Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:61])[CH2:23][CH:22]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:35]3[C:40](=[O:41])[C:39]([CH2:42][C:43]4[CH:48]=[CH:47][C:46]([C:49]5[C:50]([C:55]#[N:56])=[CH:51][CH:52]=[CH:53][CH:54]=5)=[CH:45][CH:44]=4)=[C:38]([CH2:57][CH2:58][CH3:59])[N:37]=[C:36]3[CH3:60])[CH:20]=2)[O:15]1>C(OCC)(=O)C>[CH3:61][C:14]1([CH3:13])[CH2:23][CH:22]([O:24][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:33])[CH3:34])[CH:26]([CH3:27])[CH3:28])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N:35]3[C:40](=[O:41])[C:39]([CH2:42][C:43]4[CH:44]=[CH:45][C:46]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=5[C:55]5[NH:3][C:4](=[O:7])[O:5][N:56]=5)=[CH:47][CH:48]=4)=[C:38]([CH2:57][CH2:58][CH3:59])[N:37]=[C:36]3[CH3:60])[CH:20]=2)[O:15]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A mixture of hydroxylammonium chloride (4.2 g), sodium hydrogen carbonate (6.1 g) and dimethyl sulfoxide (40 mL) was stirred at 50° C. for 30 min, 4′-[(1-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (4.1 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.5 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (4.4 g, 100%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:63]([SH:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:63]([S:70][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: Cc1cc2[nH]ncc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2[nH]ncc2cc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-6-methyl-1H-indazole (4-1, 2 g, 9.48 mmol), XANTPHOS (0.548 g, 0.948 mmol), and Pd2(dba)3 (0.868 g, 0.948 mmol) were added to an oven-dried sealed tube followed by anhydrous Dioxane (31.6 ml), DIPEA (3.31 ml, 18.95 mmol) and BENZYL MERCAPTAN (1.177 ml, 9.95 mmol). Placed in 120° C. bath. After 2 h, UPLC showed >52% P1 at 1.25 min, 15% R1 at 1.07 min, 16% byproduct at 1.56 min and several minor peaks each less than 7%. After an additional 2 h, UPLC showed no change. Cooled to RT, filtered through Celite, washed with EtOAc, concentrated to give a clear, orange oil. Dissolved in 5 mL DCM, purified by normal-phase ISCO (80 g column, 0-50% EtOAc:Hex) to give 4-3 as a yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:1](=[O:4])[CH3:2])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)NCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Acetic acid (1.321 g, 22.000 mmol) was dissolved in DMF (10 ml), 1-(4-chlorophenyl)methanamine (2.804 g, 19.800 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (7.770 g, 24.200 mmol) and N-ethyl-N,N-diisopropylamine (5.971 g, 46.200 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by preparative HPLC (the initial mobile phase was isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product-containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation and gave 2.337 g of N-(4-chlorobenzyl)acetamide (yield 57.8%).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13].O.[NH2:22][NH2:23]>CCO>[NH2:2][C:1]1[NH:23][N:22]=[C:7]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([CH2:12][CH3:13])[CH:15]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: CCc1cccc(N)c1
Solvent: O
Solvent: CCO
Product: CCc1cccc(Nc2n[nH]c(N)c2C(N)=O)c1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 3-Ethylaniline (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((3-ethylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[C:39]([CH3:42])[CH:40]=O)=[CH:34][CH:33]=1)[CH3:30].O>O1CCCC1.CCCCCC>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[C:39](\[CH3:42])/[CH:40]=[CH:4]/[CH:3]=[O:2])=[CH:34][CH:33]=1)[CH3:30]
Reactant: CCOc1ccc(C=C(C)C=O)cc1
Reactant: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(/C=C(C)/C=C/C=O)cc1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 2-hydroxyethyltriphenylphosphonium bromide (30 g, 0.077 mol) in dried tetrahydrofuran (300 ml) cooled to −40° C. under an atmosphere of nitrogen was added a solution of n-butyllithium in hexane (2.5M, 58.5 ml) dropwise. The resulting orange suspension was then stirred at 50° C. with occasional ultrasonication for 3 h, cooled to −60° C. and a solution of 3-(4-ethoxyphenyl)-2-methylpropenaldehyde (7.4 g, 0.039 ml) in dried tetrahydrofuran (25 ml) added dropwise and allowed to warm to 0° C. After ½ h, water was added and the organic phase separated. The aqueous phase was extracted with diethyl ether and the combined organic phases washed four times with water and then brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to an oil. The oil was dissolved in a minimum of diethyl ether and chromatographed on flash silica eluting with hexane then hexane-diethyl ether (3:2) to give 5-(4-ethoxyphenyl)-4-methylpent-2E,4E-dienal as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].CO>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[NH:8][CH:7]=[C:6]([C:15](=[O:17])[CH3:16])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2n1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-7-azaindole (1 g, 6.55 mmol) was added to a suspension of AlCl3 (4.37 g, 32.8 mmol) in CH2Cl2 (150 mL) under nitrogen atmosphere. The mixture was stirred at RT for 30 min, and acetyl chloride (2.34 mL, 32.8 mmol) was added dropwise. The resulting mixture was further stirred at RT for 2 h. After completion, MeOH (40 mL) was added cautiously and volatils were removed under reduced pressure. The residue was diluted in CH2Cl2 and neutralized by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified twice by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 95-5). TLC, Rf (CH2Cl2/MeOH 9:1)=0.5; MS (UPLC/MS): 195.1/197.1 [M+H]+, 193.1/195.1 [M−H]−; tR (HPLC conditions f): 1.54 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.[Cl:24]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:24][C:11]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][C:10]=1[CH:22]=[O:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (331 mg) in N,N-dimethylformamide (33 mL) was added N-chlorosuccinimide (268 mg) and the mixture was stirred at 60° C. for 1 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 250 mg, 68%).
Reaction SMILES: C(C=N[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][CH2:28][OH:29])[CH:21]=2)[C:16]([F:30])=[CH:15][N:14]=1)(O)=O.[NH2:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35]>>[OH:36][CH:33]([CH2:34][OH:35])[CH2:32][NH:31][C:28]([CH:27]=[N:26][C:11]1[CH:6]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][CH2:28][OH:29])[CH:21]=3)[C:16]([F:30])=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1)=[O:29]
Reactant: NCC(O)CO
Reactant: O=C(O)C=Nc1ccccc1Nc1ncc(F)c(Nc2cccc(NCCO)c2)n1
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(NCCO)c3)n2)c1)NCC(O)CO

Procedure:
In like manner to the preparation of N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine, N2-(carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine and 1-amino-2,3-propanediol were reacted to give N2-[3-[N-(2,3-dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.86 min.; purity: 90.0%; MS (m/e): 486.40 (MH+).
Reaction SMILES: [Na].C(O)C=C.[S:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:7][CH2:8][C:9]([O:11]CC=C)=O.Cl>O.C(OCC)C>[OH:11][C:9]1[CH2:8][CH2:7][S:6][CH2:15][C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18]
Reactant: C=CCOC(=O)CCSCCC(=O)OCC=C
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: C=CCO
Product: C=CCOC(=O)C1=C(O)CCSC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.3 %

Procedure:
To a mixture of sodium sand (23 g; 1.0 mole) (Vogel's Textbook of Practical Organic Chemistry, Fourth Ed., Longman, London, 1978, p. 313) and anhydrous diethyl ether (3.4 1), allyl alcohol (65.8 ml) was slowly added. The obtained reaction mixture was stirred for two days at room temperature and then diallyl 3,3′-thiodipropionate (129.0 g; 0.5 mole) prepared according to the process disclosed in Example 1 was slowly added drop by drop. The mixture was stirred for another day at room temperature and then under ice cooling first absolute ethanol (10 ml) and then water (400 ml) and concentrated hydrochloric acid (455 ml) were added and it was stirred until the whole was dissolved. The phases were separated. The obtained organic phase was washed with water (400 ml), a 7% sodium hydrogencarbonate solution (3×400 ml) and once more with water (200 ml). The organic phase was dried with magnesium sulfate, the drying agent was filtered off, the filtrate was evaporated and dried. The title compound (42.4 g; 42%) was obtained as a crude product in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4].C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:48][N:47]=[N:46][N:41]=2)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g), trimethylsilylazide (0.66 mL), dibutyltinoxide (0.060 g) and toluene (3 mL) was stirred at 100° C. for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.75 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:10]([O:14][C:15]([NH:17][C@@:18]1([C:28]([OH:30])=[O:29])[CH2:23][C:22](=[O:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([OH:27])=[O:26])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:29][C:28]([C@:18]1([NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:23][C:22](=[O:24])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:26])=[O:30]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Add 2-fluorobenzyl bromide (0.21 mL, 1.7 mmol) dropwise to a stirred suspension of (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.17 g, 0.57 mmol) and cesium carbonate (0.37 g, 1.14 mmol) in dry N,N-dimethylformamide (1.42 mL). Stir the resulting mixture at room temperature overnight under nitrogen. Quench with water and dilute with ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times) and wash the organic layers with brine and water. Dry over sodium sulfate, filter and concentrate to give the crude material as a pale brown oil. Purify by flash chromatography eluting with ethyl acetate:hexane (20:80 to 30:70) to give the title compound as a pale yellow oil (229 mg, 79%). MS (m/z): 538 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][CH2:8][N:9]2[C@@H:18]([C:19]([NH:21][C@H:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[CH3:23])=[O:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:38].O1CCOCC1>CO.O1CCCC1>[ClH:38].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[C@@H:18]([C:19]([NH:21][C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH3:23])=[O:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H]1Cc2ccccc2CN1CCOc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Dissolve methyl 4-[(1S)-1-[[(3R)-2-(2-(4-fluorophenoxy)ethyl)-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]benzoate (550 mg, 1.15 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL). Add a 5 N aqueous solution of sodium hydroxide (0.462 mL, 2.31 mmol), then stir the mixture at room temperature overnight. Concentrate the mixture under reduced pressure to furnish a white solid. Add a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol), and stir the mixture at room temperature for 10 min Remove the suspended solids by filtration, rinsing the solids with THF (5 mL). Concentrate the combine filtrate under reduced pressure to furnish a white solid. Triturate the material in hot diethyl ether (10 mL), and filter to furnish the title compound as a white solid (535 mg, 93% yield). Mass spectrum (m/z): 463 ([M+H]+), 485 ([M+Na]+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1.[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([Br:15])[C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1
Reactant: Clc1ccccc1CC1=NOCCO1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1ccccc1C(Br)C1=NOCCO1
Yield: 87 %

Procedure:
4.0 g (19 mmole) of 3-(2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine (prepared as described in Preparation 1) were dissolved in 40 ml of carbon tetrachloride, and then 4.1 g (23 mmole) of N-bromosuccinimide and 0.2 g of benzoyl peroxide were added to the solution, which was then stirred, whilst heating, for 8 hours. At the end of this time, 100 ml of ethyl acetate and 100 ml of hexane were added to the solution, and the mixture was stirred at room temperature for 30 minutes; insolubles were then removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, to give 4.8 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:46](=[O:68])[C@@H:47]([NH:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=2)[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:48]([C@H:47]([N:55]([CH2:56][C:57]1[CH:58]=[CH:59][C:60]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[C:46]([N:43]1[CH2:42][CH2:41][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:45][CH2:44]1)=[O:68])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCCCOc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
In an inert atmosphere, trans-4-(trifluoromethyl)cinnamic acid (28 mg, 0.13 mmol) was dissolved in DCM (0.5 mL) followed by the addition of 1-chloro-N,N,2-trimethylpropenylamine (19.4 mg, 0.145 mmol). The mixture was stirred at rt for 30 min followed by the addition of DIPEA (34 mg, 0.26 mmol) and 1-(4-benzyl-piperazin-1-yl)-2-(4-butoxy-benzylamino)-(S)-3-phenyl-propan-1-one (63 mg, 0.13 mmol). Stirring was continued for 30 min. The mixture was concentrated in vacuo and the residue was directly purified by prep. HPLC to give 51 mg (57%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-butoxy-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=684.49.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CCCCC.C([Li])(C)(C)C.CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH:28]([C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])=[O:29]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Si](C)(C)CCOCOc1cnccc1C=O
Temperature: -70 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (39.3 g, 0.174 mol) in tetrahydrofuran (250 ml), a 1.47 mol/L t-butyllithium n-pentane solution (154 ml, 0.227 mol) was added dropwise at −70° C. over 40 minutes. After stirring at −70° C. for 1 hour, N,N-dimethylformamide (40 mL, 0.522 mol) was added over 30 minutes and stirred at −70° C. for 1.5 hours. After warming to −20° C., saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 4-formyl-3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (24.5 g, 58%) as a brown oil.