Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C(Cl)Cl.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:25])=[C:17]1[C:26]([NH:28][C@H:29]([C:33]([OH:35])=O)[CH:30]([CH3:32])[CH3:31])=[O:27].[NH2:36][CH:37]([CH:46]([OH:58])[CH2:47][O:48][CH2:49][C:50]1[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:57])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(OCC)(=O)C.CCCCCC>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:25])=[C:17]1[C:26]([NH:28][C@H:29]([C:33]([NH:36][CH:37]([CH:46]([OH:58])[CH2:47][O:48][CH2:49][C:50]1[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])=[O:35])[CH:30]([CH3:31])[CH3:32])=[O:27]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)COCc1c(Cl)cccc1Cl
Reactant: Cc1c(C(=O)N[C@H](C(=O)O)C(C)C)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
1-tlydroxybenzotriazole hydrate (153 mg, 1.0 mmol) and EDAC (268 mg, 1.4 mmol) were added to a methylene chloride solution of N-(1,3-dimethylindole-2-carbonyl)valine (288 mg, 1.0 mmol, in 3 mL of methylene chloride). The resultant mixture was stirred for 10 minutes under a nitrogen atmosphere at room temperature. A methylene chloride solution of 3-amino-5-(2′,6′-dichlorobenzyloxy)-4-hydroxypentanoic acid, t-butyl ester (364 mg, 1.0 mmol, in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was first stirred for one hour under a nitrogen atmosphere at 0° C., and then for 16 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give crude product (583 mg). The crude product was subjected to flash chromatography on silica gel with ethyl acetate/hexane (2/3) to give the title product as a white solid (260 mg). TLC (ethyl acetate/hexanes 1:1): Rf=0.38.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl.[O:34]1CCC[CH2:35]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:35](=[O:34])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:12]=[CH:11][O:10][N:9]=3)=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C1CCOC1
Reactant: Brc1ccc(-c2ccon2)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ccon3)cc2)cc1
Temperature: 120 °C

Procedure:
The product from Example 42C (56.1 mg, 0.250 mmol), triethylamine (55 μL, 0.39 mmol), 4-tert-butylaniline (52 μL, 0.33 mmol), and Pd(dppf)Cl2:CH2Cl2 (20.4 mg, 0.025 mmol) were combined in tetrahydrofuran (10 mL) and heated at 120° C. under a carbon monoxide atmosphere (700 psi) for 16 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3)δ 8.51 (d, 1H), 7.96 (s, 4H), 7.82 (br s, 1H), 7.57 (d, 2H), 7.41 (d, 2H), 6.73 (d, 1H), 1.33 (s, 9H); MS (m/z) 321.
Reaction SMILES: [OH-].[Na+].[ClH:3].[CH3:4][N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].Cl>O.CO>[ClH:3].[CH3:4][N:5]([CH3:13])[CH2:6]/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10]
Reactant: COC(=O)/C=C/CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C/C=C/C(=O)O
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A solution of sodium hydroxide (6.2 g, 0.155 mol, 4 equiv) in water (40 ml) was added to a stirred solution of (E)-methyl 4-(dimethylamino)but-2-enoate hydrochloride (7 g, 0.039 mol, 1.00 equiv) in methanol (150 ml). The reaction mixture was stirred for 4 hours. 6N hydrochloric acid was added to bring the pH to 2. The reaction mixture was concentrated under reduced pressure, and ethanol (50 ml) was added and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to thick oil. The oil was crystallized in isopropanol and acetone to give the product 3.6 g. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35](O)=[O:36])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([O:32][C:33](=[O:38])[CH2:34][C:35]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:36])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (1 g, 2.380 mmol), 3-tert-butoxy-3-oxopropanoic acid (0.457 g, 2.86 mmol), EDC (1.369 g, 7.14 mmol), and DMAP (0.291 g, 2.380 mmol) in DCM (50 ml) was stirred at RT overnight. The reaction mixture was washed with HCl 1N, NaHCO3 5% and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel column (DCM:EtOAc=40:60) affording (S)-4-(2-(3-tert-butoxy-3-oxopropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (1.1303 g, 2.010 mmol, 84% yield, MS/ESI+ 562.0 [MH]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:11][CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1O
Product: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1Cl
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-(3,4-dimethoxy-phenyl)-4-hydroxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (Stage 249.1.3, 493 mg, 1.391 mmol) in POCl3 was stirred at 125° C. for 1.5 h. Then the RM was evaporated to dryness. The residue was quenched with saturated aqueous NaHCO3. The suspension was filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: tR 3.80 min (Method A); M+H=373 MS-ES)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:10][OH:11].[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Into a solution wherein 12 g of (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol obtained in Example 40 was dissolved in 120 ml of ethyl acetate was added dropwise 10 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 6.92 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 400 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed trader reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 15.2 g of oily (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 22.5 minutes ((R)-form) and 24.7 minutes ((S)-form)). 1H-NMR (400 MHz, CDCl3) δ ppm: 7.71-7.68 (1H, m), 6.96-6.92 (1H, m), 6.85-6.81 (1H, m), 4.59-4.47 (4H, m), 3.04 (3H, s), 2.51-2.48 (1H, m), 1.06-1.04 (6H, m) Optical purity: 96.0% ee
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[C:5]([CH3:15])[N:4]3[C:16](=[O:31])[N:17]([CH2:19][C:20]4[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=4)[N:18]=[C:3]3[C:2]=2[C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 161.8 %

Procedure:
To a suspension of 8-bromo-7-(4-chlorophenyl)-5-methyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (53 mg, 0.103 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.414 mmol), and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) in toluene (2 mL) was added (Ph3P)4Pd (36 mg, 0.03 mmol), and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×3). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (30-70%) in hexanes to obtain 85 mg of the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 32 mg (62%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.00 min, [M+H]+=510.4.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:21][CH:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:24])[CH2:8][CH2:7]1)([OH:3])=[O:2].CO.[CH3:27]CN=C=NCCCN(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:2][C:1]([C@@H:4]1[CH2:21][CH:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[CH2:19]2)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:24])[CH2:8][CH2:7]1)=[O:3]
Reactant: C[C@]12CCC(=O)CC1C[C@@H](C(=O)O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7α-carboxyandrostane-3,17-dione (680 mg) in CH2Cl2 (30 mL) at 0° C., MeOH (160 μL), DMAP (20 mg) and EDAC (800 mg) were added. After stirring overnight at room temperature, H2O was added and the mixture was extracted with CH2Cl2 (2×). The combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/EtOAc 60/40) to give the title compound II-bc (500 mg, 70%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.63 (3H, s), 2.85 (1H, m), 2.50-0.75 (20H, m), 1.12 (3H, s), 0.86 (3H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8](O)[C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2.FC(F)(F)C(O)=O.C(OCC)(=O)C>O>[CH2:1]([O:4][C:5]([N:7]([C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][CH:17]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3]
Reactant: c1ccc2sccc2c1
Reactant: C=CCOC(=O)NC(O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(CC(=O)O)c1csc2ccccc12
Yield: 88 %

Procedure:
A solution of 5.15 g. (29.4 mM) of DL N-allyloxycarbonyl-α-hydroxyglycine and 3.95 g. (29.4 mM) of benzo[b]thiophene in 40 ml. of trifluoroacetic acid was stirred at 22.5° C. for eighteen hours. The reaction mixture was then concentrated by evaporation under reduced pressure to give an oil, and the oil was dissolved in a mixture of 100 ml. of ethyl acetate and 100 ml. of water. The organic layer was separated, and the aqueous layer was extracted twice more with 50 ml. portions of fresh ethyl acetate. The organic extracts were combined, washed with water, and then extracted twice with 100 ml. portions of 10% aqueous sodium bicarbonate. The aqueous extracts were combined, added to 100 ml. of fresh ethyl acetate, and acidified to pH 2.0 by the addition of conc. hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted with two 50 ml. portions of fresh ethyl acetate. The organic portions were combined, dried, and the solvent was removed by evaporation to provide 7.55 g. (88% yield) of N-allyloxycarbonyl-(3-benzothienyl)glycine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (CAS Reg. No. 170850-75-6) (1 g, 3.48 mmol) in 20 ml of CH2Cl2 was added pyridine (3.9 ml) and p-toluene sulphonyl chloride (0.7 g, 3.67 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 72 hours. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (100 ml) and washed with saturated citric acid solution (50 ml) then water (50 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate:heptane (3:10) to give the title compound (1.5 g, 98%) as a colourless gum.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]1=2>C(Cl)Cl>[Br:1][CH:13]1[CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]=2[C:4]1=[O:3]
Reactant: BrBr
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Bromine (0.8 mL, 15.7 mmol) was added to a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile (2.7 g, 15.7 mmol), prepared in the previous step, in dry methylene chloride (55 mL) at 0° C. The reaction was warmed to room temperature. After 2 h, the reaction was diluted with methylene chloride and washed with 5% sodium thiosulfate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4.3 g of crude product. Purification of the crude product on silica gel using 10% ethyl acetate:hexane as the eluent gave 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (3.2 g, 81%), MS(ES) m/z 251 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.[CH3:16][C:17]1(C)[O:22]C(=O)[CH2:20][C:19](=O)[O:18]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13](=[O:15])[CH2:16][C:17]([O:18][CH2:19][CH3:20])=[O:22]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (3.01 g, 14.67 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.23 g, 15.47 mmol) and 4-dimethylaminopyridine (2.73 g, 22.35 mmol) in dichloromethane (150 mL) was added a solution of DCC (3.36 g, 16.28 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at RT for 16 h. The insoluble materials were filtered off, and the filtrate was washed with 5% NaHSO4 aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was treated with EtOH (200 mL) and the resulting mixture was stirred at 70° C. for 4 h and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with EtOAc. The organic layers were washed with water and brine, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a colorless solid (3.43 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=6.8 Hz, 3H), 3.58 (s, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.67 (s, 2H), 7.73-7.78 (m, 2H), 7.86-7.91 (m, 2H).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[F:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:11][CH:10]([NH2:12])[CH2:9]1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:7][C:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=4)([C:24]([F:25])([F:26])[F:27])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:11][CH:10]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:9]1
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
Cyclopropylcarbonylchloride (14.1 μL, 0.10 mmol) is added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (5.4 μL, 0.31 mmol) and DMAP (1.2 mg, 0.01 mmol). The reaction mixture is stirred for three days at room temperature. The mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (22 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.88 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.61-4.53 (1H, m), 4.42-4.30 (2H, m), 2.89-2.78 (2H, m), 2.65-2.55 (2H, m), 1.50-1.44 (1H, m), 0.71-0.61 (4H, m); m/z (Cl) 548.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]1([S:14]([O:17]C(C)C)(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S-])#N.[K+].O>C1COCC1>[CH2:1]([O:8][C@@H:9]([CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][C:11]1([S:14]([OH:17])(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OS(=O)(=O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Agent: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Temperature: 90 °C
Yield: 64 %

Procedure:
A mixture of (R)-isopropyl 1-(2,3-bis(benzyloxy)propyl)cyclopropane-1-sulfonate (460 g) and KSCN (170 g) in THF 2.2 L) and water (2.2 L) at 25° C. was refluxed for approximately 24 hours at 90° C. until HPLC analysis showed that the reaction had gone to completion. The reaction mixture was concentrated to about 2 L at 40° C. and extracted with MTBE (1.5 L (×3)). The organic layer was discarded and the aqueous layer was neutralized to pH 14 with KOH (30 g) in water (100 mL) and cooled to −5° C. The mixture was neutralized to a pH of between 2 and 3 with concentrated HCl (205 mL) and extracted with ETOAc (2 L (×2)). The combined organic layers was dried over Na2SO4 for approximately 16 hours, filtered and concentrated to dryness to give the product as a deep red oil (265 g).
Reaction SMILES: O.[NH2:2][NH2:3].CS([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)(=O)=O>C(O)C>[NH:2]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][N:9]=1)[NH2:3]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 15 °C

Procedure:
1.7 ml (1.7 g, 34.0 mmol) hydrazine hydrate are added to 2.0 g (8.5 mmol) 2,5-bis-(methylsulfonyl)pyridine [Woods et al., J. Heterocycl. Chem. 1984, 21, 97-101] in 15 ml ethanol and the mixture is stirred under reflux for 4 h. For working up, the reaction solution is cooled to 15° C., the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and diethyl ether and the product is dried in vacuo.