Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH:7][C@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])=[O:6])([CH3:4])[CH3:3]>CC(O)C>[CH3:4][C:2]([S@:5]([NH:7][C@:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[F:25])([CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:14])[F:16])[CH2:9][F:10])=[O:6])([CH3:1])[CH3:3]
Reactant: Cc1cccc([C@](CF)(CC(=O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Solvent: CC(C)O
Product: Cc1cccc([C@](CF)(C[C@H](O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Ru[p-cymeme](1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (2.365 g, 3.94 mmol) was added in one portion to a solution of (R)-2-methyl-N-((S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-oxopentan-2-yl)propane-2-sulfinamide (3.80 g, 9.86 mmol) in IPA (100 ml) (which had been degassed by bubbling nitrogen through the solution for 30 minutes prior to use) under N2 atmosphere. The reaction was stirred at rt for 2 h. The reaction went to completion. The reaction was quenched with saturated NaHCO3, extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-40% EtOAc/hexanes to afford a light brown solid as (R)-2-methyl-N-((2S,4S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (2.0 g, 5.16 mmol, 52.4% yield). MS m/z=387.9 [M+H]+. Calculated for C16H22F5NO2S: 387.13.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:58])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[N:45]=[C:46]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[O:47][C:48]=3[CH3:49])=[C:38]([O:56][CH3:57])[CH:37]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:57][O:56][C:38]1[CH:37]=[C:36]([CH2:35][C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=2)=[O:58])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:47][C:48]=1[CH3:49]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(CC(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (357 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 54 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-2-{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetamide (590 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-{3-[({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (159 mg, yield 21%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:52])([F:51])[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>ClCCl>[CH2:18]([O:17][N:11]1[C@@H:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C@@H:9]([NH:8][S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:51])[F:52])=[CH:36][CH:37]=3)=[CH:46][CH:45]=2)(=[O:49])=[O:48])[C:10]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)[C@H]1C[C@@H](N)C(=O)N1OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of (3R,5R)-3-amino-1-(Benzyloxy)-5-isopropyl-2-pyrrolidinone trifluoroacetate (0.036 g, 0.10 mmoles), triethylamine (0.070 mL, 0.50 mmoles) and dry dichloromethane (0.70 mL) was added in small portions 4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonyl chloride (0.034 g, 0.11 mmoles) during two minutes. The mixture was stirred under dry nitrogen at 22° C. for 60 minutes, concentrated by rotary evaporation, re-dissolved in dichloromethane (2 mL), mixed with a silica (1 g), concentrated again and then applied on a silica column. Elution with ethyl acetate/n-heptane (1:4 through 1:3) and concentration of pure fractions gave 0.030 g (57% yield) of the title compound as a white solid. LC-MS (APCI) m/z 533 (M+1). 1H NMR (CDCl3) δ 8.02 (d, J=8 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 7.72 (d, J=8 Hz, 2H) 7.70 (d, J=8 Hz, 2H), 7.40–7.30 (m, 5H), 5.43 (d, J=3 Hz, 1H), 4.99 (d, J=10 Hz, 1H), 4.88 (d, J=10 Hz, 1H), 3.76 (dt, J1=3 Hz, J2=9 Hz, 1H), 3.31 (ddd, J1=4 Hz, J2=6 Hz, J3=9 Hz, 1H), 2.40 (ddd, J1=7 Hz, J2=9 Hz, J3=13 Hz, 1H), 2.20–2.08 (m, 1H), 1.76 (dt, J1=9 Hz, J2=13 Hz, 1H), 0.85 (d, J=7 Hz, 3H) and 0.83 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:31]([CH3:42])[CH:30]=2)[C:25]([Cl:43])=[CH:24][N:23]=1>>[Cl:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[C:31]([CH3:42])[CH:30]=2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1N1CCN(C)CC1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)c(C)c3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.020 g, 24%). MP: 172-178° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.04-8.01 (m, 2H), 7.54-7.49 (m, 1H), 7.47 (s, 1H), 7.24-7.21 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 3.84 (s, 3H), 3.26 (s, 2H), 3.14 (s, 3H), 3.01-2.92 (m, 8H), 2.88-2.83 (m, 2H), 2.75-2.59 (m, 9H), 2.44-2.36 (m, 3H), 2.30 (s, 3H). MS: 593.29 (MH)+.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH:63]([CH3:66])[CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1>>[OH:65][CH2:64][CH:63]([CH3:66])[CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:46][CH:47]=4)[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CC(C)CO)c2)ccc1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)cc1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 18C) and Compound 1E with Compound 2C. 1H NMR (CD3OD, 400 MHz): δ=9.20 (br. s., 1H) 8.45 (s, 1H) 8.36 (s, 1H) 8.25 (s, 1H) 7.75 (d, J=8.8 Hz, 1H) 7.54 (d, J=7.3 Hz, 2H) 7.32 (d, J=7.6 Hz, 2H) 4.29 (dd, J=13.6, 6.32 Hz, 1H) 4.06 (quin, J=7.1 Hz, 5H) 3.47 (d, J=5.3 Hz, 2H) 3.30 (d, J=21.0 Hz, 2H, obscured) 3.00 (s, 3H) 2.21-2.32 (m, 1H) 1.25 (t, J=7.1 Hz, 6H) 0.95 (d, J=6.8 Hz, 3H). MS (ESI): m/z=677.80 [M+H]+. UPLC: tR=1.26 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]([C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[N+:21]([O-])=O)=[C:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.B#[Ni]>[C:2]1([C:8]2[C:12]([C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[NH2:21])=[C:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[NH:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: B#[Ni]
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Temperature: 60 °C
Yield: 62.5 %

Procedure:
A suspension of nickel boride (3.56 g) and 1N HCl (16 mL) in methanol (65 mL) was added to ethyl 3-phenyl-4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-5-carboxylate (1.5 g, 3.7 mmol) and the mixture heated to 60° C. for 18 hours. The reaction mixture was filtered and the filtrate concentrated via rotovap to a green solid (2.38 g). The solid was dissolved in ethyl acetate (100 mL) and extracted with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate and concentrated to a dark green oil (1.5 g) which was washed with a small amount of hexanes to yield the title compound as a yellow solid (0.855 g, 62%).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH:13](/B(O)O)=[CH:14]\[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.CCOC(C)=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2](/[CH:13]=[CH:14]/[CH3:15])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(I)cccc1[N+](=O)[O-]
Reactant: C/C=C/B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: C/C=C/c1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A suspension of 2-iodo-6-nitrobenzonitrile (Example 130d) (1.52 g, 5.53 mmol), tetrakis(tiphenylphosphine)palladium(0) (0.64 g, 0.55 mmol), trans-1-propen-1-ylboronic acid (0.95 g, 11.06 mmol), sodium carbonate (0.65 g, 6.08 mmol) and water (10.0 mL) in dimethoxyethane (DME) (40.0 mL) was heated at reflux for 15 h, under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and EtOAc (100 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined extract was washed with brine and dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (7:3), to give 0.98 g (94%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.16-8.24 (m, 2H), 7.83-7.89 (m, 1H), 6.71-6.84 (m, 2H), 1.90-2.02 (m, 3H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:28][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1)=[O:4])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a solution of compound 1 (1 equivalent) in DMF, at ambient temperature, was added benzylamine (1.2 equivalents). After 24 hours, the solvent was evaporated and the crude product 2 was utilized without purification. HPLC using method B (as described below for Example 5) provided a retention time of 3.8 minutes. FIA/MS (M+1) 319.3, (M−1) 317.2.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CCCCC>[F:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]=[C:13]2[CH2:14][CH2:15][N:10]([C@H:7]3[CH2:8][CH2:9][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)[CH2:11][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC(=O)CC2)CC1
Reactant: Nc1ccc(F)cc1
Solvent: CCCCC
Product: CC(C)[C@H]1CC[C@@H](N2CCC(=Nc3ccc(F)cc3)CC2)CC1

Procedure:
cis-1-(4-Isopropyl-cyclohexyl)-piperidine-4-on (5.0 g, 23.4 mmol), 4-fluoro aniline (3.3 g, 35.3 mmol) and molecular sieves (20 g, 4A) were stirred in 100 ml pentane at room temperature for 6 days. The molecular sieves was filtered off and the solvent was evaporated. The crude product was used without any further purification for the following step.
Reaction SMILES: [NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@:5]([Si](C(C)(C)C)(C)C)([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1>C1COCC1>[NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1
Reactant: Cc1cn([C@@]2([Si](C)(C)C(C)(C)C)C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 72 %

Procedure:
3'-O-Amino-(t-butyldimethylsilyl)thymidine was deblocked with (Bu)4 NF/THF in standard way to furnish compound 4 (72%). Crystallized from ether/hexanes/ethanol as fine needles, mp 81° C. 1H NMR (Me2SO-d6) δ 1.78 (s, 3, CH3), 2.17 and 2.45 (2m, 2, 2'CH2), 3.70 (m, 2, 5'CH2), 3.88 (m, 1, 4'H), 4.16 (m, 1, 3'H), 4.8 (br s, 1, 5'OH), 6.05 (dd, 1, 1'H), 6.2 (br s, 2 NH2), 7.48 (s, 1, C6H), and 11.24 (br s, 1NH). Anal. Calcd. for C10H15 N3O5 : C, 46.69; H, 5.87; N, 16.33; found: C, 46.55; H, 5.91; N, 16.21.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]2)=[N:11][CH:12]=1
Reactant: OCCc1cn[nH]c1
Reactant: Fc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: OCCc1cnn(-c2ccc(F)cn2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 2-(1H-pyrazol-4-yl)ethanol (1.0 g, 8.9 mmol) and 2,5-difluoropyridine (0.89 mL, 9.8 mmol) in acetonitrile (45 mL), Cs2CO3 (9.7 g, 17.8 mmol) was added, and the resulting mixture was stirred for 3 hours at 80° C. The reaction mixture was allowed to cool, then water was added thereto, followed by extraction with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=90/10 to 30/70) to obtain the title compound (0.63 g) (colorless solid).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:17](=[O:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCC#CCO
Solvent: c1ccncc1
Product: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27 (4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride (3.0 mL, 31.8 mmol). After 18 h, the solvent was evaporated and the residue co-evaporated with toluene. The residue was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH3:28])([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 50 °C
Yield: 57.7 %

Procedure:
To 4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 1.82 mmol) in DMF (14 mL) was added to NaH (60% in mineral oil, 153 mg, 6.37 mmol) and the mixture was heated at 50° C. for 30 minutes. MeI (0.47 mL, 7.64 mmol) was added and the mixture was heated at 50° C. for an additional 3 hours to afford 4-methyl-4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (390 mg, 58%) following work-up and purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[N+:21]([O-])=O)[O:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[NH2:21])[O:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[3-(3,4-Dinitro-phenoxy)-phenyl]-acetamide (Step A, 0.4 g, 1.3 mmol, 1.0 eq.) was dissolved in MeOH (10 mL) and the atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at RT at balloon pressure. The Pd/C was filtered and the obtained N-[3-(3,4-diamino-phenoxy)-phenyl]-acetamide was used crude in the next step. MS m/z=259.1 (M+H)+Calc'd for C14H15N3O2: 257.29.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH2:34])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[C:35](=O)([O-:37])[OH:36].[Na+:39].C(=O)=O>CC(C)=O>[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][C:35]([O-:37])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[Na+:39]
Reactant: O=C([O-])O
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(N)n1
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NC(=O)[O-])n1
Reaction time: 5 h
Yield: 38.4 %

Procedure:
To a solution of 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.15 g) in 50% aqueous acetone (9.2 ml) was added sodium hydrogencarbonate (193 mg) and dry ice (4.4 g) at room temperature. The mixture was stirred in a sealed tube for 5 hours. Acetone was removed under reduced pressure. The residual solution was chromatographed on non-ionic adsorption resin "Diaion HP-20" (Trademark, maker: Mitsubishi Chemical Industries) eluting with water. The desired fractions were collected and lyophilized to give sodium 7-[2-allyloxyimino-2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (500 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=2)[C:17]2[CH:46]=[C:47]([CH3:54])[C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:16]1=2)=O)(C)(C)C>C(Cl)Cl>[F:44][C:42]([F:43])([F:45])[C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=1)[CH2:31][N:22]([C@H:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:49]=[C:48]([C:50]([F:51])([F:52])[F:53])[C:47]([CH3:54])=[CH:46][C:17]1=2)[C:23]1[N:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[N:27]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO)n1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Add trifluoroacetic acid (2 mL) to a solution of (S)-5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl]-amino}-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.0650 g, 0.0952 mmol) in methylene chloride (2 mL) at room temperature, stir for 1 h. Evaporate solvents and partition the residue between saturated aqueous sodium bicarbonate solution (10 mL). Extract the mixture with methylene chloride (10 mL). Separate two layers and dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as a colorless oil (0.0340 g, 62%). MS (ES+): 583 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[C:17]([C:21]1[O:25][N:24]=[C:23]([OH:26])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+].CS(C)=O>O>[C:17]([C:21]1[O:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[C:23](=[O:26])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])o1

Procedure:
30 g of 2-(4-chloro-3-nitrobenzenesulfonyl)ethanol, 19.1 g ot 5-t-butyl-3-hydroxyiso-oxazole, 28 g of sodium bicarbonate and 200 ml of dimethylsulfoxide were mixed together and reacted at 80° C. for a period of 8 hours. After cooling, the reaction mixture was poured into of water and the mixture was extracted with ethyl acetate. The organic layer was recovered and, after removing the solvent by distillation under reduced pressure, the main product was isolated using silica gel column chromatography as an oily product.