Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH2:14][C@H:13]([NH:22][C:23]([O:25]C(C)(C)C)=O)[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:33]([O:35][CH3:36])=[O:34])[CH2:14][C@H:13]([NH:22][C:23](=[O:25])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 201.3 %

Procedure:
A vigorously-stirred, 0° C. solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (600b) (461 mg, 1.07 mmol) in THF (5 ml) and sat. aq. NaHCO3 (2.5 ml) was treated with a THF solution (0.35 ml) of methyl chloroformate (151 mg, 1.6 mmol) and the reaction was stirred for 45 min at RT. The reaction was poured onto CH2Cl2 and washed with H2O, dried over Na2SO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0% to 10% MeOH/CH2Cl2) gave 525 mg of 602j as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[NH:21][CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1CN(Cc2ccccc2)CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1-Benzyl-3-methyl-piperidin-4-one (5.00 g, 24.6 mmol) was dissolved in CHCl3 (50 mL), the reaction mixture was cooled to 0° C. and conc H2SO4 (12 mL) was added dropwise. NaN3 (3.20 g, 49.2 mmol) was added portionwise over 10 min and the reaction mixture was stirred at room temperature for 18 h and at 50° C. for 2 h. Iced water (120 mL) was added and the reaction mixture was neutralized with NaOH, extracted with DCM (2×50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (4.86 g, 91%) as an off-white solid. LCMS (ES+): 219.3 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([N:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:22])=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2F)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(4-chloro-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1.33 g, 3.96 mmol) in dry MeCN (20 mL) was added K2CO3 (1.10 g, 7.92 mmol) and benzyl bromide (521 μL, 4.36 mmol). The reaction mixture was stirred overnight at 80° C. Addition of silica (ca. 2 g) was followed by filtration; the filtrate was concentrated in vacuo. The product was co-evaporated twice with toluene (30 mL), to result in 1.75 g (99%, 95% purity) of the desired product as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:11]2[CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[N:4]([CH3:18])[CH2:3]1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:15]2[CH2:16][CH2:17][CH:12]3[N:11]4[C:10]5[C:9]([CH:13]3[CH2:14]2)=[CH:8][CH:7]=[CH:6][C:5]=5[N:4]([CH3:18])[CH2:3][C:2]4([CH3:19])[CH3:1])=[CH:31][CH:30]=1
Reactant: CN1CC(C)(C)N2c3c(cccc31)C1CNCCC12
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CC(C)(C)N2c3c(cccc31)C1CN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 1,1,3-trimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (from Example 283) (82 mg, 0.32 mmol) in dioxane (10 mL) at rt was added 4-chloro-1-(4-fluorophenyl)butan-1-one (83 mg, 0.42 mmol), K2CO3 (100 mg), KI (30 mg) and stirred at 25° C. for 24 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford the title compound (58 mg, 43%). MS [M+H]+422. 1H NMR (CDCl3, 300 MHz): δ 8.01 (m, 2H) , 7.15 (t, 2H, J=7.7 Hz), 6.65 (t, 1H, J=7.7 Hz), 6.51 (d, 1H, J=7.0 Hz), 6.43 (d, 1H, J=7.0 Hz), 3.63 (m, 1H), 3.25 (d, 1H, J=11 Hz), 3.09 (m, 2H), 2.89 (s, 3H), 2.63 (m, 2H), 2.25 (m, 2H), 2.17 (m, 2H), 1.31 (s, 3H), 1.12 (s, 3H) ppm. This racemate was then separated into its corresponding enantiomers by HPLC utilizing a Chiralcel AD column with 50% Ethanol/Methanol solvent system.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1>[CH3:27][C:26]([NH:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])=[CH:2][CH:1]=1)=[O:28]
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NC(Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
600 mg of melphalan (63) is suspended in 25 ml of water containing 500 mg of sodium carbonate. 10 ml of dioxane is added and 1 ml of acetic anhydride. After stirring at ambient temperature for 1 h citric acid is added and the mixture extracted with ethyl acetate. After washing with water and brine the organic phase is dried (sodium sulfate) and concentrated in vacuum. Removal of all volatiles yields the crude N-acetylmelphalan that is carried on to the next step without further purification.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:7][C:8]1[C:13]([CH2:14]Br)=[CH:12][CH:11]=[CH:10][N:9]=1.O>CN(C)C=O>[Br:7][C:8]1[C:13]([CH2:14][O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: BrCc1cccnc1Br
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OCc1cccnc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of isopropyl alcohol (7.31 mL, 95.65 mmol) in dimethylformamide (50 mL) at 0° C. is added sodium hydride (3.63 g, 90.87 mmol) and the mixture is stirred at room temperature for 30 minutes (this reaction is run using a shield as special protection). Then, 2-bromo-3-bromomethyl-pyridine (6 g, 23.91 mmol) in 10 mL of dimethylformamide is added via syringe and the mixture is stirred at room temperature for 1 h. Water is added and the mixture is extracted with ethyl acetate, washed with brine and water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude material is purified by normal phase Isco chromatography using ethyl acetate and hexane as eluent (gradient of 5 to 25% of ethyl acetate) to yield 3.67 g of the title compound. MS (m/z): 230, 232 (M+1, M+3)
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl.C(OCC)(=O)C>[CH2:7]([C:6]1[CH:5]=[CH:4][C:2]([O:3][C:21](=[O:22])[CH2:20][Br:19])=[C:1]([O:11][CH3:12])[CH:10]=1)[CH:8]=[CH2:9]
Reactant: O=C(Br)CBr
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCc1ccc(OC(=O)CBr)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of eugenol (500 mg, 3.03 mmol) in dichloromethane (5 mL) were added K2CO3 (1.0 g, 7.57 mmol) followed by bromo acetyl bromide (931 mg, 4.54 mmol) at 0° C. The mixture was allowed to stir at room temperature (25° C.) over a period of 1 hr. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (2×200 mL) and dried over sodium sulphate. The crude product obtained up on evaporation of the solvent was further purified by silica gel column chromatography to obtain bromo-acetic acid 4-allyl-2-methoxy-phenylester as viscous oil (550 mg, 63%).
Reaction SMILES: COC(=O)C([N:8]1[C@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C@@H:10]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]1=[O:25])=C(C)C.O=[O+][O-].O=O.CSC>C(Cl)Cl>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C@@H:10]1[C@@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[NH:8][C:9]1=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1S(C)(=O)=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1C(=O)N[C@@H]1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25 g (61.7 mmol) of 2-[(3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10° with an ozone/oxygen mixture. The disappearance of the starting material is monitored by thin layer chromatography. When the reaction is complete, 30 ml of dimethyl sulphide are added and the whole is stirred for a further 3 hours at room temperature. The solution is concentrated and the residue is taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated for 40 minutes at 70°. The solvent is then removed and the residue is evaporated twice in the presence of toluene. The crystallising oil is taken up in methylene chloride and the crystals, consisting of (3S,4R)-3-hydroxymethyl-4-methylsulphonylazetidin-2-one, are isolated by filtration. The filtrate is concentrated and (3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonylazetidin-2-one is obtained in pure form by chromatography over silica gel with toluene/ethyl acetate (3:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 49.5 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (56 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-7.5% 2M NH3/MeOH in DCM) to afford 270 as a white solid (48 mg, 49%). LCMS (Method K): RT 3.07 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.80 (1H, br s), 8.65 (1H, s), 8.16-8.04 (2H, m), 7.98 (1H, s), 7.87-7.81 (1H, m), 7.79 (1H, d, J=8.01 Hz), 7.72 (1H, dd, J=8.82, 4.90 Hz), 7.56-7.49 (1H, m), 7.21-7.10 (2H, m), 6.05 (1H, s), 3.90 (2H, d, J=6.25 Hz), 3.20 (3H, s)
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15]>>[CH2:7]([N:6]1[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:17]([NH:16][C:14](=[O:15])[C:13]([F:24])([F:12])[F:25])[CH2:18][CH2:19]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: O=C(N[C@H]1CCCNCC1)C(F)(F)F
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Product: CCn1ncc([N+](=O)[O-])c1N1CCC[C@H](NC(=O)C(F)(F)F)CC1
Yield: 44 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-ethyl-4-nitro-1H-pyrazole and (S)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.12 g, 44%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.42-6.40 (m, 1H), 4.22-4.18 (m, 1H), 4.12 (q, J=7 Hz, 2H), 3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.47 (t, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([F:16])[CH:9]=2)[S:4][C:3]=1[CH:17]1[O:21]CCO1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[O:29]C>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:16])[CH:9]=3)[S:4][C:3]=2[CH:17]=[O:21])[CH:26]=[CH:27][C:28]=1[OH:29]
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1F
Reactant: COc1ccc(B(O)O)cc1Cl
Product: Cc1c(-c2ccc(O)c(F)c2)sc(C=O)c1-c1ccc(O)c(Cl)c1
Yield: 19.5 %

Procedure:
Starting from 2-[3-bromo-5-(3-fluoro-4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (0.89 g, 2.4 mmol, made in Example 8, Step 1) and substituting 3-chloro-4-methoxyphenylboronic acid (0.53 g, 2.8 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.17 g, 33%, m.p. 252-54° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31]CC7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH:42]1([CH2:45]Br)[CH2:44][CH2:43]1>>[CH:42]1([CH2:45][O:31][C:27]2[C:26]([O:39][CH3:40])=[C:25]3[C:30]([C:21]([N:17]4[CH2:16][C:15]5[CH:41]=[C:11]([C:8]6[CH:9]=[CH:10][C:4]7[N:3]=[C:2]([CH3:1])[NH:6][C:5]=7[CH:7]=6)[CH:12]=[CH:13][C:14]=5[O:20][CH2:19][CH2:18]4)=[N:22][CH:23]=[N:24]3)=[CH:29][CH:28]=2)[CH2:44][CH2:43]1
Reactant: BrCC1CC1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Product: COc1c(OCC2CC2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and cyclopropylmethyl bromide in step 2. 1H NMR (400 MHz, d6-DMSO): 8.66 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.81 (m, 3H), 7.63 (d, 1H), 7.50 (d, 1H), 7.04 (d, 1H), 5.44 (s, 2H), 4.63 (br s, 3H) 4.53 (br s, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 0.83 (m, 1H), 0.61 (m, 2H), 0.41 (m, 2H); MS (EI) for C30H29N5O3: 508 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:18][C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[CH:20]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)c1
Yield: 57.6 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (7-04) (24.0 g, 57.60%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) and 3-methyl-benzenesulfonyl chloride (6-04) (24.67 g, 129.87 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccnc3)CC12
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(3-pyridyl)acetic acid (0.685 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (10 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of ethyl acetate (100 cc) and water (75 cc). The organic phase is washed with saturated sodium chloride solution (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a basic alumina column (diameter 2 cm, height 15 cm), eluting with ethyl acetate and collecting 50 cc fractions. Fractions 4 to 24 are concentrated to dryness under reduced pressure (2.7 kPa). The crystals obtained are recrystallized from acetonitrile (cc) to give (3aRS,7aRS)-7,7-diphenyl-2-[2-(3-pyridyl)acetyl]-4-perhydroisoindolone (0.9 g) in the form of white crystals melting at 208° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:10]1.O>C(#N)C>[Br:1][C:10]1[S:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]=1[CH:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(OC(C)(C)C)c1csc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(Br)sc2ccccc12
Reaction time: 20 h
Yield: 44 %

Procedure:
N-bromosuccinimide (67 mg, 0.37 mmol) was added at room temperature to a stirred solution of methyl 2-(1-benzothiophen-3-yl)-2-(tert-butoxy)acetate (4b) (70 mg, 0.25 mmol) in acetonitrile (2 mL) under a nitrogen atmosphere. After 20 hours, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired product (4c) as a pale oil (40 mg, 0.11 mmol, 45%).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[N:22][CH:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][CH2:33][CH2:34]O>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[N:22][CH:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:2][CH:3]=1
Reactant: COCCO
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1cnn[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 60 °C

Procedure:
(2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (20 mg, 39 μmol, 1.0 eq.) was dissolved in 2-methoxyethanol (3 mL) followed by the addition of 4 M of HCl in dioxane (295.0 μL). The mixture was heated and maintained at 60° C. for 4 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (10 mg; purity 95%). MS m/z [M+H]+ calc'd for C24H28N4O5, 453.21. found 453.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[OH:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cnn(CCO)c2)c1
Temperature: 95 °C

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (193 mg, 0.600 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 95° C. 7 h. The RM was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 25 g, EtOAc). The purified intermediate was treated with 5 M HCl in MeOH (5 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from Et2O/EtOAc afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.92 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.78 (q, J=5.47 Hz, 2H) 4.19 (t, J=5.47 Hz, 2H) 4.96 (t, J=5.08 Hz, 1H) 7.40 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (s, 1H) 8.38 (s, 1H) 8.43 (d, J=1.17 Hz, 1H) 8.88 (s, 1H) 9.03 (s, 1H) 10.63 (s, 1H).