Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a stirred solution of methyl 5-hydroxynicotinate (8.5 g, 55.6 mmol) and K2CO3 (11.5 g, 83.3 mmol) in DMF (20 mL) at 0° C. was added (bromomethyl)benzene (8 mL, 66.7 mmol) drop wise over 5 min. The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (100 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4. After filtration and evaporation of the solvent, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1) to give methyl 5-(benzyloxy)nicotinate (4 g, 30.7%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][C:10]3[N:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[N:19]1[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ncccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Sc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5 mmol of 5,6-dihydro-5-(4-aminobenzoyl)pyrido[2,3-b][1,4]benzothiazepine, 5.5 mmol of 2-methylbenzoyl chloride and 10 mmol of triethylamine in 15 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H2O, 1M citric acid, NaHCO3, brine and dried (Na2SO4). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C(=O)(O)[O-].[Na+].[Br:27][CH2:28][C:29](Cl)=[O:30]>C1C=CC=CC=1>[Br:27][CH2:28][C:29]([O:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[CH:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3)=[O:30]
Reactant: O=C(Cl)CBr
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC(=O)CBr

Procedure:
To a solution of 2.884 g (0.01 mol) of testosterone in 30 ml of dry benzene was added 1.008 g (0.012 mol) of sodium bicarbonate; then, while stirring, there were introduced dropwise 1.888 g (0.012 mol) of bromoacetyl chloride over a 5 minute period. The reaction mixture was then stirred under reflux for 6 hours until no testosterone could be traced by TLC. (Plates of Silica Gel G and a CHCH3 /CH3OH system were used.) The inorganic residue was filtered while hot, the filtrate was evaporated in vacuo and the residue was recrystallized from methanol, m.p. 144°-145° C., yield 3.2 g (78%). IR (KBr) 1735 (C=O), 1660 (C=O) cm-1. PMR as expected. The product has the formula: ##STR1590##
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:29]=[C:25]([C:26]([NH2:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(C)C>[CH2:10]([N:17]([CH2:9][C@H:7]([OH:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:26](=[O:27])[NH2:28])[CH:29]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: NC(=O)c1cc(OCCN(Cc2ccccc2)C[C@H](O)c2ccccc2)ccc1O

Procedure:
A solution of 7.2 g of (R)-2-phenyl-oxirane and 14.3 g of 5-(2-benzylamino-ethoxy)-salicylamide in 100 ml of isopropanol is refluxed for 22-24 hours. The solution is concentrated by evaporation to yield (R)-α-[N-benzyl-N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol, which is further processed in this form.
Reaction SMILES: [C:1]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([P:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)P(Cc1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
Di-t-butylchlorophosphine (75.0 g (0.415 mole)) and 0.5 mole of 12M solution of benzylmagnesium chloride in THF (200 ml) were refluxed under argon for 2 days. The reaction mixture was allowed to cool off to RT and an aqueous solution of ammonium chloride was added slowly. The organic phase was separated, and dried with magnesium sulfate. After removal of the solvent, the product was purified by distillation in vacuum. The yield of benzyldi-t-butylphosphine was 94.3 g (96%) with b.p. 56-59° C./0.1 mm. 31-P-NMR (CDCl3)+36.63 ppm. 1H NMR (CDCl3) 1.18 (s, 9H, Me3C), 1.20 (s, 9H, Me3C), 2.90 (d, 2JPH=2.92 Hz, P—CH2-Ph), 7.1-7.6 (m, 5H, aromatic protons).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: O=C1NCC(CCCl)O1
Reactant: Fc1ccccc1N1CCNCC1
Product: O=C1NCC(CCN2CCN(c3ccccc3F)CC2)O1

Procedure:
Following the procedure of Example 35, the title compound was prepared from 5-(2-chloroethyl)-2-oxazolidinone and 1-(2-fluorophenyl)piperazine, mp 121°-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=2[N:12]=[C:11]1[C:29]([F:32])([F:31])[F:30].[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[N:12]=[C:11]1[C:29]([F:30])([F:32])[F:31]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 4.57 %

Procedure:
A mixture of methyl 1-[(2,3-dichlorophenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate prepared as described in Example 51 (1.95 g, 3.99 mmol) and 2 M lithium hydroxide (0.096 g, 3.99 mmol) in Tetrahydrofuran (THF) was stirred at 50° C. for 3 h. The reaction was cooled to room temperature, the organic solvent was removed under reduced pressure and the aqueous residue was acidified (pH 4) by the addition of 1N HCl. A gummy precipitate formed. After standing at rt overnight, it turned into a solid. The precipitate was collected, washed with water and dried to give crude desired product (1.83 g, 3.86 mmol, 97% yield) as a gray solid. A portion of this material (148 mg) was purified by reverse phase-HPLC (15-95% AcCN in water plus 0.1% TFA). The fractions containing product were combined and the volume was reduced to about ⅓ of the original. The precipitate formed was collected, washed with water and dried in a vacuum oven to give desired product (88.3 mg, 0.182 mmol, 4.57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.64 (d, J=2.53 Hz, 1H), 7.61 (dd, J=8.08, 1.26 Hz, 1H), 7.44 (d, J=2.27 Hz, 1H), 7.24 (t, J=8.08 Hz, 1H), 6.26 (dd, J=7.83, 1.26 Hz, 1H), 5.77 (s, 2H), 3.66-3.81 (m, 4H), 3.12-3.25 (m, 4H). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=3[C:15]=2[CH3:16])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[ClH:23]>[Pd].C(O)(=O)C>[ClH:23].[N:1]1([CH:6]2[CH:15]([CH3:16])[C:14]3[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1=C(n2ccnc2)CCc2ccc(C(=O)O)cc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC1c2cc(C(=O)O)ccc2CCC1n1ccnc1
Reaction time: 8 h

Procedure:
A mixture of 5,6-dihydro-7(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxylic acid (1.5 g), 10% palladium on activated carbon (0.65 g), ethanol 95% (100 ml), glacial acetic acid (30 ml) and concentrated hydrochloric acid (10 ml) is hydrogenated for 8 hours at room temperature in a Parr-Burgess low pressure apparatus at an initial pressure of 50 psi. At the end of this time the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off, washed with 95% ethanol, and the solution is evaporated under reduced pressure. The solid residue is crystallized from 95% ethanol-ethyl ether mixture, giving 1.4 g of 5,6,7,8-tetrahydro-7-(1H-imidazol-1-yl)-8-methyl-2-naphthalenecarboxylic acid hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=C)=[C:6]([Cl:8])[CH:7]=1.[O:22]1CCOCC1.O.[O-]I(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([C:11]2[C:15]([Cl:16])=[C:14]([O:17][CH:18]([F:20])[F:19])[N:13]([CH3:21])[N:12]=2)=[N:4][C:5]([CH:9]=[O:22])=[C:6]([Cl:8])[CH:7]=1
Reactant: C1COCCO1
Reactant: C=Cc1nc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(-c2nc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 8 h

Procedure:
13.2 g of 3-(3-fluoro-5-chloro-6-vinyl-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1 H]-pyrazole (Example H35) are initially introduced into a mixture of 120 ml of dioxane and 40 ml of water. 16.7 g of sodium (meta)periodate (NalO4) and a spatula-tip of osmium tetroxide are added, while stirring, and the mixture is subsequently stirred overnight at 22° C. The following day, the resulting mixture is taken up in ethyl acetate and washed first with dilute hydrochloric acid and then with brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated in vacuo. After purification over a silica gel flash column (eluting agent: n-hexane/ethyl acetate 2/1), 9.4 g of the desired title compound are obtained as a white solid of melting point 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[F:9][C:10]([F:22])([F:21])[C:11]([NH:13][C@@H:14]1[C:19](=[O:20])[O:18][C:16](=[O:17])[CH2:15]1)=[O:12].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[F:9][C:10]([F:21])([F:22])[C:11]([NH:13][C@@H:14]([CH2:15][C:16](=[O:17])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([F:8])[CH:4]=1)[C:19]([OH:20])=[O:18])=[O:12]
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: Fc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
To an ice-cooled solution of 1,2-difluorobenzene (25 ml; 0.256 mol) in dry dichloromethane (170 ml), (S)-N-trifluoroacetylaspartic anhydride (12 g.; 0.054 mol) was added in one portion. To the resulting solution, anhydrous aluminium trichloride (21.5 g; 0.16 mol.) was slowly added portionwise, under vigorous stirring and dry nitrogen atmosphere, maintaining the temperature below 10° C. The so obtained deep-yellow suspension was stirred at room temperature for 3 hrs. and then at 50° C. for 5 hrs. The resulting reaction mixture was then poured into ice (400 g), and extracted with dichlorometane (3×100 ml), the collected organic extracts were washed with brine (2×50 ml ), dried (Na2SO4), and evaporated in vacuum to afford the crude product (7.3 g) as an oily material. Recrystallisation from hexane/ethyl ether afforded the pure titled compound as colourless prisms (8 g; 47%), m.p. 136°-137° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:28]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: N#Cc1ccc(O)cc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Oc3ccc(C#N)cc3)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-Hydroxy-benzonitrile and (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 372(MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1COCC1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part D) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4×25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96% yield) by flash chromatography on silica gel eluting with EtOAc(100-95%)/Et3N(0-5%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][CH:3]=1>N.CO.O.[Ni]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][NH2:12])[NH:4][CH:3]=1
Reactant: N#Cc1cccc2[nH]cc(Cl)c12
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NCc1cccc2[nH]cc(Cl)c12
Yield: 98.2 %

Procedure:
To a solution of 3-chloro-1H-indole-4-carbonitrile (630.0 mg, 3.57 mmol) in ammonia in MeOH (2M, 45 mL) was added Raney Ni (3.05 g) in water (2 mL). The reaction mixture was then hydrogenated under H2 balloon at 1 atm for 20 h. The reaction mixture was filtered through a pad of Celite®, and the pad was washed alternatively with MeOH (10 mL×3) and water (10 mL×3). Volatile solvents were removed from the filtrate. The remaining crude was extracted with EtOAc (3×75 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization from ether/heptane afforded (3-chloro-1H-indol-4-yl)methanamine (133) as a white solid (633 mg, 98.2%). 1H NMR (400 MHz, DMSO) δ 11.33 (br s, 1H), 7.44 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.11-7.01 (m, 2H), 4.18 (s, 2H), 1.73 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:23][C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH2:14][CH3:15])[C:10]([N:27]1[CH2:28][C@H:24]([OH:23])[CH2:25][C@H:26]1[C:29]([O:31][CH3:32])=[O:30])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.5 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid (all material from step 1, 1.00 g, 3.32 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate-HCl salt (0.663 g, 3.65 mmol), HATU (1.26 g, 3.32 mmol) and CH2Cl2 (30 mL). To the mixture was added N,N-diisopropylethylamine (1.75 mL, 9.95 mmol). The mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel and was thrice washed with aq. HCl (1M); then brine. The organic solution was dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil (1.53 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]2[C:32](=[O:33])[O:31]C(C)(C)[O:29][C:28]2=[O:36])=[O:22])=[CH:16][CH:15]=1.O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:23][CH2:24][CH2:25][CH2:26][CH:27]([C:32]([OH:33])=[O:31])[C:28]([OH:36])=[O:29])=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCCC3C(=O)OC(C)(C)OC3=O)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCCC(C(=O)O)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propyl)urea (100 mg, 0.19 mmol, 1.00 equiv) in 2,2,2-trifluoroacetic acid (10 mL), and water (2 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with methanol:water (60%). The residue was lyophilized. This resulted in 36.3 mg (30%) of a TFA salt of the title compound as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.55 (s, 1H), 7.64 (s, 1H), 7.39-7.42 (d, J=8.7 Hz, 2H), 7.09-7.12 (d, J=8.4 Hz, 2H), 6.79 (s, 1H), 6.23-6.27 (m, 1H), 4.33-4.50 (m, 3H), 3.62 (s, 1H), 3.19 (m, 1H), 3.08-3.10 (d, J=5.7 Hz, 2H), 2.94 (s, 3H), 1.70-1.77 (d, J=23.1 Hz, 2H), 1.41-1.46 (d, J=12 Hz, 2H). MS (ES, m/z): 494 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]1[O:12][C:11]([SiH:13]([CH3:15])[CH3:14])=[CH:10][C@@H:9]([OH:16])[C@@H:8]1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OC=C)(=[O:20])[CH3:19]>>[C:18]([O:16][C@H:9]1[C@H:8]([OH:17])[C@@H:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[O:12][C:11]([SiH:13]([CH3:14])[CH3:15])=[CH:10]1)(=[O:20])[CH3:19]
Reactant: C[SiH](C)C1=C[C@@H](O)[C@H](O)[C@@H](COC(C)(C)C)O1
Reactant: C=COC(C)=O
Product: CC(=O)O[C@@H]1C=C([SiH](C)C)O[C@H](COC(C)(C)C)[C@H]1O
Reaction time: 3.5 h
Yield: 85 %

Procedure:
1.0 g (4 mmol) of 6-O-tert.butyldimethylsilyl-glucal in 5-10 ml of vinyl acetate is stirred with 1.0 g of lipase from Pseudomonas spec. at room temperature for 3-4 hours. Filtration, concentration and chromatography (SiO2, ether/hexane 1:3) yields the desired 3-O-acetyl-6-O-tert.-butyldimethylsilyl-glucal in approximately 85% yield (0.98-1.0 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][C:13](O)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][C:13]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:14]
Reactant: Nc1ccccn1
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(CC(c1ccccc1)N1Cc2ccccc2C1=O)Nc1ccccn1

Procedure:
3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid (0.42 mmol, 1 eq), 2-amino pyridine (1.5 eq), HBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat], (1.5 eq) and N-ethyl diisopropylamine (1.5 eq) are suspended in chloroform and reacted in the microwave (90 min, 120° C., Emrys Optimizer). The resulting mixture is partitioned between chloroform and water. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. The crude product is dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide (“A1”) is obtained as brown solid (36% yield); ES-MS (MH+)=358.2; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 10.72 (s, 1H), 8.29 (d, 1H, 4.8 Hz), 7.97 (d, 1H, 8.3 Hz), 7.73-7.27 (m, 10H), 7.08-7.05 (m, 1H), 5.95-5.92 (m, 1H), 4.62 (d, 1H, 17.5 Hz), 4.18 (d, 1H, 17.5 Hz), 3.39-3.32 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A round-bottom flask was charged with 2,3-dinitrophenol (11.04 g, 60 mmol, commercially available from Fluka-Sigma-Aldrich), tert-butyl bromoacetate (14.05 g, 66 mmol), acetonitrile (120 mL) and cesium carbonate (21.6 g). The mixture was stirred at room temperature overnight. The mixture was filtered, and the recovered solid was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and combined organic solvent was washed with saturated brine, dried and concentrated under reduced pressure. The residue was triturated with ether to give ethyl 2-(2,3-dinitrophenoxy)acetate (13.0 g, 70% yield). 1H-NMR (DMSO-d6) δ 7.84 (d, 2H), 7.42 (s, 1H), 4.90 (s, 2H), 1.40 (S, 9H).