Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([OH:18])=O)[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH:20]1([N:23]2[CH:27]=[N:26][N:25]=[C:24]2[C:28]2[S:29][CH:30]=[C:31]([NH2:33])[N:32]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([NH:33][C:31]4[N:32]=[C:28]([C:24]5[N:23]([CH:20]6[CH2:22][CH2:21]6)[CH:27]=[N:26][N:25]=5)[S:29][CH:30]=4)=[O:18])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Nc1csc(-c2nncn2C2CC2)n1
Reactant: O=C(O)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1csc(-c2nncn2C2CC2)n1)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Reaction time: 2 h

Procedure:
To a mixture of intermediate C.HCl (340 mg, 1.2 mmol), intermediate A (261 mg, 1.26 mmol), HATU (638 mg, 1.68 mmol), and N-methyl morpholine (330 μL, 3.00 mmol) was added DMF (5 mL) and the reaction was stirred for 2 hours. The mixture was concentrated, redissolved in a minimal amount of CH3CN, and water was added dropwise until a thick slurry was formed. The solids were isolated by filtration and washed with CH3CN to afford 320 mg (61% y). M+1=437.2
Reaction SMILES: FCC[N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40][CH2:41][CH2:42][CH2:43]N=[N+]=[N-]>>[F:39][CH2:40][CH2:41][CH2:42][CH2:43][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: [N-]=[N+]=NCCCCF
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Product: O=C1C(=O)N(Cc2cn(CCCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that 4-fluorobutylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C=O.[CH:18](O)=O>CO>[CH3:8][C@H:6]1[N:7]([CH3:18])[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: O=CO
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: C=O
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C
Temperature: 70 °C
Yield: 73.2 %

Procedure:
(3R,5S)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate (1.50 g, 7.00 mmol) was dissolved in 70 mL of methanol. To this was added 37% aqueous formaldehyde (1.17 mL, 14.0 mmol) and formic acid (1.14 mL, 24.5 mmol). The reaction mixture was heated to 70° C. for 24 hours, then concentrated under reduced pressure. The resulting oil was taken up in EtOAc, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated to give 1.17 g (73%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:3]=1.[C:20]([C:24]1[CH:29]=[C:28](C)[CH:27]=[C:26](C(C)(C)C)[C:25]=1O)(C)(C)[CH3:21].C([Sn](CCCC)(CCCC)C#CC1C=CC=CC=1)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=[C:4]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=1
Reactant: Cc1cc(Br)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C#Cc2ccccc2)nc(Oc2cc(C(F)(F)F)nn2C)c1
Yield: 43 %

Procedure:
To a solution of 2-bromo-4-methyl-6-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)pyridine (3.0 g, 7.1 mmol), tetrakistriphenyl-phosphine palladium (0.2 g, 1.8 mmol) and 2,6-di-tert-butyl-4-methylphenol (3 crystals) in toluene (40 ml) under a nitrogen atmosphere is added dropwise tributyl-phenylethynyl-stannane (2.9 ml, 7.8 mmol) and the resulting mixture is heated at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and dried. 43% of the product (1.1 g, mp. 56° C.) is obtained by flash chromatography.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1.B1([O-])O[O:30]1.O.O.O.O.[Na+]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:30])=[CH:13][CH:14]=2)[C:9]([C:25]([F:28])([F:27])[F:26])=[N:8]1
Reactant: CC1(C)OB(c2ccc3c(c2)c(C(F)(F)F)nn3C2CCCCO2)OC1(C)C
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)c(C(F)(F)F)nn2C1CCCCO1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-indazole (415 mg, 1.047 mmol) in THF (4 mL) and water (4.00 mL) was added sodium perborate tetrahydrate (483 mg, 3.14 mmol). The reaction mixture was heated at 50° C. for 2 h. The organic solvents were evaporated, extracted with EtOAc and washed with water and brine solution, then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography on silica gel using 50% EtOAc/Petroleum Ether to give 1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-ol (255 mg, 85%). 1HNMR 400 MHz, CDCl3: 6 ppm 1.68-1.75 (m, 4H), 2.05-2.17 (m, 2H), 2.46-2.52 (m, 1H), 3.71-3.77 (m, 1H), 3.98-4.01 (m, 1H), 4.89 (s, 1H), 5.74 (dd, J=2.40, 9.00 Hz, 1H), 7.08 (dd, J=2.40, 9.00 Hz, 1H), 7.13 (d, J=0.80 Hz, 1H), 7.59 (d, J=0.40 Hz, 1H).
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].N#N.C1OC1CO.Cl>CS(C)=O.OCC(CO)O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: N#N
Agent: OCC1CO1
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Reaction time: 1.5 h

Procedure:
4.35 g of p-hydroxy cinnamic acid was dissolved in 5 ml of DMSO, and 50 mg of potassium hydroxide was added. The mixture was stirred and heated to 90° C. under flow of N2 gas. 10.0 g of glycidol was added gradually, heating and agitation was carried out for 1.5 hours, neutralized by adding hydrochloric acid and the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([P:15](=[O:44])([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42]C)[N:31]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28]C)[N:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.[NH+]1C=CC=CC=1.[OH-].[K+]>O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([P:15](=[O:44])([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[OH:42])[N:31]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[N:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1cccc(P(=O)(c2cccc(-c3ccccc3OC)n2)c2cccc(-c3ccccc3OC)n2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=P(c1cccc(-c2ccccc2O)n1)(c1cccc(-c2ccccc2O)n1)c1cccc(-c2ccccc2O)n1
Temperature: 130 °C
Reaction time: 12 h

Procedure:
A mixture of 30.0 g (50 mmol) of tris(6-(2-methoxyphenyl)-2-pyridyl)phosphine oxide and 104.0 g (900 mmol) of pyridinium hydrochloride was stirred at 130° C. for 12 h. After the melt had been cooled to 80° C., it was admixed with 300 ml of water and then with a solution of 44.9 g (800 mmol) of potassium hydroxide in 100 ml of water. The aqueous phase was extracted three times with 500 ml of dichloromethane. The combined organic phases were washed three times with 500 ml of water. After the organic phase had been dried over magnesium sulfate and the dichloromethane had been removed, the oily residue was taken up in 100 ml of methyl tert-butyl ether and admixed with 100 ml of n-heptane. After standing for 12 h, the colorless crystals were filtered off with suction and recrystallized from methyl tert-butyl ether/n-heptane. The yield was 10.9 g (39.1%) at a purity of greater than 99.0% by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[H-].[Na+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18].[OH-].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])[CH:7]=[C:8]([O:10][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(=S)N(C)C)cc(OC(=S)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a stirred solution of 3,5-dihydroxybenzoic acid methyl ester (10.0 g, 59.5 mmol) in DMF (200 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 5.00 g, 125 mmol, 2.1 eq.) in small portions. The reaction mixture was stirred at 0° C. for 15 min then warmed to room temperature. After 1 h, the reaction mixture was cooled to 0° C. and then added dimethylthiocarbamoyl chloride (14.7 g, 119 mmol). Following the addition, the reaction was stirred for 45 min at 0° C., then for 30 min at room temperature and then heated to 80° C. After 2 h at 80° C., the reaction mixture was cooled to room temperature and then added to 1% aqueous KOH (500 mL). The resulting mixture was extracted with ethyl ether (2×500 mL). The organic layer was washed with H2O (500 mL), brine (300 mL), dried over MgSO4 and concentrated in vacuo to afford 3,5-bis-dimethylthiocarbamoyloxybenzoic acid methyl ester (13.0 g). This material was used without further purification.
Reaction SMILES: S[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C([O-])([O-])=[O:14].[K+].[K+]>CN(C=O)C>[O:10]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:14])[OH:8])[OH:6])[OH:4]
Reactant: OC[C@H]1O[C@@H](S)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
0.2 g of Polymer 4 was dissolved in 8 ml of DMF in 25 mL single-neck round bottom flask. 0.2 g of 1-thio-β-D-glucose was added, following by 0.5 g of anhydrous K2CO3. The reaction mixture was stirred at room temperature for 30 hrs, and then transferred into a dialysis tube for dialysis against water for 2 days (10 water changes). The solution obtained in dialysis tube was then transferred into a single-neck round bottom flask. After removal of water, glucose-functionalized Polymer 4 was obtained as a black solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:10]([O:24]CC1C=CC=CC=1)[C@H:11]1[CH2:16][O:15][C@@H:14]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:13]([CH3:23])[NH:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@@H:10]([C@H:11]1[CH2:16][O:15][C@@H:14]([O:17][CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C@H:13]([CH3:23])[NH:12]1)[OH:24]
Reactant: C[C@@H]1N[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Yield: 98.4 %

Procedure:
Add 20% palladium hydroxide on carbon (679 mg) to a solution of dibenzyl-{(1S,2R)-2-benzyloxy-1-(3,5-difluorobenzyl)-2-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-ethyl}-amine (284 mg, 0.442 mmol) in absolute ethanol (5 mL) and stir under 1 atmosphere of hydrogen gas at room temperature for 18 hours. Filter through a pad of Celite®, wash thoroughly with ethanol and concentrate to give the desired compound as a glass (162 mg, 98%).
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.[ClH:19]>O>[ClH:19].[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Agent: Cl
Solvent: O
Product: Nc1nccc2c(C(=O)O)cccc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
1-(t-Butylamino)isoquinoline-5-carboxylic acid (35 mg, 0.28 mmol) obtained in Step (6) above was stirred in a solvent of distilled water (0.4 mL). The reaction solution was added with concentrated HCl (0.15 mL), followed by stirring for about 3 hours at 90° C. The reaction mixture was cooled to room temperature, and the solvent was distilled under reduced pressure. The concentrate was added with toluene, followed by distillation under reduced pressure for 2˜3 times to obtain the title compound (30 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cnc(-c3ccc(OC(F)(F)F)cc3)nc2)cc1
Yield: 44.2 %

Procedure:
4-(2-Chloropyrimidin-5-yl)-benzaldehyde (0.92 mmol), 4-trifluoromethoxyphenyl boronic acid (1.10 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.01 mmol), 2 M potassium carbonate (0.92 mL) and dioxane (5 mL) were combined in a vial and irradiated by microwave for 10 min at 150° C. The organic layer from the reaction mixture was loaded directly onto silica and dried in vacuo. Purification by silica gel chromatography (EtOAc/hexanes) yielded the product (140 mg) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.07 (s, 2H), 8.57 (d, J=9.0 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[C:22]([F:28])[CH:21]=1.Cl>CN(C)C=O.ClC1C=CC=CC=1.O>[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7](=[O:12])[C:8]2=[O:11])=[C:22]([F:28])[CH:21]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(Br)cc2F)c2c(Cl)cccc21
Temperature: 25 °C

Procedure:
A suspension of 7-chloroindoline-2,3-dione (15g.) and potassium carbonate (15 g.) in N,N-dimethylformamide (100 ml.) was stirred and treated with a solution of 4-bromo-2-fluorobenzyl bromide (24.7 g.) in chlorobenzene (100 ml.). The mixture was stirred at 90° C. for five hours, cooled to ambient temperature, and diluted with a mixture of water (500 ml.) and petrol ether (b.p 60°-80° C.) (500 ml). The aqueous phase was adjusted to pH3 with 10 M hydrochloric acid. The mixture obtained was separated by filtration. The solid obtained was washed with further petrol ether, then with water, and recrystallised from ethanol to give 1-(4-bromo-2-fluorobenzyl)-7- chloro-indoline-2,3-dione (15.5 g.), m.p. 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:40][CH2:39][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:23][CH2:22]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:19]([CH2:20][N:21]2[CH2:22][CH2:23][C:24]3([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]4[N:33]=[C:34]([CH2:37][CH3:38])[S:35][CH:36]=4)=[O:31])[CH2:25]3)[CH2:39][CH2:40]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4Cl)CC3)C2)cs1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4Cl)CC3)C2)cs1
Reaction time: 18 h
Yield: 200 %

Procedure:
A solution of tert-butyl 3-(2-chloro-3-((4-(2-ethylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate (limiting reagent) (step d) in DCM (2.8 volumes) was cooled to 5° C. Trifluoroacetic acid (10 molar equivalents) was added over 20 min (exotherm to 15° C.). The reaction mixture was warmed to ambient and stirred for 18 hr. Toluene (3 volumes) was added and the mixture was evaporated. The resulting gum was triturated with toluene (2×1.5 volumes) and evaporated to give a brown gum. Yield: 200% of theoretical. (carried through crude—NMR assay shows ˜45% by weight purity with remaining weight due to TFA trapped in the gum)
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4].C[N:14](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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>[C:3]([C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[N:14])=[CH:10][CH:11]=1)([CH3:1])[CH3:5])#[N:4]
Reactant: Cc1ccc(C(C)(C)C#N)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
2-methyl-2-(4-methylphenyl)propanenitrile (3.51 g, 15.7 mmol) is dissolved in dry DMF (10 mL). Zn(CN)2 (2.02 g, 17.2 mmol) and Pd(PPh3)4 (906 mg, 5 mol %) are added and the mixture heated at 100° C. for 3 hours. The reaction mixture is diluted with water and the solid recovered by filtration. The solid residue is dissolved in methanol, filtered to remove insoluble impurities, concentrated under vacuo and purified by normal phase MPLC (SiO2, hexane to EtOAc), giving 4-(1-cyano-1-methylethyl)benzonitrile (2.28 g, 13.4 mmol, 85%) as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.70 (s, 6H) 7.73 (dt, J=8.64, 2.03 Hz, 2H) 7.92 (dt, J=8.69, 2.00 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][S:27][S:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
2-Bromoacetonitrile (0.473 ml, 6.78 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.444 ml, 2.49 mmol) were added to a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2k-A) (700 mg, 2.26 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30) to afford (R)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-A) (748 mg, 95%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:11])[CH3:10].Cl>N1C=CC=CC=1>[CH3:1][C:2]([CH3:8])([CH2:6][O:7][C:9](=[O:11])[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 632.7 %

Procedure:
2,2-dimethyl-3-hydroxypropionic acid (11.8 g, 100 mmol) was dissolved in pyridine (30 mL), and the reaction solution was cooled to 0° C. Acetyl chloride (11.8 g, 15.0 mmol) was slowly added dropwise, the temperature was then raised to room temperature, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, 1N HCl (30 mL) was added to adjust pH to 3-4, and then the reaction mixture was extracted with EtOAc. The organic extracts were washed with 1N HCl, 4-5 times, dried over MgSO4, and concentrated in vacuo, give the title compound (15.2 g, 95.0%)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](O/C(/C(OCC)=O)=C\C2C=CC=CC=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([CH2:47][C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:44]=[CH:45][CH:46]=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:54]/[C:48](/[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47]\[C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:40]([F:55])([F:56])[F:39])[CH:42]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(C(F)(F)F)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-(trifluoromethyl)phenyl)-2-oxopropanoate B10 (100 mg, 0.384 mmol), sodium hydride (10.14 mg, 0.544 mmol) and 2,3,4,6 tetra-O-acetyl-α-D-galactose bromide (158 mg, 0.384 mmol). The resulting compound was isolated in the form of white solid in 22% yield.