Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.[N-]=[N+]=[N-].[CH2:9]([O:11][Si:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10]>P([O-])([O-])(O)=O.[Na+].[Na+].C(Cl)Cl>[CH2:9]([O:11][Si:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25]([N:1]=[N+:2]=[N-:3])(=[O:27])=[O:26])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[Si](CCCCCCS(=O)(=O)Cl)(OCC)OCC
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO[Si](CCCCCCS(=O)(=O)N=[N+]=[N-])(OCC)OCC
Temperature: 25 °C

Procedure:
Sodium azide (1.5 equivalent) in 4 ml of sodium hydrogen phosphate and hydrogen chloride buffer (14.4 g or Na2HPO4 to 4.4 mil conc HCl in 1 liter of distilled water) per gram of azide is added dropwise to a stirred 50 percent solution of triethoxysilylhexane sulfonyl chloride in methylene chloride containing 1 percent Aliquat 336. The mixture is stirred at room temperature for thirty minutes after the addition is complete. The layers are separated. The methylene chloride layer is washed with a saturated salt solution, dried over magnesium sulfate and the methylene chloride is evaporated. Ninety percent solids of a light yellow liquid triethoxysilylhexane sulfonyl azide of about 90 percent purity are obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Product: O=C(O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 3B. MS m/z 473 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[S:14][N:13]=[N:12][C:11]=2[C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](Cl)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([NH:17][C:15]([C:11]1[N:12]=[N:13][S:14][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])(=[O:20])[CH3:19]
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1nnsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To an ice-cooled suspension of NaH (16 mg 60% in oil, 0.23 mmol) in 1.5 mL of DMF was added 0.5 mL of DMF solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (50 mg, 0.23 mmole). The mixture was stirred at room temperature for 1 h, and then cooled in an ice bath. To the cooled solution was added acetyl chloride (18.6 mg, 0.24 mmole), resulting in the. formation of a yellowish solution that was kept stirring at room temperature for 1.5 h. The reaction was then quenched with a mixture of 5 mL of saturated aqueous NH4Cl, 5 mL of saturated aqueous NaCl and 5 mL of EtOAc. The aqueous phase was extracted with EtOAc (2×6 mL). The combined organic layers were dried with Na2SO4, concentrated, and then loaded onto a preparative TLC plate, which was sequentially eluted with hexane-EtOAc (2:1) and EtOAc-acetone-H2O (4:1:0.15). The product (24 mg) was obtained as a yellowish solid. 1H NMR (ppm, in DMSO-d6): 12.84 (s, br., 1 H), 7.79 (d, 2 H), 7.64 (s, br., 1 H), 7.53 (t, 2 H), 7.40 (t, 1 H), 2.39 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(Cl)Cl.[CH3:25][Si:26](OS(C(F)(F)F)(=O)=O)([CH3:28])[CH3:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([O:21][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12
Reaction time: 12 h

Procedure:
10 g of 3-methoxy-estra-1,3,5(10)-trien-17-one (35.2 mmol) is mixed with exclusion of moisture under inert gas with 30 ml of methylene chloride distilled on P2O5 and 10.5 g of trifluoromethanesulfonic acid trimethylsilyl ester (47.2 mmol, D=1.15). Then, about 7 ml of triethylamine (KOH dried, M=101.2; D=0.726) is added in portions with stirring and gentle cooling, and the solution reacts clearly in an alkaline way. Then, it is allowed to stand for 12 hours at room temperature, and after the reaction has been completed, the solvent is removed in a vacuum. The remaining viscous residue is extracted three times with about 20 ml of absolute ether under inert gas. The ether solution, in which the steroid is present, is used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>>[CH3:35][O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC(=O)OC
Product: COC(=O)/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodo-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and methyl acrylate analogous to Example 97, step A.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[CH3:14][NH:15][C:16]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:22][CH:21]=1)=[O:17]>>[CH3:14][NH:15][C:16]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:29][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:28])=[CH:22][CH:21]=1)=[O:17]
Reactant: CNC(=O)COc1ccc(CC(C)N)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: CNC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetylthiazole and 2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethylamine, followed by reduction and purification of the base on a silica gel column using methylene chloride/methanol=9:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:13][CH:12]([CH2:11][OH:14])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Br)cc1
Reactant: C=CCO
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-Bromo-benzaldehyde oxime (162 g, 789.9 mmol) and allyl alcohol (130.5 ml) were added to tetrahydrofuran (1000 ml) and then bleach (5305 ml) was added. The reaction was cooled to 0° C. and stirred for 3 hrs. The precipitate was collected and washed with water (2×300 ml) to give the desired product (137 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12])C.O.[NH2:15][NH2:16].O>C(O)C>[O:12]=[C:7]1[N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH2:11][CH2:10][O:9][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)CN1CCOCC1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1CCOCC1=O
Temperature: 80 °C

Procedure:
Ethyl-2-(3-oxomorpholino)acetate (600 mg, 3.21 mmol) was dissolved in ethanol (3 mL) and hydrazine hydrate (160.46 mg, 3.21 mmol) was added at room temperature. The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was transferred into 50 mL water and extracted with EtOAc (3×50 mL) The combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product, which was used without further purification in the subsequent step (Crude yield: 54%). LCMS m/z 174.05 [M+H]+ tR 2.489 min.
Reaction SMILES: C1C=[C:9]2[C:4]([CH:5]=[C:6]([CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8]2)=CC=1.C([O-])(=O)CC[C@H](NC(C1C=CC(NCC2CNC3N=C(NC(C=3N=2)=O)N)=CC=1)=O)C(O)=[O:22]>>[NH2:16][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][C:9]([OH:22])=[CH:4][CH:5]=1
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
An L-3-(2-naphthyl)-alanine mutant of mouse dihydrofolate reductase (DHFR) was generated and characterized to confirm the ability of the mtRNACUATyr/SS 12-TyrRS pair to site-specifically incorporate L-3-(2-naphthyl)-alanine in response to an amber stop codon. The Tyr163 codon of the mouse DHFR gene was mutated to TAG, and a His6 tag was added to the COOH-terminus of DHFR to facilitate protein purification using Ni2+ affinity chromatography. As a positive control, wild-type M. jannaschii TyrRS was coexpressed with the mtRNACUATyr resulting in efficient suppression of the TAG codon with tyrosine (FIG. 4). When SS12-TyrRS was coexpressed with the mu tRNACUATyr in the presence of 1 mM L-3-(2-naphthyl)-alanine, full-length mouse DHFR was also generated (with yield of 2.2 mg/L in liquid GMML minimal medium). In the absence of either L-3-(2-naphthyl)-alanine, mtRNACUATyr, or SS12-TyrRS, no full length DHFR was produced. A penta-His antibody was used to detect the His6 tag at the COOH-terminus of DHFR in a Western blot. No DHFR could be detected in the absence of each of the above three components.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1)([O:16][CH3:17])=[O:15]>>[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23]/[N:24]=[C:10](/[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)\[CH3:11])=[CH:20][CH:19]=1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(CON)cc1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Product: COC(=O)c1ccc(CO/N=C(\C)c2ccc(OC)c(O)c2)cc1
Yield: 71.6 %

Procedure:
Acetophenone 12 (50 mg, 0.301 mmol) was condensed with O-(4-carbomethoxybenzyl)hydroxylamine hydrochloride (27) (72 mg, 0.331 mmol) according to the general procedure II-B defined above. After being heated at reflux for 15 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (15 mL) and the resulting solution washed with H2O (2×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (1:9 v/v ethyl acetate/hexane elution) to afford the title compound CP30263 (71 mg, 82%) as a white solid, m.p. 97.7-98.7° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: C1CNCCN1
Reactant: Clc1ncccn1
Product: c1cnc(C2CNCCN2)nc1
Reaction time: 21 h

Procedure:
A mixture of 2-chloropyrimidine (10.0 g) and piperazine (16 g) in alcohol (120 ml) is stirred for 21 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated to give 2-pyrimidinyl piperazine. The 2-pyrimidinyl piperazine (4.64 g) is stirred at 70° in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,2-dione (11.52 g) and potassium carbonate (3.75 g) for 1.5 hr and at 20°-25° for 2 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with 4 to 6% methanol/methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound which is crystallized from ethyl acetate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:9])[CH:7]=[CH2:8]>O1CCCC1>[N:1]1([CH2:8][CH2:7][CH2:6][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CC#N
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: NCCCn1ccnc1

Procedure:
A mixture of 41 g. of imidazole and 75 ml. of acrylonitrile was heated on a steam bath for 3 hours, then concentrated under reduced pressure to remove excess acrylonitrile. A 300 ml. portion of methanol was added to the residue together with 100 ml. of concentrated ammonium hydroxide and 8 g. of Raney nickel catalyst. This mixture was hydrogenated in a Parr apparatus until hydrogen uptake ceased and then filtered giving a light green liquid. A 300 ml. portion of tetrahydrofuran was added to this liquid and the mixture filtered through diatomaceous earth. The filtrate was concentrated twice from toluene, giving 75.2 g. of the desired intermediate as a clear oil.
Reaction SMILES: FC(F)(F)C(O)=O.[OH-].[K+].[CH:10]1([CH:15]([NH:17][C:18]2[CH:38]=[CH:37][C:21]([C:22]([CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])=[O:23])=[CH:20][CH:19]=2)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([CH:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23])=[CH:37][CH:38]=2)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NC(C)C2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(=O)c1ccc(NC(C)C2CCCC2)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. of tert-butyl ethyl 4-(1-cyclopentylethylamino)benzoylmalonate 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords ethyl 4-(1-cyclopentylethylamino)benzoylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:14]=1[C:15]([O:17]CC)=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]NOC.C[Mg]Br>C1COCC1>[C:15]([C:14]1[C:13]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:10]([CH3:12])[CH3:11])=[N:23][CH:22]=[C:21]([Cl:24])[CH:20]=1)(=[O:17])[CH3:26]
Reactant: CCOC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CNOC
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 65.5 %

Procedure:
To a solution of ethyl(S)-2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloronicotinate (104 mg, 291 μmol) and N,O-dimethylhydroxylamine hydrochloride (45.5 mg, 466 μmol) in THF (1 mL) was added dropwise methylmagnesium bromide (1.4 M in 3:1 toluene:THF, 1.04 mL) at −20° C. The mixture was stirred at −20° C. for 45 min, at which point it was quenched carefully with cold saturated aqueous ammonium chloride (10 mL). The mixture was extracted with EtOAc (20 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 60%) to afford 62.3 mg of tert-butyl(S)-(1-(3-acetyl-5-chloropyridin-2-yl)-2-methylpropyl)carbamate (56% yield). LC-MS tR=1.08 min in 1 min chromatography, MS (ESI) m/z 327.4 [M+H]+.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][C:4](N)=[O:5].[Br:9][CH:10](Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][CH2:10][CH2:11][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][C:4]1=[O:5]
Reactant: CC(Br)Br
Reactant: NC(=O)CCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1CCC(=O)N1CCBr

Procedure:
49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h.
Reaction SMILES: [O:1]([CH2:9][C:10]([F:13])([F:12])[F:11])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:20]([O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27](O)=[CH:26][C:25]=1[CH3:32])(=[O:22])[CH3:21]>CC(=O)CC>[C:20]([O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([O:1][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[CH3:32])(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1c(C)cc(O)cc1C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1c(C)cc(OCC(F)(F)F)cc1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 74.9 %

Procedure:
2,2,2-Trifluoroethyl triflate (1.02 g, 4.40 mmol) and potassium carbonate (1.10 g, 1.01 mmol) were added to a solution of 4-hydroxy-2,6-dimethylphenyl acetate (673 mg, 3.73 mmol) in 2-butanone (15 mL). The mixture was stirred at 70° C. for 72 hours, then cooled to room temperature and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine and dried. The solvent was removed in vacuo and the residue purified on silica gel, eluting with 10% ethyl acetate in hexanes, to give 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl acetate (733 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]3[C:9]=2[C:10]([NH2:24])=[N:11][NH:12]3)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>ClCCl>[NH2:24][C:10]1[C:9]2[C:13](=[C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=[CH:16][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)=[O:34])=[CH:3][CH:4]=2)[NH:12][N:11]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)c3[nH]nc(N)c23)cc1
Solvent: ClCCl
Product: Nc1n[nH]c2c(CN3CCOCC3)ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 15G (50 mg, 0.155 mmol) in dichloromethane was cooled to 0° C., treated with 1-fluoro-3-isocyanatobenzene (0.021 mL), stirred at room temperature overnight, and concentrated. The concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide 24 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.79 (m, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.16 (m, 1H), 7.32 (m, 1H), 7.42 (m, 3H), 7.52 (m, 1H), 7.63 (d, J=8.81 Hz, 2H), 9.12 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 461 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].ClC(O[CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=O.N1C=CC=CC=1>O1CCCC1>[C:1]([O:6][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])(=[O:5])[C:2]([CH3:4])=[O:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)C(=O)O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of 3.3 g (37.5 mmole) of pyruvic acid and 7.9 g (37.5 mmole) of trichloroethyl chloroformate in 20 ml of dry tetrahydrofuran at 0° is added dropwise 0.6 ml of pyridine. After stirring for 2 hours at room temperature, the mixture is concentrated in vacuum, diluted with water and extracted with ethyl acetate. The extract is washed with 5% HCl, dried over MgSO4, evaporated and distilled in vacuum to give 4.0 g (50%) trichloroethyl pyruvate, bp 75°-82° (17 mm).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH:10](O)=[O:11]>>[CH:10]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:11]
Reactant: Cc1cccc(C)c1N
Reactant: O=CO
Product: Cc1cccc(C)c1NC=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
125 g. of 2,6 dimethyl aniline and 375 ml. of 88% formic acid are mixed in a 1 liter bomb with magnetic stirrer. The temperature (oil bath) is brought to 120° C. The bomb is kept at this temperature for 24 hours. The bomb is then allowed to cool to room temperature and stirring continued for 48 hours. The pressure is released and the mixture is poured into an 800 ml. ice with stirring. The mixture is filtered and the solid washed extensively with water and sucked dry and then dried in vacuo at 90°-95° to give N-formyl-2,6-dimethylaniline (m.p. 163°-164.5° C.).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCCC(C)C)[nH]n1
Yield: 73.1 %

Procedure:
Hydrazine hydrate (0.943 mL, 1.91 mmol) was added to a stirring room temperature solution of 16 (0.4354 g, 1.91 mmol) in EtOH (1.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.3132 g (63.1%) of 17. 1H (CDCl3, 400 MHz): δ 9.60 (1H, broad s), 6.58 (1H, s), 4.34 (2H, q, J=7.2 Hz), 2.66 (2H, t, J=7.7 Hz), 1.67-1.57 (2H, m), 1.58 (1H, m), 1.36 (3H, t, J=7.2 Hz), 1.24-1.15 (2H, m), 0.85 (6H, d, J=6.5 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.22, 106.59, 61.17, 38.58, 27.99, 27.20, 26.57, 22.72, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 22.72, 14.48; CH2 carbons: 61.17, 38.58, 27.20, 26.57; CH carbons: 106.59, 27.99 ppm. HPLC: 10.072 min.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]=[C:1]=[O:4])[CH3:15])=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](N=C=O)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tint=2-5° C. for 30 min, at which point HPLC analysis indicates >99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4% yield). 1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2 H), 7.26 (d, J=8.2 Hz, 2 H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3 H). The material was used in Step 3 without further purification.