred at RT for 20 h. After completion, water is added and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (1 N), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) afford the title compound (484 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1>C(O)(=O)C>[C:1]([C:14]1([NH:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:17][CH2:16][CH2:15]1)#[N:2]
Reactant: O=C1CCC1
Reactant: [C-]#N
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC1(Nc2ccc(C(=O)O)cc2)CCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
Sodium cyanide (0.245 g, 5 mmol) was added to a mixture of 4-aminobenzoic acid (0.274 g, 2 mmol) and cyclobutanone (0.21 g, 3 mmol) in 90% acetic acid (4.5 ml). The reaction mixture was stirred at room temperature for 15 hours. The mixture was washed with aqueous HCl (pH 2) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness under vacuum to yield 4-(1-cyanocyclobutylamino)benzoic acid (51a) (0.426 g, 1.97 mmol, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](I)[C:5](I)=[CH:4][C:3]=1[NH2:10].[C:11]([Cu])#[N:12].C(N(CC(O)=O)CC(O)=O)[CH2:15][N:16](CC(O)=O)CC(O)=O>>[NH2:1][C:2]1[CH:7]=[C:6]([C:15]#[N:16])[C:5]([C:11]#[N:12])=[CH:4][C:3]=1[NH2:10]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: N#C[Cu]
Reactant: Nc1cc(I)c(I)cc1N
Product: N#Cc1cc(N)c(N)cc1C#N
Temperature: 120 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A 50 mL round-bottom flask was charged with 2 (6.94 g, 19.3 mmol), and CuCN (6.91 g, 77.2 mmol, 4 eq), and a magnetic stirring bar. The vessel was capped with a septum and flushed with Ar for 10 min, and NMP (20 mL) was added. The vessel was heated to 120° C. for 3 h, then diluted with DMF (20 mL) and added to a hot aqueous solution of EDTA (88 g, 232 mmol, in 500 mL H2O) in a 1 L conical flask. Oxygen was bubbled through the mixture as it was stirred and heated for 2 h. After 2 h of this treatment, the dark heterogeneous mixture turned to a homogeneous green solution. The hot green solution was extracted twice with ethyl acetate, and the extracts were washed with water, followed by brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was recrystallized (EtOH/water), giving tiny tan needles (1.66 g, 55%): mp 262-264° C.; 1H NMR (d6-acetone) δ 5.40 (br s, 4H), 7.04 (s, 2H); 13C NMR (d6-acetone) δ 103.8, 117.1, 117.4, 139.4; FAB-MS obsd 158.0591, calcd 158.0592 (C6H6N4).
Reaction SMILES: [C:1](#[N:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)O.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CN(C=[O:28])C>>[O:28]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:2][C:1]#[N:10])[Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Reactant: N#CC(O)c1ccccc1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CC#N
Temperature: 35 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
Mandelonitrile (50 g, 0.38 moles) and imidazole (64 g, 0.94 moles) were dissolved in DMF (100 cm3) and the resulting solution cooled in an ice-water bath. tert-Butyldimethylsilyl chloride (68 g, 0.45 moles) was then added portionwise over a period of 20 minutes. The flask contents were then warmed to 35° C. and stirred at that temperature for 18 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (3×100 cm3) and deionised water (100 cm3). The combined organic fractions were then washed with brine (100 cm3), dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give the crude product as a yellow oil. Flash chromatography (600 g kieselgel 60 silica) eluting with 20% dichloromethane in pentane gave the title compound as an oil (77 g, 0.31 moles, 82%), δH (300 MHz;CDCl3) 0.1 (3H, s), 0.2 (3H, s), 1.0 (9H, s), 5.5 (1H, s), and 7.4 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH2:19]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][C:12](=[S:11])[NH:19][C:18]2[CH:20]=[C:21]([F:23])[CH:22]=[C:16]([Cl:15])[CH:17]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CC#N
Product: O=C(NC(=S)Nc1cc(F)cc(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
4-Chlorobenzoyl chloride (10.2 g, 58.5 mmol) was dissolved in acetonitrile (230 mL) and the reaction vessel containing this mixture was cooled in an ice/water bath. To this mixture was added potassium thiocyanate (6.25 g, 64.4 mol, 1.10 equiv). The cooling bath was removed from the reaction vessel after 15 minutes and the resulting reaction slurry was stirred at room temperature for approximately 1 hour. 3-Chloro-5-fluoroaniline (7.05 mL, 70.2 mol, 1.2 equiv) was added as a solution in acetonitrile (7 mL) over 5 minutes to the reaction mixture. Next, the reaction mixture was stirred at room temperature overnight and then quenched with water (230 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was filtered to collect the solids, the isolated solids were rinsed with acetonitrile/water (1/1 mixture by volume, 50 mL), and the resulting solid was dried at 60° C. in vacuo to provide 20.5 g the title compound as a solid. 1H NMR (DMSO-d6) of the title compound: δ 12.5 (s, 1H), 11.8 (s, 1H), 8.01 (t, 1H, J=1.8), 7.96 (d, 2H, J=8.6), 7.67 (m, 2H), 7.59 (d, 2H, J=8.6), 7.33 (d, 1H, J=8.4). HPLC: >99% purity at 23.52 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:57](=[O:58])[N:31]2[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:33]([C@@H:36]3[C:40](=[C:41]=[O:42])[CH2:39][C@H:38]([O:43][CH3:44])[O:37]3)[CH2:34][S:35][C@H:30]12>CN(C)C=O.N1C=CC=CC=1>[CH3:44][O:43][C@@H:38]1[O:37][C@H:36]([C:33]2[CH2:34][S:35][C@@H:30]3[C@H:29]([NH:28][C:8](=[O:10])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:11]\[O:12][CH3:13])[C:57](=[O:58])[N:31]3[C:32]=2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])[C:40](=[C:41]=[O:42])[CH2:39]1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3O[C@@H](OC)CC3=C=O)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3O[C@@H](OC)CC3=C=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
A stirred solution of 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (20.1 mg) and N,N-diisopropylethylamine (0.0176 ml) in dimethylformamide (0.3 ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.0081 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxy-carbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (41 mg) in dimethylformamide (0.3 ml) was added followed by pyridine (0.0073 ml). The mixture was then stored at 0° C. for 1 h and then at room temperature for 0.5 h. The reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase washed with water and brine. The solution was dried over magnesium sulphate and evaporated, and the title compound (31 mg) isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); νmax (CHCl3) 3496, 3397, 1784, 1733 and 1684 cm-1.