Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(NC(C)C)(C)C.[C:38]1([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: O=C(O)CCCCNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 42.6 %

Procedure:
The target compound was prepared as a pale yellow oil in an amount 3.8 g at a yield of 42.6% in the same manner as in Example 1 except that 5.7 g (22 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 23 ml of THF and 5.35 g (33 mmol) of CDI was dividedly added several times; 5.8 ml (44 mmol) of diisopropylamine and 10 ml of THF were added and 27.5 ml (44 mmol) of 1.63N BA solution was added dropwise; 6.6 ml (44 mmol) of ethyl phenylacetate instead of methyl phenylacetate was dissolved in 10 ml of THF; and 30 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 50 g of 4N hydrochloric acid was added, and 100 ml of ethyl acetate was further added. The analytical results on the target compound are given below.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].CCN.[C:22]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:24])[CH3:23]>CO>[C:22]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])(=[O:24])[CH3:23].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CCN
Solvent: CO
Product: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Resolution of 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine. A 3 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulphonyl)-eth-2-ylamine (137.0 g 500 mmol), N-acetyl-L-leucine (52 g, 300 mmol), and methanol (1.0 L). The stirred slurry was heated to reflux for 1 hour. The stirred mixture was allowed to cool to ambient temperature and stirring was continued for another 3 hours at ambient temperature. The slurry was filtered and washed with methanol (250 L). The solid was air-dried and then dried in vacuo at ambient temperature to a constant weight, giving 109.5 g (98% yield) of the crude product (85.8% ee). The crude solid (55.0 g) and methanol (440 mL) were brought to reflux for 1 hour, cooled to room temperature and stirred for an additional 3 hours at ambient temperature. The slurry was filtered and the filter cake was washed with methanol (200 mL). The solid was air-dried and then dried in vacuo at 30° C. to a constant weight, yielding 49.6 g (90% recovery) of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine-N-acetyl-L-leucine salt (98.4% ee). Chiral HPLC (1/99 EtOH/20 mM KH2PO4 @pH 7.0, Ultron Chiral ES-OVS from Agilent Technologies, 150 mm×4.6 mm, 0.5 mL/min., @240 nm): 18.4 min (S-isomer, 99.2%), 25.5 min (R-isomer, 0.8%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Br:60][C:61]1[CH:62]=[C:63]([CH2:68][NH2:69])[CH:64]=[CH:65][C:66]=1[F:67]>ClCCl>[Br:60][C:61]1[CH:62]=[C:63]([CH2:68][NH:69][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[CH:65][C:66]=1[F:67]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (481 mg, 2.000 mmol), and TEA (0.836 mL, 6.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. It was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (875 mg, 1.329 mmol, 66.5% yield) as a white solid. LC-MS m/z 651.3 (M+H)+, 0.98 min (ret time).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26]Br)/[C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[CH3:11][O:12]/[N:13]=[C:14](\[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: Cc1ccccc1O
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
o-Cresol (5.9 g, 0.542 mol) was added to a suspension solution of sodium hydride (95%, 2 g, 0.813 mol) in DMF (100 mL) at 0 ° C., the reaction mixture was stirred for 1 hour at room temperature. This above reaction solution was added dropwise to a solution of methyl E-2-bromomethyl-6-methylphenylglyoxylate O-methyl oxime (16.2 g, 0.542 mol) in DMF (100 mL) for 30 min at 0 ° C. After was stirred for 1 hour at room temperature, the reaction mixture was added water (200 mL) and extracted with ether (100 mL) three times. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the crude product which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][NH:4][C:3]1=[S:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(O)(=O)C>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][S:13][C:3]1[N:2]([CH3:1])[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:4]=1
Reactant: ClCCCBr
Reactant: Cn1c(C2CCOCC2)n[nH]c1=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1C1CCOCC1
Temperature: 90 °C

Procedure:
To 4-methyl-5-(tetrahydro-2H-pyran-4-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, prepared in analogy to the method described in Preparation 2) in ethanol (6 ml) sodium ethanolate (0.83 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.30 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to give the title compound as white solid (0.173 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([N:28]=[C:29]=[O:30])[CH2:25][CH2:26][CH3:27].Cl>C(C(C)=O)C>[CH2:24]([NH:28][C:29]([NH:17][S:14]([C:3]1[C:4]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:16])=[O:15])=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(Cl)cccc1S(=O)(=O)N(C)C
Temperature: 25 °C

Procedure:
To 140 mL of methyl ethyl ketone was added 14.3 g of 3-chloro-N,N-dimethyl-1,2-benzenedisulfonamide, 7.2 g of potassium carbonate and 7.5 ml of n-butyl isocyanate. This mixture was heated at reflux temperature for 3 hours, cooled to room temperature, poured into 1500 mL of ice water, and acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water, and dried to afford 17.4 g of N'-butylaminocarbonyl-3-chloro-N,N-dimethyl-1,2-benzenedisulfonamide as a white powder, m.p. 107°-115° C.; NMR (CDCl3): δ0.9 (br t, 3H), 1.2-1.7 (m, 4H), 3.0 (s, 6H), 3.3-3.4 (m, 2H), 6.6 (t, 1H), 7.6-8.0 (m, 2H), 8.5 (dd, 1H), 9.0 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O.N1(C(C2C=CC(Br)=CC=2[F:58])=O)CCC1>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:26][CH2:27][CH2:28]3)=[O:24])=[C:19]([F:58])[CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ccc(Br)cc1F)N1CCC1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) and azetidin-1-yl-(4-bromo-2-fluoro-phenyl)-methanone. 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J=8.21 Hz, 1 H) 7.25 (s, 1 H) 7.22 (s, 1 H) 6.78 (dd, J=8.59, 2.27 Hz, 1 H) 6.66 (dd, J=11.12, 2.27 Hz, 1 H) 4.18-4.29 (m, 2 H) 4.15 (t, J=7.58 Hz, 2 H) 3.88 (s, 3 H) 2.88 (s, 2 H) 2.30-2.41 (m, J=7.75, 7.75, 7.75, 7.58 Hz, 2 H) 1.48 (s, 6 H); LCMS for C22H22FNO5 m/z 400.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[C:22][Si](C)(C)C)[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-]>CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:21]#[CH:22])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(C#C[Si](C)(C)C)c2c(N)ncnn12
Agent: O=C([O-])[O-]
Solvent: CO
Product: C#Cc1cc([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)n2ncnc(N)c12
Yield: 28 %

Procedure:
a solution of Compound 16 (2.0 mg, 5.3 μmol in methanol (0.20 mL) was stirred with MP-carbonate (2.9 mmol/g, 18 mg, 53 μmol) for 30 min. The solution was decanted from the resin and concentrated in vacuo, affording rendering Compound 17 (0.45 mg, 28%) as a white solid: ESI-MS m/z 305.2 ([M+H]+); 1H NMR (d6-DMSO) δ 7.92 (s, 1H), 6.97 (s, 1H), 5.35 (s, 1H), 4.91-4.73 (m, 3H), 4.38 (s, 1H), 3.76-3.57 (m, 4H), 0.80 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][O-:4].[Na+].[H-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[C:20]([Br:21])=[C:19](CC)[N:18]=[C:17](S(C)(=O)=O)[N:16]=1)=[O:14])[CH3:11]>C(O)C(F)(F)F>[CH2:10]([O:12][C:13]([C:15]1[C:20]([Br:21])=[CH:19][N:18]=[C:17]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)nc(CC)c1Br
Reactant: [O-]CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Product: CCOC(=O)c1nc(OCC(F)(F)F)ncc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of sodium trifluoroethoxide, prepared from trifluoroethanol (2 ml) and sodium hydride (37 mg, 0.84 mmol) at 0-5° C., was added dropwise a solution of ethyl 5-bromo-2-(methylsulfonyl)pyrimidine-4-carboxylic acid ethyl ester (200 mg, 0.65 mmol; example 126, step 1) dissolved in trifluoroethanol (2 ml) at the same temperature. The ice bath was removed after 15 min and the mixture was stirred at r.t. for 4 h. The reaction mixture was poured into ethyl acetate (20 ml) and extracted with potassium hydrogen sulfate (10%, 10 ml). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (186 mg, 87%).
Reaction SMILES: S(=O)(=O)(O)O.[B-](F)(F)(F)F.[Na+].[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>O>[CH3:13][CH2:14][CH2:15][CH2:16][O:12][C@H:15]([CH2:16][OH:12])[CH2:14][CH3:13]
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCO[C@@H](CC)CO
Temperature: 30 °C
Reaction time: 0.67 h

Procedure:
In the same reaction apparatus as in Example 15, 126 g of 25% fuming sulfuric acid containing 0.9 g of sodium borofluoride was dropped from the dropping funnel into 600 g of tetrahydrofuran at -10° C. with stirring over 40 minutes, after which the resulting mixture was subjected to reaction at -10° C. for one hour. The conversion at the end of this reaction was 39%. Then, the reaction mixture was heated to 30° C. and subjected to reaction at this temperature for 2 hours, after which 10 g of water was added to the mixture to terminate the polymerization. The final conversion was 60%. Then, 530 g of water was added (sulfuric acid concentration was about 20%), and the reaction solution was heated and hydrolyzed in an oil bath at 80° C. while distilling off the unreacted tetrahydrofuran in the same manner as in Example 1, and then 204 g of a 48% by weight sodium hydroxide solution (corresponding to 90% neutralization degree) was added continuously over a period of one hour while the internal temperature was kept at 100° C. to continue the hydrolysis. The recovery of unreacted tetrahydrofuran by distillation was continued during these operations. Then, in the same manner as in Example 1, the reaction mixture was allowed to stand to cause separation of layers, after which the aqueous layer was withdrawn. The PTMG layer was washed at 80° C. for one hour with 350 g of a 20% by weight aqueous sodium sulfate solution. After separating and withdrawing the aqueous layer again, the volatile matters were removed in the same manner as in the foregoing Examples and the residue was filtered through a 10-μ mesh membrane filter to obtain PTMG. The results of the analyses of the thus obtained PTMG were as shown in Table 2.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33].O1CCCC1.O.[Li+].[OH-].Cl>CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33]
Reactant: COC(=O)c1cccc(OCC2=C(c3cccnc3)C[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@@H]1CC(COc2cccc(C(=O)O)c2)=C(c2cccnc2)C[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a solution of Example 9B (18 mg, 0.037 mmol) in mixture of tetrahydrofuran/H2O (0.5 mL/0.25 mL), LiOH (9.4 mg, 0.22 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until the pH=3 and purified by reverse-phase high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (14 mg, 80%). 1H NMR (500 MHz, methanol-d4) δ ppm 8.65-8.76 (m, 2H), 8.25-8.33 (m, 1H), 7.81-7.91 (m, 1H), 7.48-7.65 (m, 3H), 7.30-7.44 (m, 3H), 7.01-7.10 (m, 1H), 4.48-4.59 (m, 2H), 4.00-4.12 (m, 1H), 3.74-3.87 (m, 1H), 2.60-3.02 (m, 4H). MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]#[N:21])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]#[N:21])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: N#C[C@H]1CC[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Agent: [Pd]
Solvent: CO
Product: N#C[C@H]1CC[C@@H](Nc2c(N)cnc3ccsc23)CC1
Reaction time: 4 h

Procedure:
A mixture of cis-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanecarbonitrile (32 mg, 0.10 mmol) and 10% palladium on carbon (4 mg) in methanol (1 mL) was hydrogenated under balloon pressure of H2 at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C14H17N4S (M+H)+: m/z=273.1. Found: 273.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.ClC1N=CC=CN=1>C1COCC1>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Clc1ncccn1
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2 was charged the product from step (iv) above (301.2 g, 250.0 g active, 0.816 mol), tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 252.8 g, 0.680 mol), pTSA.H2O (24.7 g, 0.130 mol) and THF (7600 mL). The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (iv), 22.24% the product of step (vi), 8.98% chloropyrimidine starting material and 64.08% the product of step (v). Further product from step (iv) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (iv), 30.23% the product of step (vi), 4.50% starting chloropyrimidine and 58.61% the product of step (v).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C@H:8]([S:11][S:12][CH3:13])[CH2:9][NH2:10])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:19](=O)([O:31]C1C=CC([N+]([O-])=O)=CC=1)[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[N+:29]=[N-:30])=[CH:24][CH:23]=1.C(N(CC([O-])=O)CC([O-])=O)CN(CC(O)=O)CC(O)=O.[Na+].[Na+]>O.CC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:1][C@@H:2]([CH2:6][CH2:7][C@H:8]([S:11][S:12][CH3:13])[CH2:9][NH:10][C:19]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]=[N+:29]=[N-:30])=[CH:26][CH:27]=1)=[O:31])[C:3]([OH:5])=[O:4]
Reactant: CSS[C@H](CN)CC[C@H](N)C(=O)O
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Cu+2]
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CSS[C@@H](CC[C@H](N)C(=O)O)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Reaction time: 25.75 h
Yield: 16 %

Procedure:
A solution of copper sulfate pentahydrate (100 mg, 0.4 mmol) in water (0.3 mL) was added to a solution of (2S,5S)-2,6-diamino-5-(methyldisulfanyl)hexanoic acid (Compound tk6) (176 mg, 0.785 mol) and sodium bicarbonate (659 mg, 7.85 mmol) in water (1.2 mL) at room temperature, followed by addition of a solution of 4-azidobenzyl (4-nitrophenyl) carbonate synthesized by the method described in the literature (Bioconjugate Chem. 2008, 19, 714) (296 mg, 0.941 mmol) in acetone (2.7 mL). The reaction mixture was stirred at the same temperature for 25.75 hours and then filtered, and the solid on the filter paper was washed with water. The solid collected by filtration was suspended in water (10 mL)-methanol (1 mL), followed by addition of disodium dihydrogen ethylenediaminetetraacetate (350 mg, 0.941 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 7.75 hours and then filtered, and the white solid on the filter paper was purified by reverse-phase silica gel column chromatography (10 mM ammonium acetate aqueous solution/methanol) to afford (2S,5S)-2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)-5-(methyldisulfanyl)hexanoic acid (Lys(5S-SSMe)(Acbz)) (Compound tk7) (50.2 mg, 16%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C.[CH3:21][O:22][N:23]=[C:24]([C:41](=[O:43])[CH3:42])[C:25]([NH:27][CH:28]1[C:39](=[O:40])[N:30]2[CH:31]([C:36]([OH:38])=[O:37])[CH:32](O)[CH2:33][S:34][C@H:29]12)=[O:26].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:21][O:22][N:23]=[C:24]([C:41](=[O:43])[CH3:42])[C:25]([NH:27][CH:28]1[C:39](=[O:40])[N:30]2[C:31]([C:36]([OH:38])=[O:37])=[CH:32][CH2:33][S:34][C@H:29]12)=[O:26]
Reactant: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
Trifluoroaceticanhydride (0.2 ml.) and triethylamine (0.12 ml.) were added to a solution of 7-(2-methoxyimino-3-oxobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 100 mg.) in dry tetrahydrofuran (10 ml.), and allowed to stand at room temperature for 10 minutes. Ethyl acetate (30 ml.) and water (10 ml.) were added to the reaction mixture and adjusted to pH 2 with hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then evaporated in vacuo. The residue was crystallized with diethyl ether to give 7-(2-methoxyimino-3-oxobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 66 mg.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH2:22].N1C=CC=CC=1>O>[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: NC1C2CC3C1C3C2Cl
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1C2CC3C(C2Cl)C31)c1cnc2ccccc2n1
Yield: 37.1 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 5-chlorotricyclo[2.2.1.0(2,6)]hept-3-ylamine (129 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 100 mg (37%) of (167):