Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25].Cl>ClCCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 46.4 g. (0.25 mole) of p-nitrobenzoyl chloride in 100 ml. 1,2-dichloroethane is added portionwise to a suspension of 32.2 g. (0.25 mole) aluminum cloride in 100 ml. 1,2-dichloroethane. This mixture is added dropwise to a chilled solution of 30.0 g. (0.25 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. 1,2-dichloroethane. After the addition is complete, the mixture is stirred for twenty minutes at room temperature and then refluxed for four minutes. It is poured into ice acidified with 2N hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting semi-solid residue is triturated with cold methanol from which the product, 5-(p-nitrobenzoyl)-1-methylpyrrole-2-acetonitrile, crystallizes. It is removed by filtration and purified by recrystallization from acetone, m.p. 167-169° C.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:13]1[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:19])[CH2:14]1>>[N:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)=[O:19])[CH2:14]3)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCC(n2ccnc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccnc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-imidazol-1-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:2][C:3]([C@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:6]1)=[O:4])[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Yield: 22.6 %

Procedure:
In a dry flask (3S,4R)-4-[(R)-1-phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (13.78 g, 38.0 mmol) was dissolved in ethanol (400 mL) along with 3 Å molecular sieves (1.04 g). The mixture was heated to reflux over 2.5 hours. Potassium carbonate (26.3 g) was added and refluxing continued for 4 additional hours. The reaction mixture was cooled, filtered through a bed of celite, and concentrated in vacuo to give a crude oil (16.05 g). Purification by flash column chromatography (20-50% ethyl acetate/hexanes) provided a colorless oil (3.24 g, 23%). Unepimerized ethyl ester was also isolated (7.55 g, 53%).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N-dimethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([O:30][CH3:31])[C:23]=4[CH:22]=3)=[CH:19][N:20]=2)[N:17]=1>C1COCC1>[CH3:31][O:30][C:24]1[C:23]2[CH:22]=[C:21]([C:18]3[N:16]4[N:17]=[C:12]([O:8][CH2:7][C@@H:2]5[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]5)[CH:13]=[CH:14][C:15]4=[N:20][CH:19]=3)[O:29][C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: COc1nccc2oc(-c3cnc4ccc(Cl)nn34)cc12
Reactant: OC[C@@H]1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2oc(-c3cnc4ccc(OC[C@@H]5CCCCN5)nn34)cc12
Temperature: 40 °C
Reaction time: 72 h

Procedure:
At 0° C. 86 mg (0.44 mmol) (2S)-piperidin-2-ylmethanol were added to 132 mg (3.3 mmol) sodium hydride (60% in mineral oil) in 4 mL anhydrous THF. After 15 min of stirring on the ice bath, 141 mg (0.33 mmol) of 6-chloro-3-(4-methoxyfuro[3,2-c]-pyridin-2-yl)imidazo[1,2-b]pyridazine were added. The ice bath was removed and the mixture was stirred for 72 h at 40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Al](Cl)(C)C.[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][C@@H:23]([CH3:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:19]([C:32](OCC)=[O:33])=[CH:18][C:16]=2[CH:17]=1>ClCCCl>[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][CH:23]([CH3:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][C:19]([C:32]([NH:1][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)=[O:33])=[CH:18][C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1cc(O[C@@H](C)Cc2ccccc2)c2sc(C)cc2c1
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1cc2cc(C(=O)Nc3ccn(C)n3)cc(OC(C)Cc3ccccc3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
3-Amino-1-methyl pyrazole (649 mg, 6.69 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (6.69 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-7-[(1S)-1-methyl-2-phenylethoxy]-1-benzothiophene-5-carboxylate (237 mg, 0.669 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (155 mg, 57%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.59 (s, 3 H) 2.95 (dd, J=13.75, 6.22 Hz, 1 H) 3.16 (dd, J=13.75, 6.03 Hz, 1 H) 3.74 (s, 3 H) 4.78-5.01 (m, 1 H) 6.89 (d, J=2.26H) 7.00 (d, J−1.13 Hz, 1 H) 7.12-7.23 (m, 1 H) 7.26-7.42 (m, 6 H) 7.81 (d, J=1.13 Hz, 1 H) 9.60 (s, 1 H). LCMS m/z 406.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:22]([S:26]([C:29]1[S:33][C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([S:26]([C:29]1[S:33][C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:36][CH2:35]2)=[N:31][CH:30]=1)(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C(F)(F)F)CC2)s1
Yield: 65 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 38(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 65%). MS (m/e): 584.3 (M+H+, 100%), 601.4 (M+NH4+, 60%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([OH:24])=O)[C:17]=1[CH3:25].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH2:31][CH2:32]2)=[O:24])[C:17]=1[CH3:25]
Reactant: COCCN1CCNCC1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Product: COCCN1CCN(C(=O)c2nn(C)c(-c3ccccc3-c3cc4ccccc4o3)c2C)CC1

Procedure:
In analogy to the procedure described in Example 18], 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) and 1-(2-methoxy-ethyl)-piperazine gave the title compound in quant. yield as light brown foam. MS: 459.3 (MH+).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:15]([NH2:17])=[N:14][S:13](=[O:19])(=[O:18])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[C:15]([NH2:17])=[N:14][S:13](=[O:18])(=[O:19])[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Product: CS(=O)CCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Yield: 90 %

Procedure:
Prepared as in Example 245 from 5-(3-(methylthio)propoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (Example 247) by the reaction with 1.0 equivalent of MCPBA as a white solid in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 2.18-2.22 (m, 2H), 2.54 (s, 3H), 2.75-2.78 (m, 1H), 2.89-2.93 (m, 1H), 4.26 (t, J=6.4 Hz, 2H), 6.60-6.61 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.83 (s, 1H), 8.30 (s, 1H), 10.92 (s, 1H). MS 318 (MH+).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=[O:12])[CH2:6]1)(=[NH:4])[NH2:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCCC(C(=O)O)C1
Reactant: Oc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCCC(C(=O)Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
A mixture of 3 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride, 1.4 g of phenol, 3 g of dicyclohexylcarbodiimide and 40 ml of dry pyridine was stirred at room temperature for 2 days. After removal of any insoluble materials, the solvent was removed under reduced pressure to give a light yellow oil. The oil was washed twice with ethyl acetate to give white powder. The powder was washed with dry ether and dried under reduced pressure to obtain 3 g of phenyl 1-amidino-3-piperidinecarboxylate hydrochloride as hygroscopic white powder having a melting point of 54° to 60° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCOS(C)(=O)=O)cc1)Oc1ccccc1

Procedure:
In a similar manner to that described in Reference example 3(g), a reaction was carried out using ethyl 3-[4-(2-hydroxyethoxy)phenyl]-2-phenoxypropionate (3.27 g), which is the product of Reference example 4(e), triethylamine (2.07 ml) and methanesulfonyl chloride (0.84 ml) and the reaction mixture was treated to afford the desired compound (4.20 g) as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH3:15])[CH2:12][C:13]#[N:14])[C:6](=O)[C:5]12[O:21][CH2:20][CH2:19][CH2:18][O:17]1.N>[Ni].CCO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH:11]([CH3:15])[CH2:12][CH2:13][N:14]=[C:6]3[C:5]3([O:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:4]=2[CH:3]=1
Reactant: CC(CC#N)N1C(=O)C2(OCCCO2)c2cc(Br)ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC1CCN=C2N1c1ccc(Br)cc1C21OCCCO1
Temperature: 135 °C
Yield: 13.4 %

Procedure:
A mixture of 3-(5′-bromo-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl)butanenitrile (0.751 g, 2.14 mmol), and wet Raney Nickel (0.75 g) in 2M EtOH.NH3 (10 mL) was hydrogenated in a Parr Hydrogenation Bottle (500 mL) at 55 lb/in2 H2 for 23 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel and heated at 135° C. for 69 hr. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (98/2/1) to give the title compound as a white solid (0.097 g, 13% yield). Anal. Calc'd for C15H17BrN2O2: C, 53.43; H, 5.08; N, 8.31. Found: C, 53.61; H, 5.12; N, 8.11. NMR (300 Mz, DMSO-d6): consistent. MS: (ES+) m/z 337/339 [M+H]; one Br pattern observed. m.p.: 69-72° C.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C@@:5]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:24][C:25]([S@@:28]([NH2:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:25]([S@@:28](/[N:30]=[CH:2]/[CH2:3][CH2:4][C@@:5]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:29])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COC(=O)[C@]1(CCC=O)CCCN1C(=O)OCc1ccccc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Reaction time: 25 h

Procedure:
To a mixture of 1-benzyl 2-methyl (2R)-2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate from Step A (1.69 g, 5.29 mmol) and anhydrous CuSO4 (2.36 g, 10.6 mmol) in CH2Cl2 (10 mL) was added (S)-2-methylpropane-2-sulfinamide (0.641 g, 5.29 mmol). This mixture was stirred for 25 h before being filtered through a pad of celite. Additional CH2Cl2 was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 0:100, to give the title compound. MS: m/z=423 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[N:6][C:5]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C#Cc4cccc(O)c4)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(S(=O)(=O)C3CCNCC3)cc2)nc1C#Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
Crude tert-butyl 4-[4-[5-amino-6-[2-(3-hydroxyphenyl)ethynyl]pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (184.3 mg, 0.3447 mmol—assumed quantitative yield from Step 3) was dissolved in DCM (5 mL) and TFA (1 mL, 12.98 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the mono-TFA salt of the title compound as a yellow solid (10.3 mg, 5% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.65-1.74 (m, 2H), 2.06 (d, 2H), 2.85-2.90 (m, 2H), 3.36 (d, 2H), 3.59-3.65 (m, 1H), 6.89 (dd, 1H), 7.14-7.21 (m, 2H), 7.27 (t, 1H), 7.90 (d, 2H), 8.23 (br s, 1H), 8.28 (d, 2H), 8.54 (br s, 1H), 8.77 (s, 1H) and 9.78 (s, 1H) ppm; MS (ES+) 435.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[NH2:11].[C:12](O)(=[O:16])[C:13](O)=[O:14].Cl>>[Cl:10][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[CH2:8][CH3:9])[NH:1][C:13](=[O:14])[C:12](=[O:16])[NH:11]2
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(N)c(N)cc1Cl
Agent: Cl
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 228 mg (1.33 mmol) of 38 and 124 mg (1.38 mmol) of oxalic acid in 4 mL of aqueous 2N HCl was refluxed for 4 h. It was cooled to room temperature, filtered, and dried to leave 275 mg (92%) of a brown solid; mp>400° C.; 1H NMR (DMSO-d6), 1.134 (t, 3, J=7.4), 2.635 (q, 2, J=7.4), 7.026 (s, 1), 7.107 (s, 1), 11.890 (s, 1), 11.927 (s, 1). MS, 224 (M+, 100), 209 (45), 181 (80). HRMS, Cacld for C10H9ClN2O2 224.0348; Found 224.0359.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=S)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1[O:17]C1C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:17])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: S=C1N[C@@H](Cc2ccccc2)CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](Cc2ccccc2)CS1
Reaction time: 2 h

Procedure:
To a solution (4S)-4-benzyl-1,3-thiazolidine-2-thione (38 g) in dichloromethane (350 mL), cooled to 0° C. was added propylene oxide (12.7 mL) and trifluoroacetic acid (14 mL). After stirring the reaction mixture for 2 hours, the solvents were evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (0.9 g). Mass (m/z): 194.18
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26](O)=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1>[Cl:21][C:22]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:23]=1[O:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[O:27]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1ccc(OC)c(N)c1)OC(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1NC(=O)COc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 8.2 %

Procedure:
30 mg of Ethyl 3-(3-amino-4-methoxyphenyl)-2-isopropoxypropanoate and 20 mg of 2,4-dichlorophenoxyacetic acid were dissolved in 0.5 ml of tetrahydrofuran, and 30 mg of carbonyldiimidazole and 0.05 ml of triethylamine were added, and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer was concentrated. The residue was dissolved in 0.6 ml of ethanol, and 0.12 ml of 5N sodium hydroxide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by HPLC using a reverse-phase column and a water-acetonitrile-trifluoroacetic acid elution solvent, to give 3.4 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([OH:9])=O)[CH:2]=[CH2:3].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[NH2:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][CH:45]=[CH2:46])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:11]=[C:12]([NH:15][CH:16]=[O:17])[S:13][CH:14]=1)[C:7]([NH:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][CH:45]=[CH2:46])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
2-Allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(0.80 g) and dry ethyl acetate (10 ml) were added at 0° to 5° C. with stirring to a suspension of Vilsmeier reagent prepared from dry dimethylformamide (0.25 g) and phosphorus oxychloride (0.528 g) in dry ethyl acetate (0.75 ml) by conventional method, and the resulting mixture was stirred for 30 minutes at the same temperature to give an yellow solution. The solution was added at -10° C. with stirring to a solution of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.11 g) and trimethylsilylacetamide (2.96 g) in dry ethyl acetate (15 ml), and the mixture was stirred for 1.5 hours at the same temperature. After addition of water (15 ml) to the reaction mixture, the ethyl acetate layer was separated and extracted with an aqueous solution of sodium bicarbonate (30 ml). The aqueous extract was acifified to pH 2.0 with 10 % hydrochloric acid and extracted with ethyl acetate (150 ml). The extract was washed with water, dried and evaporated. The residue was pulverized with diisopropyl ether to give colorless powder of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.48 g).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>C(O)CO>[C:9]1([C:6]2([NH2:5])[CH2:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)NC1(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: NC1(c2ccccc2)CC1
Temperature: 110 °C
Yield: 8.4 %

Procedure:
To a suspension of 0.84 g (4.1 mmol) of the above carbamate in a 1:2 mixture of H2O:ethylene glycol (4.5 mL) was added 1.0 g (25 mmol) of sodium hydroxide as a solid in one portion. The slurry was heated to 110° C. for 15 h during which time a solid precipitated out of solution. The mixture was cooled to room temperature and poured into a solution of 2N HCl (30 mL). The mixture was washed with Et2O and the aqueous layer made basic to pH 12 by addition of 6N NaOH. The aqueous phase was washed with CH2Cl2 and the combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 0.046 g (8%) of 1-phenyl -cyclopropylamine as a clear oil. m/z cacld. C9H12N [M+H]+: 134.20. Found: 133.90.