Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.N.CC(O)C.C[N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([NH2:39])=[O:32])[CH2:26][CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](C(N)=O)CC1

Procedure:
A mixture trans-4-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (15.0 mg, 0.035 mmol), 2M of NH3 in i-PrOH (0.1 mL, 0.20 mmol), TBTU (22.5 mg, 0.070 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was used for Gilson HPLC purification. The fractions containing the pure product were collected and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.63-1.76 (m, 2H), 1.78-1.90 (m, 2H), 2.08 (t, J=13.4 Hz, 4H), 3.00-3.10 (m, 1H) 6.94 (d, J=5.6 Hz, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 7.20 (t, J=7.3 Hz, 1H), 7.36-7.44 (m, 3H), 7.58 (d, J=8.6 Hz, 2H). MS (ES+): m/z 427.96 (100) [MH+]. HPLC: tR=2.16 min (polar—5 min).
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]([NH:20][CH3:21])[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]O>>[CH:3]1([CH:9]([OH:10])[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH2:11][N:20]([CH3:21])[CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1C=C(c2ccccc2)C(c2ccccc2)O1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Sodium borohydride (10.3 g) is added over approximately 30 minutes at a temperature in the region of 5° C. to a solution of 2,3-diphenyl-5-methylamino-2,5-dihydrofuran (9.7 g) in methanol (90 cc) and distilled water (10 cc). The reaction mixture is then stirred for 18 hours at a temperature in the region of 20° C., and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is triturated with methylene chloride (100 cc); the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica gel (400 g) in a 4 cm diameter column [eluent: methanol/aqueous ammonia (98/2 by volume)]. Elution is first carried out with solvent (400 cc); the corresponding eluate is discarded; elution then continues with solvent (600 cc); the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is recrystallised from a mixture of hexane (70 cc) and isopropanol (10 cc). In this way 1,2-diphenyl-4-methylamino-2-buten-1-ol (Z) (3.8 g) is obtained in the form of white crystals melting at 90° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1>C(O)(=O)C>[C:1]([O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][N:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: BrCc1ccccc1-c1cc(-c2ccccc2)on1
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccccc1-c1cc(-c2ccccc2)on1

Procedure:
A mixture of 12.5 g. potassium acetate (0.128 mole), 20.1 g. (0.064 mole) α-bromo-o-(5-phenyl-3-isoxazolyl)toluene and 200 ml. acetic acid is refluxed for 22 hours. The mixture is cooled and the acetic acid evaporated in vacuo. The residue is distilled on high vacuum and the fraction distilling at 140°-150° C. (0.25 mm) is collected and then crystallized from peteroleum ether containing a small amount of ether to give o-(5-phenyl-3-isoxazolyl)benzyl acetate; m.p. 50° to 62° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:5]([O:13]C)=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1>Br>[Cl:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:4][C:5]2[O:13][C:9](=[O:11])[CH:8]([CH3:12])[C:6]=2[CH:7]=1
Reactant: COc1cc(N2CCOCC2)c(Cl)cc1C(C)C(=O)O
Agent: Br
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Cl)cc21

Procedure:
8.99 g of 2-(5-chloro-2-methoxy-4-morpholinophenyl)-propionic acid (0.03 mole) are boiled in 48% hydrogen bromide solution for 2 hours. The reaction mixture is cooled and concentrated and extracted 3 times with methylene chloride. The organic phases are washed neutral, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. In this manner 5-chloro-3-methyl-6-(morpholin-4-yl)-benzofuran-2(3H)-one having a melting point of 103°-105° is obtained.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH:52]([CH3:96])[CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90]CC)[O:87][CH2:88][CH3:89])=[CH:83][CH:82]=4)[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH:52]([CH3:96])[CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:78])([F:79])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:82]=[CH:83][C:84]([CH2:85][P:86](=[O:90])([OH:93])[O:87][CH2:88][CH3:89])=[CH:94][CH:95]=4)[N:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)cc1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)cc1

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 20B). 1H NMR (CD3OD, 400 MHz): δ=9.20 (br. s., 1H), 8.51 (br. s., 1H), 8.34 (s, 1H), 8.25 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.42 (br. s., 2H), 7.35 (d, J=6.6 Hz, 2H), 4.29 (dd, J=6.6, 13.6 Hz, 1H), 4.15-4.04 (m, 1H), 3.85 (t, J=6.9 Hz, 2H), 3.48 (d, J=5.3 Hz, 2H), 3.05-2.91 (m, 5H), 2.33-2.22 (m, 1H), 1.14 (t, J=6.9 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H). MS (ESI): m/z=649.70 [M+H]+. UPLC: tR=1.13 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:23]([O-])=O)=[C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:23][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][C:12]=1[N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1N
Yield: 93.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(2-t-butyl-4-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.09 g), palladium on carbon (10%, 0.15 g) and methanol (20 ml) and the reaction mixture was purified to give the title compound (0.95 g).
Reaction SMILES: [F-].[K+].C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].Br[CH2:37][C:38]([NH2:40])=[O:39]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:37][C:38]([NH2:40])=[O:39])[CH3:32]
Reactant: NC(=O)CBr
Reactant: CCNCC
Agent: [Pd]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCN(CC)CC(N)=O
Temperature: 105 °C

Procedure:
All coupling reactions were carried out under argon using Schlenk techniques. Toluene was freshly distilled from CaH2 prior to use and tetrahydrofuran (THF) was dried by passage through solvent purification system VAC to provide water content of less than 25 ppm as was determined by coulometric KF titrator Mettler Toledo. All other solvents were used as purchased from commercial sources. 2-Dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (DavePhos), diethylamine, 2-bromoacetamide and tris(dibenzylideneacetone)dipalladium were used as purchased (Sigma-Aldrich, St.-Louis, Mo.). The 2-diethylaminoacetamide was synthesized following in-house developed procedure. All iodo-carboranes were azeotropically dried with benzene to remove any trace of water. Tribasic potassium phosphate was ground to a fine powder and then dried thoroughly by heating under vacuum at 105° C. All solids were stored in an argon-filled glove box. Silica gel was used as purchased (63-200 μm, Sorbent Technologies, Inc.). Analytical thin-layer chromatography (TLC) for carborane identification was performed by using pre-coated silica-gel XHL plates (Sorbent Technologies, Inc.) and visualized by dipping into an acidified (hydrochloric acid) solution of PdCl2 followed by heating. 11B NMR spectra were obtained using BrukerAvance 400 and Avance 500 spectrometers and externally referenced to BF3 Et2O and the peaks upfield of the reference were designated as negative. 1H NMR and 13C NMR spectra were acquired on BrukerAvance 400 and Avance 500 spectrometers. Chemical shifts are given in ppm relative to residual solvent signals (CDCl3, δ=7.24 ppm for 1H NMR and 77.0 ppm for 13C NMR). 19F NMR spectra were acquired on BrukerAvance 400 and chemical shifts are given relative to the external BF3-Et2O reference (δ=−153.0 ppm). Mass spectra were obtained on an ABI QSTAR and Mariner Biospectrometry Workstation by PerSeptive Biosystems. Melting points were obtained using automated melting point system OptiMelt (Stanford research system). Measurements were conducted in open-end Kimble Chase capillary tubes from borosilicate glass (L=90 mm). The melting point range is defined as the interval between the onset and clear points using 0.5° C./min ramp rate.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:5]=1[C:19]([NH2:21])=[O:20].[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:12]([C:7]1[N:8]([CH2:9][CH2:10][CH3:11])[C:4]([NH:3][C:26](=[O:22])[C:25]2[CH:11]=[CH:10][CH:9]=[CH:23][C:24]=2[O:20][CH2:19][CH3:5])=[C:5]([C:19]([NH2:21])=[O:20])[N:6]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCn1c(Cc2ccccc2)nc(C(N)=O)c1N
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(Cc2ccccc2)nc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) was added to a solution of 5-amino-2-benzyl-1-n-propylimidazole-4-carboxamide (Preparation 2; 200 mg, 0.77 mmol) in tetrahydrofuran (5 mL), and the mixture stirred for 3 hours at room temperature. The prepared solution of acid chloride (from (i) above) was then added and the reaction stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, the residue partitioned between dichloromethane and water, and the layers separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel twice, using an elution gradient of dichloromethane: methanol (100:0 to 95:5) to afford the title compound (114 mg, 36%).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([N:8]2[C:7]3[C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2ccccc2)c2c(c1)ncn2-c1ccccc1
Yield: 47.3 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1 mmol), benzeneboronic acid (180 mg, 1.5 mmol), potassium carbonate (700 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) was stirred at reflux overnight. The cooled mixture was partitioned between water and ethyl acetate. The organic phase was collected, washed with brine, dried and concentrated under reduced pressure. Recrystallisation from methanol afforded the product as an off-white solid (160 mg, 47%), m/z, 339.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]C(=O)[O-])=[CH:25][CH:24]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)[O-])=[CH:13][CH:12]=2)[O:5][C:6](=[O:8])[CH:7]=1.[C:33]([C:37]1[CH:42]=[C:41]([CH2:43][OH:44])[C:40]([CH3:45])=[CH:39][C:38]=1[S:46]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.C(O)(=O)C>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C:4]2([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[O:5][C:6](=[O:8])[C:7]([S:46][C:38]3[CH:39]=[C:40]([CH3:45])[C:41]([CH2:43][OH:44])=[CH:42][C:37]=3[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:2]([OH:1])[CH2:3]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C([O-])Nc1ccc(CCC2(CCc3ccc(NC(=O)[O-])cc3)CC(O)=CC(=O)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(N)cc3)(CCc3ccc(N)cc3)OC2=O)c(C(C)(C)C)cc1CO
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.38 g (0.69 mmol) of (1,1-dimethylethyl)[(3,6-dihydro-4-hydroxy-6-oxo-2H-pyran-2,2-diyl)bis[2, 1-ethanediyl-(4,1-phenylene)]biscarbamate prepared in Example OO, 0.35 g (0.96 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.58 g (4.2 mmol) of K2CO3, and 5 mL of DMF. The reaction mixture was stirred overnight, and then poured into glacial acetic acid (5 mL) and EtOAc (20 mL). After standard workup, the residue was chromatographed on silica gel, eluting with 1:1 hexane:EtOAc, to give the BOC-protected intermediate. This material was dissolved in CH2Cl2, cooled in an ice bath, and treated with a steady stream of gaseous HCl for 10 minutes. The solvent was evaporated. The residue was suspended in H2O which was then made basic to pH 11.5 with 10% NaOH and stirred for 20 minutes. The solution was made basic to pH 6.5 with HOAc and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound, m.p. 144-146° C. 1H NMR (DMSO-d6) δ 1.43 (s, 9 H), 1.81 (s, 3 H), 1.95 (m, 4 H), 2.42 (m, partially obscured by DMSO, 4 H), 2.87 (br s, 2 H), 4.30 (s, 2 H), 4.90 (br s, 1 H), 6.45 (d, 4 H), 6.65 (s, 1 H), 6.80 (d, 4 H), 7.20 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]O)[CH:18]=1.P(Cl)(Cl)([Cl:27])=O.O.CO>CN(C)C=O>[Cl:27][CH2:23][C:19]1[CH:18]=[C:17]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=2[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To {2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (30.0 g) was added N,N-dimethylformamide (90 mL), and the mixture was stirred for 20 min. To the mixture was added dropwise at 25° C. a separately prepared solution of phosphorus oxychloride (17.2 g) in N,N-dimethylformamide (54.0 mL), and the mixture was stirred at 25° C. for 4 hr. Water (30 mL) and then methanol (30 mL) were added dropwise. Seed crystal was added, and the mixture was stirred for 1 hr. Methanol (120 mL) was added, and the mixture was stirred for 1 hr. Then, water (120 mL) was added dropwise, and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, and washed with water (300 mL). The obtained crystals were suspended in water (300 mL), and the mixture was stirred. The crystals were collected by filtration, washed with water (300 mL), and dried at 60° C. to give 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (28.8 g).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:48]2[C@H:49]([CH3:72])[C@H:50]3[C@@H:67]([C@H:68]([OH:70])[CH3:69])[C:66](=[O:71])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:48]4[C@H:49]([CH3:72])[C@@H:50]5[C@@H:67]([C@H:68]([OH:70])[CH3:69])[C:66](=[O:71])[N:51]5[C:52]=4[C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=4)=[O:54])[CH2:6]3)[S:10][CH:11]=2)=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-acetylthio-1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidine (380 mg, 1.0 mmol) (obtained as described in Reference Example 2) in dimethylformamide (15 ml) was added hydrazine acetate (115 mg, 1.25 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 3 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (695 mg, 1.17 mmol) in acetonitrile (30 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.84 ml, 4.82 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate) to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a brown foaming solid (336 mg, yield 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14](=[O:15])[NH:13][C:12]2[N:11]=[CH:10][C:9](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:8][C:7]=2[CH2:6]1)=[O:4].Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:18](=[O:20])/[CH:17]=[CH:16]/[C:9]3[CH:8]=[C:7]4[C:12](=[N:11][CH:10]=3)[NH:13][C:14](=[O:15])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)[CH2:33][CH2:34]2)=[CH:35][CH:36]=1
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: Fc1ccc(OCC2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To a solution of (2E)-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylic acid (96 mg, 0.35 mmol; which may be prepared as described in Step 4) in DMF (8 mL) were added 4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (102 mg, 0.42 mmol; which may be prepared as described in Step 2), DIPEA (144 μL, 0.83 mmol), 4-DMAP (17 mg, 0.14 mmol) and EDAC (80 mg, 0.42 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane/MeOH from 100/0 to 80/20) to give a first solid which is purified again on preparative TLC (eluent: dichloromethane/MeOH 95/5) to give the title compound (15 mg, 8%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[I-].[NH2:4][C:5]1[C:6]([C:27]2[CH:32]=[CH:31][N+:30]([CH3:33])=[CH:29][CH:28]=2)=[N:7][C:8]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH:24]([CH3:26])[CH3:25])[N:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.Cl>CO.C(Cl)(Cl)Cl.CC(C)=O>[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH:24]([CH3:26])[CH3:25])[N:18]=2)=[N:7][C:6]=1[C:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]=1
Reactant: CC(C)n1nc(-c2nc(-c3cc[n+](C)cc3)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)n1nc(-c2nc(C3=CCN(C)CC3)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Under ice-cooling, sodium borohydride (30.7 mg) was added to a solution of 4-[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]-1-methylpyridinium iodide (142 mg) in MeOH (4.26 ml) and the mixture was stirred at the same temperature for 30 minutes. After addition of 1N HCl (0.6 ml), MeOH was evaporated under reduced pressure to give a residue. The residue was dissolved in CHCl3, dried over MgSO4 and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (5:95 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-6-(1-methyl-1,2,3,6-tetrahydro-4-pyridyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (15 mg).