Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Br:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Br:13])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCBr)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a mixture of pentafluorophenol (3.3 g, 17.96 mmol), 4-bromobutanoic acid (3.0 g, 17.96 mmol) and DMAP (0.440 g, 3.59 mmol) in CH2Cl2 (30 ml), cooled to 0° C., EDAC.HCl (5.2 g, 26.94 mmol) was added in portion. The mixture was then stirred at 0° C. for 30 minutes. Then it was gradually warmed to room temperature and stirred for 480 minutes. Then the mixture was diluted with NaH2PO4 aqueous (5%, 50 ml) and acidified with HCl 1N to pH 3-4. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×50 ml). The organic phase washed with brine, dried over Na2SO4 and evaporated to give an oil that was purified by flash chromatography (n-Hexane/EtOAc 98:2) to yield 4-bromobutanoic acid pentafluorophenyl ester (5.2 g, 86%) as a colorless oil.
Reaction SMILES: C([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.O.Cl.[NH2:29][NH:30][C:31]([NH2:33])=[O:32].[CH2:34](O)C>>[NH:30]([N:29]=[CH:34][N:8]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:31]([NH2:33])=[O:32]
Reactant: NNC(N)=O
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCCCN(C=NNC(N)=O)C(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 10 ml of ethanol was dissolved 850 mg of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 2 ml of water and 1.0 g of semicarbazide hydrochloride were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was purified by medium-pressure column chromatography on silica gel to obtain 900 mg of the titled compound as a colorless crystal.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.CCCCCC>[F:10][CH:11]([F:14])[CH2:12][NH:13][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCC(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CNCC(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
tert-Butyl bromoacetate (2.72 g) was added to a suspension of 2,2-difluoroethylamine (1.46 g) and potassium carbonate (2.48 g) in acetonitrile (5 mL) and the mixture was stirred at RT for 24 h. The mixture was diluted with EtOAc (10 mL) and hexane (10 mL). The suspension was washed with the mixture of aqueous NaHCO3 (20 mL) and brine (10 mL). The organic extracts were dried and concentrated in vacuo to provide crude product. The crude product was purified by vacuum distillation (12 hPa, 78-80° C.) to afford sub-title compound (1.85 g) as a colourless oil; 1H NMR (300 MHz, CDCl3); 5.82 (1H, tt, J=4.4, 56 Hz), 3.45 (2H, s), 2.98 (2H, dt, J=4.4, 15.1 Hz), 1.45 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)[CH:7]=2)=[CH:14][N:13]=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 130.8 %

Procedure:
A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (1.5 g, 5.65 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.527 g, 7.34 mmol) in dioxane (20 mL) was sparged with Ar, treated with a solution of K2CO3 (1.171 g, 8.47 mmol) in water (5 mL) and Pd(PPh3)4 (0.326 g, 0.282 mmol) and heated at 80° C. overnight. The mixture was cooled to RT, treated with water, extracted with DCM (4×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine (2.3 g, 75%). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.43-8.42 (m, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.83 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.34 (s, 3H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)nc1

Procedure:
In analogy to example 79, step a) using 5-cyano-2-pyridinecarboxylic acid (CAS 53234-55-2) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][NH:37][C:38]([C:40]1[CH:44]=[C:43]([Cl:45])[S:42][C:41]=1[Cl:46])=[O:39])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:47])=[O:5])=[C:10]([CH2:36][NH:37][C:38]([C:40]4[CH:44]=[C:43]([Cl:45])[S:42][C:41]=4[Cl:46])=[O:39])[CH:11]=3)[N:19]=2)=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of the 3-(4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-{[(2,5-dichloro-thiophene-3-carbonyl)-amino]-methyl}-phenyl)-propionic acid tert-butyl ester (367 mg, 0.531 mmol) in CH2Cl2 (20 mL) was treated with anisole (2.0 mL) then TFA (6.0 mL). The mixture was stirred at room temperature for 2 h and concentrated. The residue was co-evaporated with CCl4 three times, dried under vacuum, triturated with ether, and filtered to obtain the title compound as a white solid (301 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 2.38 (t, 2H, J=8.3 Hz), 2.71 (t, 2H, J=7.3 Hz), 2.82 (t, 2H, J=6.3 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.28 (d, 2H, J=4.9 Hz), 6.68 (d, 1H, J=9.3 Hz), 6.77 (s, 1H), 7.00 (d, 1H, J=8.3 Hz), 7.24 (s, 1H), 7.29 (t, 1H, J=5.9 Hz), 7.39 (t, 2H, J=7.8 Hz), 7.63 (t, 2H, J=7.8 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.88 (d, 2H, J=8.3 Hz), 8.69 (t, 2H, J=5.9 Hz). MS (ES) m/e 635.1 [M+1].
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1F)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
18 mg (0.056 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-fluorobenzonitrile are dissolved under an argon atmosphere in 5 ml abs. dichloromethane, and 21.2 mg (0.111 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and again stirred for 2 h. It is then diluted with 10 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 3:7). 7 mg (35.4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[C:5]([CH3:17])[C:4]([C:18]([OH:20])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[CH3:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:18]([C:4]2[C:5]([CH3:17])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:16])([F:14])[F:15])[N:2]([CH3:1])[CH:3]=2)=[O:20])=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)cn(C)c1-c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn(C)c1-c1ccccc1C(F)(F)F
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid (56 mg, 0.20 mmol) in DCM (4 mL) was added oxalyl chloride (22 pt, 0.25 mmol). After stirring 30 min, solvent was removed in vacuo to give an oil, which was re-dissolved in anhyd THF (4 mL). To this solution were added 4-methanesulfonyl-aniline (68 mg, 0.40 mmol) and DIEA (140 μL, 0.8 mmol) and the mixture was stirred at 60° C. overnight. After cooling, solvent was removed in vacuo to give a crude residue, which was purified by column chromatography on silica gel, eluted with EtOAc-hexane (0:100 to 25:75) to give the title compound (24 mg, 28%). 1H-NMR (CDCl3): δ 7.89-7.91 (m, 2H), 7.80 (m, 3H), 7.57-7.66 (m, 3H), 7.33 (d, 1H), 7.30 (s, 1H), 3.32 (s, 3H), 3.05 (s, 3H), 2.12 (s, 3H). MS (ES): 437 (MH+). E. In a manner similar to that described for Example 16D, the following compounds were prepared from the appropriate anilines:
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:10][CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.N12CCCN=C1CCCCC2.O>O1CCCC1>[N:31]1([O:1][C:2]2[C:3]3[O:10][CH:9]=[C:8]([CH:11]4[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(O)ncnc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Yield: 84.7 %

Procedure:
Under an argon atmosphere, tert-butyl 4-(4-hydroxyfuro[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.06 g, 3.22 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (1.81 g, 3.49 mmol) were dissolved in anhydrous tetrahydrofuran (17 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (656 mg, 4.31 mmol) was added to the solution, and then the resultant solution was stirred at room temperature for 40 minutes. Water was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (1.19 g, 83%) as a white amorphous.
Reaction SMILES: [NH2-].[Na+].CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]#[N:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]Cl)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=2)[C:17]#[N:18])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reaction time: 5 h
Yield: 67.6 %

Procedure:
1.95 g of sodium amide are added in small quantities to an ether solution of 9.3 g of 3,4-dichlorophenylacetonitrile. The mixture is heated for 2 hours to reflux, 11.8 g of 2-(4-benzylpiperidino)-1-chloro ethane are added and heating is repeated for another 5 hours to reflux. The resulting mixture is cooled and 200 ml of water are added, after what the organic phase is decanted, washed with water and extracted with a 10% solution of hydrochloric acid. The aqueous phase is then neutralized with soda, extracted with ether, washed with water, dried over magnesium sulfate and evaporated. 13 g of oily product are thus obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Br:14]Br>ClCCl>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[Br:14]
Reactant: BrBr
Reactant: O=Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Powdered aluminium trichloride (226 g) was suspended in dry dichloromethane (250 cm3) and the suspension was cooled to 0° C. 4-Fluorobenzaldehyde (124 g) was added to the stirred suspension, the temperature of the mixture being maintained below 10° C. during the addition. Stirring of the dark reaction mixture was continued at 0° C. for 15 minutes and bromine (176g) was then added in a single addition. The mixture was then heated at the reflux temperature for a total of 14 hours, the mixture being stood overnight at the ambient temperature twice within this heating period. At this point, analysis by GLC suggested only 78% bromination. Further bromine (5 cm3) was added and heating at the reflux temperature continued for a further 2 hours, but little change was observed on GLC analysis. The mixture was cooled to the ambient temperature and poured into ice (1 kg). After the ice had melted, the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with sodium metabisulphite solution, to remove unreacted bromine, and brine and then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a red oil which was purified by distillation using a 15 cm Vigreux column. The title compound (84 g) was collected as the major fraction, boiling at 144° C./28 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[CH2:22][O:23]S(C)(=O)=O)=[CH:4][C:3]=1[F:28].O=[C:30]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=[CH:32][NH:31]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:22][O:23][C:30]2[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:4][C:3]=1[F:28]
Reactant: COC(=O)c1ccc[nH]c1=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Product: COC(=O)c1cccnc1OC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1
Product: Cl

Procedure:
Using tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate and methyl 2-oxo-1,2-dihydropyridine-3-carboxylate, and by a method similar to that in Example 31, steps C and E, the title compound was obtained.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][C:16]2[C:21]([Cl:22])=[C:20]([CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:16]([NH:15][CH2:14][C:13]2[CH:25]=[CH:26][C:10]([OH:9])=[CH:11][CH:12]=2)=[N:17][C:18]([CH3:24])=[N:19][C:20]=1[CH3:23]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c(Cl)c(NCc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
112 g (0.286 mol) of (4-benzyloxybenzyl)(5-Chloro-2,6-dimethylpyrimidin-4-yl)amine hydrochloride (from example A1) are suspended in ethanol (1.1 l) and 12.5 N hydrochloric acid (1.1 l) and the suspension is heated at reflux for 1 h. The yellow solution is cooled to room temperature and stirred into ice-water (4 l). The solution is then adjusted to a pH of 8 using 10 N sodium hydroxide solution and extracted with ethyl acetate (3×1 l). The combined organic extracts are washed with water (1 l), dried over sodium sulfate and concentrated to a volume of about 100 ml. The residue is taken up in ethyl acetate (100 ml) and diisopropyl ether (200 ml) and stirred at room temperature for 15 min. The crystals are filtered and washed with diisopropyl ether/ethyl acetate) (2:1). Drying in a vacuum drying cabinet at 40° C. gives 38.4 g (51%) of the title compound as a pale beige solid. m.p.: 202° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C1C=CC=CN=1)C>C1COCC1>[C:16]([NH:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.33 h

Procedure:
N-hydroxysuccinimide (0.534 g, 4.64 mmol) was added to a solution of Gly-1-Me-HOPO (1.220 g, 3.87 mmol) in dry THF (60 ml) under a nitrogen atmosphere. After stirring for 20 min, dicyclohexylcarbodiimide (DCC, 0.956, 4.64 mmol) and dimethylaminopyridine (DMAP, 0.044 g, 0.46 mmol) were added. After 9 h, a white precipitate of dicyclohexylurea (DCU) had formed and the formation of the NHS-activated ester was judged to be complete by TLC. TREN (0.141 g, 0.967 mmol, 0.25equiv.) was added. The solvent was evaporated and the residue taken up in a 1.0M aqueous solution of HCl (50 ml). The suspension was filtered and the filtrate washed with CH2Cl2 (2×50 ml). The combined organic fractions were then back-extracted once with 1.0 M HCl (50 ml). 10M NaOH was added drop-wise to the combined aqueous fractions until the pH reached 11. The aqueous fractions were then extracted with CH2Cl2 (10×50 ml) and EtOAc (3×50 ml). The organic extracts were combined, dried (Na2SO4) and evaporated to dryness. The product was perified by a gradient flash silica column (2-8% CH3OH in CH2Cl2). Evaporation of the solvent afforded a white foam (Yield: 0.753 g, 56%). 1H NMR (CDCl3, 400 MHz): δ=8.58 (t, J=5.4 Hz, 3H, HOPO-glycine NH), 7.27-7.51 (m, 18H, Bn and glycine-TREN NH), 7.00 (d, J=7.2 Hz, 3H, HOPO), 6.59 (d, J=7.2 Hz, 3H, HOPO), 5.42 (s, 6H, Bn CH2), 3.85 (d, J=5.4 Hz, 6H, glycine CH2), 3.51 (s, 9H, N-CH3), 3.20 (m, 6H, TREN NHCH2), 2.51 (m, 6H, TREN NCH2) ppm. Anal. Calcd (Found) for C54H60N10O12.2H2O: C, 60.21 (59.96); H, 5.99 (5.96); N, 13.00 (12.93). FAB-MS (+): m/z: 1041.5 [M+H]+.
Reaction SMILES: [CH2:1]([SH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]CC.[Na+].[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[CH2:1]([S:11][CH2:18][CH2:17][C:16]#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=CC#N
Reactant: CCCCCCCCCCS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCSCCC#N
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a 250 mL round-bottomed flask fitted with an overhead mechanical stirrer, a thermometer and an addition funnel were charged 87 g of 1-decanethiol and 20 drops of a 21% by weight solution of sodium ethoxide in ethanol. The mixture was cooled to 10° C. using an ice bath. Then the dropwise addition of 53 g of acrylonitrile was started. After addition of a portion of the acrylonitrile, 10 drops of 21% by weight solution of sodium ethoxide in ethanol were added. The temperature of the reaction mixture during the addition of the remaining acrylonitrile ranged between 30° C. and 35° C. The reaction mixture was then kept at room temperature overnight (~19 hours). The unreacted acrylonitrile was then removed by distillation at atmospheric pressure. The remaining material was then distilled at ~1 mm pressure. A first fraction was collected from 150° C. to 160° C. Fraction one had a strong odor of thiol. A second and final fraction was collected at 160° C. The second fraction had a faint odor of thiol. An NMR spectrum indicated the second fraction to be the desired product 83.5% of theoretical (94.9 g) based upon the weight of 1-decanethiol employed.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22]>C(Cl)Cl>[Si:8]([O:7][CH2:6][C@H:2]1[CH2:3][CH2:4][O:5][C:21](=[O:22])[NH:1]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](N)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCOC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R)-3-amino-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-ol (2.63 g, 12 mmol) in DCM (100 mL) at 0° C. was added pyridine (3 mL) followed by phosgene (20% solution in toluene, 1.9 M, 8.5 mL) dropwise and the mixture was stirred for 30 min and allowed to warm to rt, and quenched with water. The layers were separated and the water layer extracted with DCM once. The organic layers were dried over MgSO4, filtered and concentrated. The desired product (4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazinan-2-one was obtained from crystallization from ether/hexanes at −20° C. as a light yellow solid. 1H NMR (400 MHz, CDCl3) 5.52 (br s, 1H), 4.38-4.33 (m, 1H), 4.28-4.22 (m, 1H), 3.70-3.59 (m, 2H), 3.46 (t, 1H), 1.97-1.93 (m, 1H), 1.72-1.67 (m, 1H), 0.91 (s, 9H), 0.90 (s, 6H).