Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14](Cl)=[O:15].[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O.CN1CCCC1=O.O>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:14]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[C:20]4[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=4)[CH:6]=3)[CH:1]=2)=[O:15])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C(=O)c2ccc3cc(C(=O)c4ccc(OC)cc4)ccc3c2)cc1
Temperature: 25 °C

Procedure:
A stirred reactor comprising a 750 ml sulfonation flask, thermometer, condenser and nitrogen inlet is charged with 25.3 g (0.1 mol) of naphthalene-2,6-dicarbonyl dichloride and 32.4 g (0.2 mol) of anisole in 200 ml of nitrobenzene and, with stirring, 26.6 g (0.2 mol) of aluminium chloride are added over 15 minutes at 12°-18° C. The reaction mixture is thereafter allowed to react for 90 minutes at 40° C., then cooled to room temperature and thoroughly mixed with 1.5 liters of water containing HCl. The resultant suspension is diluted with 1.2 liters of N-methylpyrrolidone, and the mixture is heated to 130° C. The clear solution so obtained is cooled and the crystallised product is isolated by filtration. The filter residue is vacuum dried at 130° C., giving 25.9 g (65.4% of theory) of the desired product, which melts at 251° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[CH2:19]([NH:21][C:22](=S)[NH:23][NH2:24])[CH3:20]>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:22]([NH:21][CH2:19][CH3:20])=[N:23][N:24]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: CCNC(=S)NN
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCO
Product: CCNc1nnc2ccc(-c3cccc(N(C)C(C)=O)c3)nn12
Yield: 16.9 %

Procedure:
A solution of 6.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 5.5 g 4-ethyl-3-thiosemicarbazide in 200 ml ethanol was refluxed for 18 hours and treated in similar fashion to Example 67. Chromatography on silica gel and recrystalization from dichloromethane-hexane afforded 1.2 g yellow crystals, mp 225°-227° C.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33](B(O)O)[CH:32]=1>>[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:32]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cnc2ccccc2c1
Yield: 24 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and quinolin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (24% yield); 1H-NMR (d6-DMSO) 0.97 (9H, s), 3.78 (2H, t), 4.18 (3H, t), 6.69 (1H, s), 7.55-7.59 (1H, m), 7.66-7.70 (1H, m), 7.92-8.00 (2H, m), 8.08 (1H, d), 8.77 (1H, d); 13C-NMR (CDCl3) 27.7, 41.7, 66.9, 126.8, 127.4, 128.7, 129.2, 133.6, 148.8; MS ES(+) 313.0 (M++1); HRMS m/z calcd for C18H20N2O3+H+ 313.1552 [M+H+]. Found 313.1556. IR λmax=1697, 1636 cm−1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:34])([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][CH2:57][NH:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][N+:60]=1[O-:65]>C1COCC1>[CH3:34][C:21]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:55][CH2:56][CH2:57][NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][N+:60]=2[O-:65])=[CH:19][CH:18]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CC(C)(Cc1ccc(O)cc1)c1cccnc1
Reactant: [O-][n+]1ccccc1NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(Cc1ccc(OCCCNc2cccc[n+]2[O-])cc1)c1cccnc1
Reaction time: 0.25 h

Procedure:
A solution of diethyl azodicarboxylate (157 mg, 0.9 mmol) in 2 ml THF was added to a solution of the product of STEP 7 (197 mg, 0.66 mmol) and triphenylphosphine (236 mg, 0.9 mmol) in 5 ml THF at room temperature and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (168 mg, 0.9 mmol) was added. The reaction was stirred at room temperature for 18 h. THF was evaporated and the residue was purified by chromatography (on silica gel, CH2Cl2/CH3OH/NH4OH-98.5/1/0.5) to afford a clean product in 154 mg. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:14]C(=O)C)([CH3:13])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH2:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)NC(C)(C)Cc1ccc(C(C)C)cc1
Agent: Cl
Product: CC(C)c1ccc(CC(C)(C)N)cc1

Procedure:
Reaction of 9.80 g (42 mmol) of N-[2-(4-isopropylphenyl)-1,1-dimethylethyl]acetamide analogously to the method for Example 9(c). Yield: 7.00 g (71%, hydrochloride); melting point 202° C.-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH:37](OCC)(OCC)OCC>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([C:21]4[O:22][CH:37]=[N:24][N:23]=4)[CH:25]=[C:26]([F:28])[CH:27]=3)[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)[C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[C:35]#[N:36])=[CH:6][CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1C
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2nnco2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A solution of 41 mg (0.081 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide and 1.5 mL triethyl orthoformate in 2 mL of xylene was stirred for 3.5 at 125° C., followed by concentration to remove solvents. The residue was purified by silica gel chromatography with hexane/ethyl acetate/ammonia in MeOH to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.23(d, 3H, J=22 Hz), 1.29(d, 3H, J=22 Hz), 2.34 (t, 1H, J=8 Hz), 2.89 (t, 1H, J=8 Hz), 2.98 (m, 1H), 3.02 (t, 1H, J=11 Hz), 3.25 (m, 1H), 3.63 (t, 1H, J =6 Hz), 4.23 (s, 1H), 7.11-7.73 (m, 11H), 8.51(s, 1H); Mass Spectrum: m/e=519 (M+1, 35Cl), 521 (M+1, 37Cl).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[C:67]([Cl:68])=[CH:66][CH:65]=[CH:64][C:63]=3[Cl:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:68][C:67]1[CH:66]=[CH:65][CH:64]=[C:63]([Cl:69])[C:62]=1[N:59]1[C:55]2[N:56]=[CH:57][N:58]=[C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][N:46]=3)=[O:43])[C:54]=2[CH:61]=[N:60]1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl)C(=O)Nc1ccc(F)cn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cn1)[C@H](COCCO)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.838 mL, 0.84 mmol) was added dropwise to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-fluoropyridin-2-yl)propanamide (Intermediate BA1) (0.625 g, 0.84 mmol) in THF (10.34 mL) at ambient temperature under nitrogen. The resulting solution was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (70 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (70 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 25 to 100% EtOAc in isohexane to afford the product (0.307 g, 72.1%). 1H NMR (400 MHz, CDCl3) δ 2.60 (1H, t), 3.71-3.81 (4H, m), 4.16-4.25 (2H, m), 6.10 (1H, t), 7.43-7.49 (2H, m), 7.53-7.55 (2H, m), 8.14 (1H, d), 8.22-8.25 (1H, m), 8.48 (1H, s), 8.60 (1H, s), 9.00 (1H, s); m/z (ES−) (M+H)+=507.31; HPLC tR=2.67 min.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[N:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=1.14 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]1[CH2:11][S:8](=[O:10])(=[O:9])[O:7][CH2:6]1>O.CC(C)=O>[N:1]([CH2:6][CH2:5][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S1(=O)CCCO1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a stirred solution of sodium azide (3.5 g, 50 mmol) in water (25 mL) was added a solution of 1,3-propane sultone (6.1 g, 50 mmol) in acetone (25 mL). The reaction mixture was stirred at room temperature for 24 h then concentrated to dryness. The resulting solid was suspended in diethyl ether (100 mL) and stirred at reflux for 1 h. The suspension was cooled to room temperature and the solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum, affording of 3-azido-1-propanesulfonic acid (7.6 g, 80%).
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:48][C:49]1[C:54]([CH:55]=O)=[C:53]([Cl:57])[N:52]=[CH:51][N:50]=1>C1COCC1>[Cl:48][C:49]1[C:54](/[CH:55]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[C:53]([Cl:57])[N:52]=[CH:51][N:50]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1c(Cl)ncnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1c(Cl)ncnc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 125 %

Procedure:
To a solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (2.460 mL, 11.63 mmol) in 70 mL of THF at −78° C. was added 18-CROWN-6 (9.14 g, 34.6 mmol). Added KHMDS (23.05 mL, 11.53 mmol) dropwise over 15 min and allowed the resulting mixture to stir at −78° C. for 30 min. Then 4,6-dichloropyrimidine-5-carbaldehyde (1.7 g, 9.61 mmol) was added in 20 mL of THF and the resulting mixture was allowed to stir at −78° C. for 1.5 h. The reaction was quenched with about 25 mL sat'd NH4Cl, allowed to warm to RT and then most of the THF was removed by rotary evaporator. The resulting mixture was diluted with 1:1 hexane/ethyl acetate, washed with 1N HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford an oil (2.8 g). The residue was purified by silica gel chromatography (80 g ISCO cartridge, 0-80% ethyl acetate/hexane) to afford Example 116A (1.55 g, 69%) as an oil, which was contaminated with ˜10% of the (E)-olefin isomer. The material was used without further purification. LRMS (ESI): 233.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([C:12]#[N:13])=[C:7](OCC)[N:6]=1)=[O:4].[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C([O-])([O-])=O.[Na+].[Na+].Cl>COC.O.C(O)C>[NH2:11][C:9]1[C:8]([C:12]#[N:13])=[C:7]([C:19]2[CH:20]=[CH:21][S:17][CH:18]=2)[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=1
Reactant: OB(O)c1ccsc1
Reactant: CCOc1nc(C(=O)OC)cc(N)c1C#N
Agent: COC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: N#Cc1c(N)cc(C(=O)O)nc1-c1ccsc1
Yield: 20.8 %

Procedure:
A suspension of Example 181D (212 mg, 1.0 mmol), 3-thiopheneboronic acid (134 mg, 1.05 mmol), dichlorobis(triphenylphosphine)-palladium(II) (Ph3P)2PdCl2 (7 mg, 0.01 mmol), and Na2CO3 (212 mg, 2.0 mmol) in dimethyl ether: water: ethanol (7:3:2, 4 mL) was heated at 150° C. for 10 minutes in a microwave reactor. The crude mixture was acidified with 2N HCl (2 mL) and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. It was triturated with acetonitrile to provide the titled compound (51 mg, 21% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:28][C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:60](=[O:62])[CH3:61])(=O)C>N1C=CC=CC=1>[C:1]([O:51][C@@H:23]([C@H:22]([O:52][C:60](=[O:62])[CH3:61])[C@H:21]([O:53][C:24](=[O:25])[CH3:23])[C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:54][O:55][C:17](=[O:18])[CH3:12])[C:24]([NH:26][C@H:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:28][C:29]([O:31][CH:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:30])=[O:25])(=[O:8])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (200 mg) in pyridine (5 ml) was added acetic anhydride (3 ml) and the mixture was stirred at room temperature for 4 days. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-hexane (1:1). The effective fractions were combined and concentrated under reduced pressure to afford the title compound (85 mg).
Reaction SMILES: [CH2:1]([O:11][C:12](=[O:28])[CH:13]=[C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[OH:27])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C(OC(=O)C=C(C1C=CC(N(CC)CC)=CC=1O)C)C.C(O)CCCCCCCC=C>>[CH2:1]([O:11][C:12](=[O:28])/[CH:13]=[C:14](/[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:18][C:17]=1[OH:27])\[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCOC(=O)C=C(C)c1ccc(N(CC)CC)cc1O
Agent: C=CCCCCCCCCO
Agent: CCOC(=O)C=C(C)c1ccc(N(CC)CC)cc1O
Product: C=CCCCCCCCCOC(=O)/C=C(\C)c1ccc(N(CC)CC)cc1O

Procedure:
According to the same procedure, 3-(4-diethylamino-2-hydroxy-phenyl)-but-2-enoic acid dec-9-enyl ester was prepared from 3-(4-diethylamino-2-hydroxy-phenyl)-but-2-enoic acid ethyl ester, dec-9-en-1-ol and tetraisopropyl-o-titanate.
Reaction SMILES: [I-:1].[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:64][O:65][CH:66]([F:68])[F:67])[C:28]([NH:30][CH:31]2[C:62](=[O:63])[N:33]3[C:34]([C:46]([O:48][CH:49]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:47])=[C:35]([CH:39]([CH3:45])[NH+:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:36][S:37](=O)[C@H:32]23)=[O:29])[N:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)Cl.C(OC(C)C)(C)C>C(#N)C>[I-:1].[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:64][O:65][CH:66]([F:67])[F:68])[C:28]([NH:30][CH:31]2[C:62](=[O:63])[N:33]3[C:34]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:47])=[C:35]([CH:39]([CH3:45])[NH+:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2S(=O)C1)[NH+]1CCCC1
Agent: [I-]
Solvent: CN(C)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClP(Cl)Cl
Product: CC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1)[NH+]1CCCC1

Procedure:
A mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate-1-oxide iodide (syn isomer) (1.45 g) and acetonitrile (14 ml) was stirred under cooling in an ice-bath, and N,N-dimethylaniline (490 mg) and phosphorus trichloride (555 mg) were added thereto. The mixture was stirred for one hour under cooling in an ice-bath, and then diisopropyl ether was added to the reaction mixture. The separated oil was triturated with diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate iodide. This compound was dissolved in a solution of tetrahydrofuran (54 ml) and water (3.6 ml). The solution was subjected to column chromatography on Amberlite IRA-400 (CF3COO⃝ form) and the elution was carried out with a solution of water and tetrahydrofuran (1:15). The fractions containing the object compound were collected and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7-[ 2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (1.30 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[N+:33]([O-])=O)[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C.[Pt]>[NH2:33][C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[NH:22][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reaction time: 4 h
Yield: 86.7 %

Procedure:
tert-Butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[(3-nitroquinolin-4-yl)amino]pentylcarbamate (5.65 g, 11.2 mmol) was dissolved in 100 mL of acetonitrile and the solution was placed in a pressure bottle. Platinum on carbon (5%, 1.2 g) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 4 hours, an additional 500 mg of platinum on carbon was added and shaking was continued for 3 hours. The reaction mixture was then filtered through a pad of CELITE filter agent. The pad was rinsed with acetonitrile and the combined filtrates were concentrated under reduced pressure to give tert-butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (4.61 g) as an orange foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[N:12][N:11]3[C:31]=2I)=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[N:12][N:11]3[C:31]=2[C:47]2[CH:48]=[CH:49][N:44]=[CH:45][CH:46]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nn2c(I)c(-c3ccc(F)cc3)nc2c1C
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nn2c(-c3ccncc3)c(-c3ccc(F)cc3)nc2c1C
Yield: 73 %

Procedure:
To a mixture of 0.66 g (1.2 mmol) of tert-butyl 4-[2-(4-fluorophenyl)-3-iodo-7,8-dimethylimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in 15 mL of a mixture of tetrahydrofuran and water (9:1), are added 1.17 g (3.6 mmol) of cesium carbonate and 0.31 g (1.4 mmol) of (pyrid-4-yl)boronic acid. After sparging with a stream of argon for a few moments, 88 mg (0.11 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) are added and the reaction mixture is refluxed under argon for 18 hours. The mixture is then poured into water and the product is extracted with dichloromethane, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give a brown solid. The product is purified by chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3/7) to give 0.44 g of a white powder.