Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9](I)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Li+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[Cl:1][C:2]1[C:9]([CH2:14][CH:13]=[CH2:12])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1c(F)ccc(I)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(F)c(C#N)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-fluoro-3-iodobenzonitrile (800 mg, 2.85 mmol), allyltributylstannane (1.245 mg, 3.761 mmol), LiCl (431 mg, 10.3 mmol) and Pd(PPh3)4 (100 mg) in 50 mL toluene was heated at 100° C. overnight. Cooled to rt. and diluted with 50 mL EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified via prep-TLC (ethyl acetate/Pet ether=1:5) to give 2-chloro-6-fluoro-3-(prop-2-en-1-yl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.37˜7.41 (m, 1H), 7.01˜7.06 (m, 1H), 5.78˜5.87 (m, 1H), 4.99˜5.12 (m, 2H), 3.44 (d, J=6.3 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([SH:22])[N:16]=1.O>CN1CCN(C)C1=O>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([S:22][C:17]1[N:18]=[C:19]([CH3:21])[CH:20]=[C:15]([CH3:14])[N:16]=1)=[CH:3][CH:4]=[N:5]2
Reactant: Cc1cc(C)nc(S)n1
Reactant: Clc1cc(Cl)c2c(Cl)ccnc2c1
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: Cc1cc(C)nc(Sc2ccnc3cc(Cl)cc(Cl)c23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution was prepared by dissolving 15.7 g of 4,5,7-trichloroquinoline in 60 ml of dry dimethylimidazolidinone. To the solution, 10.4 g of 4,6-dimethyl-2-mercaptopyrimidine was added with stirring at the room temperature. The reaction was progressed with heat evolution and the temperature of the reaction mixture was increased to 50° C. Crystals were precipitated in the course of the reaction. After finishing the addition, stirring was continued for about 2 hours to complete the reaction. The reaction mixture was mixed with 300 ml of water. Precipitated crystals were filtered and recrystallized from acetone to obtain 20.8 g (91.9% yield) of 5,7-dichloro-4-(4,6-dimethyl-2-pyrimidinylthio)quinoline. Melting point was 182.0°-183.2° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[O:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>S1CCCC1>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[C:6](=[O:7])[C:2]([CH3:9])([CH3:1])[C:3](=[O:4])[NH:33][C:31]4=[O:32])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(N)=O)cc3)CC2)cc1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: C1CCSC1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)NC(=O)C(C)(C)C4=O)cc3)CC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
2,2-Dimethylmalonyl chloride (0.057 mol) was added to a solution of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea (0.057 mol) in tetrahydrothiophene, 1,1-dioxide (200 ml). After stirring for 15 minutes, the reaction mixture was heated to 40° C. for 3 hours and at 50° C. for 2 hours. The reaction mixture was allowed to stand overnight at 25° C. The product was precipitated with diethyl ether and crystallized by trituration. The product was recrystallized from 2-propanol, yielding 20.1 g of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl)phenyl]-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (interm. 16).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:22]3[CH:27]=[CH:28][C:19]([O:18][CH3:17])=[CH:20][C:21]=3[O:26][CH2:25][CH2:24]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1ccc2c(c1)OCCN2
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCOc3cc(OC)ccc32)c1=O

Procedure:
Prepared in a similar fashion as described for Example aaa using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3) δ 6.91 (d, J=9.5 Hz, 1H), 6.69 (s, 1H), 6.46–6.41 (m, 2H), 4.92–4.82 (m, 1H), 4.34–4.31 (m, 2H), 4.20–4.16 (m, 2H), 3.76 (s, 3H), 2.64–2.50 (m, 1H), 2.24–2.12 (m, 1H), 1.96–1.40 (m, 7H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 390.1595 [(M+H)+, calcd for C20H25N3O3Cl 390.1584].
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N1C=N[N:19]2[C:24]([N:25]3[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26]3)=[CH:23][N:22]=[CH:21][C:20]=12.[CH2:31]([N:33](CC)C(C)C)[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:33]1[CH:31]=[CH:32][N:22]2[CH:21]=[CH:20][N:19]=[C:24]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:12]([C:9]4[N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[O:11][N:10]=4)=[O:14])[CH2:26]3)[C:23]=12
Reactant: CCN(CC)C(C)C
Reactant: O=C(O)c1noc(-c2ccccc2)n1
Reactant: N[C@H]1CCN(c2cncc3ncnn23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(c2nccn3ccnc23)C1)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a suspension of the above 5-phenyl-1,2,4-oxadiazole-3-carboxylic acid (58 mg, 0.3 mmol), (S)-1-([1,2,4]triazolo[1,5-a]pyrazin-5-yl)pyrrolidin-3-amine hydrochloride salt (90 mg, 0.32 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was then diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue was purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 26 mg of the title compound (23% yield) as a white solid. MS: (ES) m/z found 376.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: OCC1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCC(CO)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-hydroxymethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene (2.72 g,) and potassium carbonate (3.17 g) in acetonitrile, ethyl bromoacetate (2 ml) was added at room temperature. After stirring overnight at room temperature, the reaction mixture was poured into water and extracted with ether. The extract was washed with saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=6:4) to give the title compound (4.10 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(N)on1
Product: CC(C)(C)c1noc(N)c1Br
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole was prepared from 5-amino-3-tert-butylisoxazole and N-bromosuccinimide in 64% yield as described in Example 25a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([NH2:12])=[CH:5][CH:4]=1.C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[OH:17][C:18]1[N:19]=[C:8]([OH:10])[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[N:12]=1
Reactant: N#C[O-]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nc(O)nc(O)c2c1
Yield: 82 %

Procedure:
A mixture of 5-methoxy anthranilic acid (40 g, 0.24M), acetic acid (18.0 g, 0.3M) and 1 liter warm water (35° ) was stirred and allowed to cool. A solution of potassium cyanate (24.3 g, 0.3M) in water (100 ml) was added over 15 minutes and then stirred for a further 30 minutes. Sodium hydroxide (320 g, 8.0M) solid was added portionwise and the reaction was then heated at 90° for 30 minutes and allowed to cool overnight. The solid was filtered off and dissolved in hot water (500 ml) and then acidified with dilute sulphuric acid to precipitate the product. The solid was filtered off and washed free of acid with water and then dried at 100°/vacuum to yield the title compound (37.7 g) m.p. >290°.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[CH:21]=[CH:22][CH:23]=1)=O.[C:30](O)(=[O:32])C>>[O:32]1[CH:30]=[CH:9][CH:10]=[C:11]1[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:28])[CH2:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8]
Reactant: Nc1n[nH]cc1-c1ccco1
Reactant: CCC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CC(=O)O
Product: CCC(=O)Nc1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1

Procedure:
A solution of 1.77 g 3-amino-4-furanylpyrazole and 2.46 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide in 50 ml of glacial acetic acid was refluxed for 8 hours. Removal of all solvents gave a gum which was partitioned between an aqueous saturated sodium bicarbonate solution and methylene chloride. The methylene chloride extract was dried with powdered anhydrous sodium sulfate and then passed through a short column of a hydrous magnesium silicate adsorbent. The eluate was refluxed on a steam bath with gradual addition of hexanes until turbidity was noted. The desired product was collected by filtration of the cooled crystallization mixture, (2.05 g, mp 185°-186° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:16]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:11][C:10](=[O:12])[CH:9]([CH2:13][CH2:14][Cl:15])[C:6]21[O:8][CH2:7]2)=O.C(O[CH2:35][CH3:36])(=O)C.[OH2:37]>C[Si](C)(C)CCO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:35][CH2:36][O:37][C:3]([C:5]1([CH:16]([O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[NH:11][C:10](=[O:12])[CH:9]([CH2:13][CH2:14][Cl:15])[C:6]21[O:8][CH2:7]2)=[O:2]
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C(CCCl)C12CO2
Reactant: O
Reactant: CCOC(C)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: C[Si](C)(C)CCO
Product: CC(C)(C)[Si](C)(C)OC(C1CCCCC1)C1(C(=O)OCC[Si](C)(C)C)NC(=O)C(CCCl)C12CO2
Temperature: 23 °C
Yield: 74 %

Procedure:
Titanium (IV) isopropoxide (0.30 ml, 0.42 g, 1.5 mmol, 11.5 equiv) was added to a stirred solution of 4-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-7-(2-chloro-ethyl)-6-oxo-1-oxa-5-aza-spiro[2.4]heptane-4-carboxylic acid methyl ester (60 mg, 0.13 mmol, 1.0 equiv) in 2-trimethylsilanyl-ethanol (1.5 ml), and the resultant solution was heated at 100° C. for 17 h. The reaction mixture was allowed to cool to 23° C. and ethyl acetate (30 ml) and water (20 ml) was added. The resultant solution was stirred for 10 min and filtered through Celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 ml×2). The combined organic layers were dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to afford 4-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-7-(2-chloro-ethyl)-6-oxo-1-oxa-5-aza-spiro[2.4]heptane-4-carboxylic acid 2-trimethylsilanyl-ethyl ester (61 mg, 74%) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([CH:10]([OH:13])[C:11]#[N:12])[CH2:7][CH2:8][CH3:9].C#N>O>[OH:13][CH:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]([NH2:12])=[O:2]
Reactant: CCCCC(O)C#N
Reactant: O=S(=O)(O)O
Agent: C#N
Solvent: O
Product: CCCCC(O)C(N)=O
Reaction time: 0.5 h

Procedure:
A stirrer, a thermometer and a dropping funnel were set to a 1,000-mL four-necked flask and to a reaction apparatus, 95% sulfuric acid (450 g, 4.4 mol) was added and cooled so that the liquid temperature was lower than 30° C. To the cooled sulfuric acid with stirring, was added α-n-butyl-α-hydroxyacetonitrile prepared from n-butyl aldehyde and hydrocyanic acid (1.5 mol, content 87 to 94%, further containing unreacted hydrocyanic acid, starting material n-butyl aldehyde and water) with the use of dropping funnel. The addition was conducted in such a way that the reaction solution was kept at a temperature of lower than 40° C. After the dropwise addition, the reaction solution was aged at 40° C. for 0.5 hr. The pH of the reaction solution was less than 1. A part of the reaction solution was sampled and analyzed by HPLC. In result, the ratio of conversion of the starting materials was 100% and the corresponding 2-hydroxyhexanoic acid amide and 2-hydroxysulfonyl oxy hexanoic acid amide were produced.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[N+:9]([O-:12])(O)=[O:10].[CH:13]12[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:23]1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=1>C(Cl)Cl>[N+:9]([C:17]1[CH:16]=[CH:15][C:14]2[CH:13]3[CH2:30][CH:20]([CH2:21][N:22]([C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:23]3)[C:19]=2[CH:18]=1)([O-:12])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to −78 ° C. and treated with 1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.5 g, 13.7 mmol) in CH2Cl2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was stirred at −78° C. for 30 minutes then warmed to 0° C. for 1 hour. The reaction mixture was poured into a vigorously stirred ice (100 g). The layers were separated and the aqueous layer extracted with CH2Cl2 (3×30 ml). The organic layer was combined and washed with H2O (3×30 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (20 mL) and H2O (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4.2 g). Chromatography yielded pure product as a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanes Rf 0.23). 1H NMR (400 MHz, CDCl3) δ 8.12 (br d, J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43–3.35 (m, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS m/e 300 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][C@@H:23]([NH2:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:31][C@H:23]([CH3:22])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)Cc1ccccc1
Reactant: Nc1ccnc(C(F)(F)F)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](Cc1ccccc1)NC(=O)c1c(N)ccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-amino-2-(trifluoromethyl)nicotinic acid (15 g, 61.83 mmol) was suspended in a mixture of anhydrous DMF (300 mL) and anhydrous dichloromethane (500 mL). To this was added triethylamine (30.4 mL, 216 mmol), followed by L-amphetamine hydrochloride (12.7 g, 74.2 mmol). HBTU (30.5 g, 80.4 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo to remove dichloromethane. The resultant DMF solution was poured into water, extracted with ethyl acetate (1 L). The organic layer was washed successively with 1N NaOH, saturated sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel column chromatography using 40-70% ethyl acetate/heptanes as eluant to provide the product as a colorless foam (18.3 g, 92% yield). 1H NMR (400 MHz, CDCl3) δ 8.2 (d, 1H), 7.2-7.4 (m, 5H), 6.6 (d, 1H), 5.8 (d, 1H), 4.7 (bs, 2H), 4.5 (m, 1H), 2.9 (m, 2H), 1.25 (d, 3H). MS m/z 324.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])C=C[C:3]=1[C:4](=O)[CH2:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.[CH2:17]([NH2:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.[C:28]1(C)C=CC=C[CH:29]=1>>[Cl:16][C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:6]1[N:10]([CH2:28][CH:29]=[N:26][CH2:17][CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[CH:8][N:7]=1
Reactant: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1
Reactant: NCC=Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nccn2CC=NCC=Cc2ccccc2)c(Cl)c1

Procedure:
12.34 g (0.048 mol) of 2,4-dichlorophenacylimidazole and 6.66 g (0.05 mol) of cinnamylamine were suspended in 100 ml of toluene and the suspension was heated under reflux, using a water separator, until no further water of reaction was separated off. The solvent was removed in vacuo, after which 17.4 g (98% of theory) of a viscous oil were obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1Cl>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][C:29]2[CH:28]=[CH:27][C:26]([N+:31]([O-:33])=[O:32])=[CH:25][C:24]=2[Cl:23])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1ccc(Sc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.2 mL, 7.8 mmol) was added dropwise to a solution of 4-tert-butylthiophenol (0.95 g, 5.7 mmol), 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), and DMF (15 mL). The solution was stirred for 1 h at ambient temperature then 1 h at 60° C. The mixture was allowed to cool and was poured over ice. The resulting yellow precipitate was collected and dried. The crude product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:6]=[CH:5][N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:7]2[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:4][CH:5]=[N:6]2)=[O:30])[N:17]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CN)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CNC(=N)N)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (25 mg, 0.047 mmol) and pyrazole-1-carboxamidine hydrochloride (10.9 mg, 0.099 mmol) in DMF (470 μL) was added DIPEA (33 μL, 0.188 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (13 mg, 42%) as a white powder. LCMS: Rt=0.29 min, m/z=574.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.96-7.78 (m, 1H), 7.41-6.96 (m, 5H), 6.80-6.71 (m, 1H), 6.55 (s, 1H), 5.42-5.32 (m, 1H), 4.75-4.63 (m, 1H), 4.62-4.42 (m, 1H), 4.39-4.28 (m, 1H), 1.38 (s, 3H) 1.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[CH2:13])[CH:6]=2.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[CH2:23]([O:22][C:20]([NH:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]=[CH2:13])[CH:6]=2)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccc2cc(N)c(C(=O)O)nc2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)O)nc2c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A vial containing the crude 3-amino-7-vinylquinoline-2-carboxylic acid (0.75 g, 3.5 mmol), water (60 mL) and NaOH (7.0 g, 180 mmol) was cooled to −10° C. Benzyl chloroformate (5.0 mL, 33 mmol) was added slowly to the mixture. The mixture was allowed to warm to room temperature and stirred for 1 h. The organic solvent was then removed under reduced pressure. The remaining aqueous layer was neutralized with aq. HCl. The yellow precipitate formed was collected by vacuum filtration, and washed with cold MeOH to give the sub-title compound (1.12 g, 92%) as light yellow powder. LCMS calc. for C20H17N2O4 (M+H)+: m/z=349.1. Found: 349.1.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][SiH:15]([Cl:17])[Cl:16]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:7]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][CH2:13][Si:15]([Cl:17])([Cl:16])[Cl:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOCCOc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: Cl[Si](Cl)(Cl)CCCOCCOc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Under a nitrogen atmosphere, 8 mg of hexachloroplatinic acid are added to 178 g (1.0 mol) of 2-allyloxyethyl phenyl ether, the preparation of which is described above under a), and the mixture is heated to 70° C. 169 g (1.25 mol) of trichlorosilane are added dropwise to the mixture over a period of 2 hours and the mixture is stirred for a further 2 hours at 70° C. The crude product is purified by distillation in vacuo, giving 250 g of 3-(2-phenoxyethoxy)propyltrichlorosilane having an acid number of 531.