Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[CH2:36][S:37]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)(=[O:39])=[O:38]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][CH2:36][S:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:39])=[O:38])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Reactant: O=S(=O)(CCCI)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCS(=O)(=O)N1CCCC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (206 mg, 0.556 mmol) in N,N-dimethylformamide (2 mL) was added cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours, after which additional cesium carbonate (362 mg, 1.11 mmol) and 1-[(3-iodopropyl)sulfonyl]pyrrolidine (253 mg, 0.834 mmol) were added. The reaction mixture was stirred at 80° C. for an additional 7 hours. The reaction mixture was cooled and diluted with toluene. The resulting mixture was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5% gradient, methanol in dichloromethane) provided ethyl 5-[(4-fluorophenyl)methyl]-3-{[3-(1-pyrrolidinylsulfonyl)propyl]amino}-2-pyridinecarboxylate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=1.3 Hz, 1 H), 7.79 (t, J=5.7 Hz, 1 H), 7.13 (dd, J=8.5, 5.4 Hz, 2 H), 6.97 (t, J=8.7 Hz, 2 H), 6.86 (s, 1 H), 4.41 (q, J=7.2 Hz, 2 H), 4.26 (t, J=6.2 Hz, 2 H), 3.91 (s, 2 H), 3.37-3.31 (m, 4 H), 3.03 (m, 2 H), 2.19-2.09 (m, 2 H), 1.95-1.89 (m, 4 H), 1.42 (t, J=6.9 Hz, 3 H); MS m/z 450 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:10])[N:8]=[C:7]([O-:11])[NH:6][C:4]1=[O:5].[Na+].ClCC([O-])=O.[Na+].[Cl-].[Cl-].[Ca+2].CN(C=O)C>CO>[CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:4]1=[O:5]
Reactant: CCC1(c2ccccc2)C(=O)N=C([O-])NC1=O
Agent: O=C([O-])CCl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC1(c2ccccc2)C(=O)NC(=O)NC1=O
Yield: 36.9 %

Procedure:
A solution of sodium phenobarbitone (8.8 g, 35 mmoles), and sodium chloroacetate (4.5 g, 38 mmoles) in methanol (250 ml) was mixed with a solution of CaCl2 (3 g) in methanol (50 ml). After addition of 5 ml DMF the mixture was refluxed for 36 hours. After removal of the solvent, the residue was treated with water (100 ml) and acidified with conc. HCl followed by extraction with chloroform. The organic layer was evaporated to dryness and the residue treated with 10% NaHCO3 solution. Extraction with chloroform and evaporation of the organic layer yielded 3 g of unreacted phenobarbital. The bicarbonate layer was acidified with conc. HCl and extracted with chloroform. Evaporation of the dried (MgSO4) chloroform yielded 4.5 g of a gummy material which solidified slowly on standing. TLC and NMR showed this to be nearly pure monoacid with only traces of unreacted phenobarbitone and dialkylated derivative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:26]2[O:25][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Reactant: OB(O)c1ccco1
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3ccco3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 207 from methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206) and furan-2-boronic acid.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]3[C:19](=[N:21][OH:22])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:23][C:24]([O:26]CC)=[O:25])[C:13]=2[CH3:29])=[CH:7][CH:6]=1.C(O)(=O)C>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]3[C:19](=[N:21][OH:22])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:13]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c1CCCC2=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(n1CC(=O)O)CCCC2=NO
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Aqueous sodium hydroxide (1M, 10 mL, 10 mmol) and water (20 mL) were added to a stirred suspension of ethyl [3-(4-chloro-phenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (4.0 g, 10.2 mmol) and ethanol 40 mL) and the mixture was warmed up to 40° C. After 1.5 h at this temperature, the reaction mixture was allowed to cool to r.t. and held overnight. The suspension was reheated to 33° C. and acetic acid (1.7 mL, 29.7 mmol) added to the resulting solution. The mixture was allowed to cool to r.t., the solid product was collected by filtration, washed with water (2×20 mL), then dried under vacuum at 30° C. to provide the title compound as a solid; 2.94 g (79%); purity by HPLC 98.9 area %
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C@:20]([CH3:24])([C@@H:21]([CH3:23])[CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]3)[CH2:9][CH2:8]2)(=O)C.C([O-])(=O)C.[Na+].[I:31]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.C(OCC)(=O)C.CCCCCC>[I:31][C@H:22]1[C@H:21]([CH3:23])[C@@:20]2([CH3:24])[C:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])=[CH:6][C:5]1=[O:4]
Reactant: CC(=O)OC1=C[C@H](C)[C@@]2(C)C(=C1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@H]1[C@H](I)C(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: -10 °C
Reaction time: 8 h

Procedure:
68.95 g of 88.8% (0.179 mol) 3-acetoxy-1α-methyl-androsta-2,4-dien-17-one (DE-A 3715869) is dissolved in 800 ml of acetone, mixed with 32.9 g (0.4 mol) of anhydrous sodium acetate and cooled with stirring to -10° C. Then, 29 g (0.179 mol) of iodine chloride (iodine monochloride) is added under nitrogen atmosphere at -10° C. and it is stirred for another 30 minutes. Then, it is added to 6 l of ice water mixed with 6.65 g of sodium thiosulfate, the product is extracted with ethyl acetate, the organic phase is dried on sodium sulfate, filtered and concentrated by evaporation up to 200 ml. After standing overnight, the precipitated solid is suctioned off and dried. 49 g (64% of theory) of product is obtained. After chromatography of the mother liquor on silica gel with ethyl acetate/hexane as mobile solvent, another 10 g (13% of theory) of the title compound is obtained. The total yield is 59 g (77% of theory) of 2β-iodo-1α-methylandrost-4-ene-3,17-dione.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:14][C:15]1[C:16](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:14][C:15]1[C:16]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12]2)=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([NH2:21])=[N:19][CH:20]=1
Reactant: Cn1ccnc1CN1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 65 °C
Reaction time: 17 h
Yield: 51 %

Procedure:
The resulting 1-((1-methyl-1H-imidazol-2-yl)methyl)piperazine (supposedly 0.320 g, 1.78 mmol, 1 eq) was suspended in iPrOH (5.4 mL) and DIPEA (1.4 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.400 g, 1.62 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×6 mL), Et2O (2×6 mL) and dried to give the title compound as a bright yellow powder (0.370 g, 51%); 1H-NMR (500 MHz, DMSO-d6): δ 2.97-3.08 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 3.66 (s, 3H, imidazole Me), 6.75 (s, 1H, imidazole H-4), 6.96 (s, 2H, NH2), 7.08 (s, 1H, imidazole H-5), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.07 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Compound 1, (1.56 g, 3.58 mmol) was dissolved in anhydrous CH2Cl2 (50 mL). The solution was stirred while cooling the temperature to 0° C. in an ice water bath. After allowing it to stir for another 10 minutes, AlCl3 (1.91 g, 14.32 mmol) was added slowly. This was followed by stirring the reaction for an additional 20 minutes, and subsequently increasing the temperature to 80° C. After one hour, the reaction was shown to be complete by TLC and LC/MS. It was worked up with EtOAc (2×50 mL) and 10% Potassium Sodium Tartrate (2×50 mL). Upon being treated to this work up, the aluminum was removed from the solution. The organic layer was then dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by HPLC to afford Compound 58 (402 mg, 27%): LCMS m/z (%)=423 (M+H37Cl, 100), 421 (M+H35Cl, 28). 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 7.60 (s, 1H), 7.48 (d, J=8 Hz, 2H), 7.39 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.32 (d, J=8 Hz, 2H), 7.28 (d, J=2 Hz, 1H), 6.96 (d, J=12 Hz, 1H), 3.67 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][CH3:22])=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:22][O:21][CH2:20][C:17]1[CH:16]=[N:15][C:14]([N:1]2[CH2:6][CH2:5][CH:4]([C@H:7]3[CH2:9][C@H:8]3[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]2)=[N:19][CH:18]=1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: COCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (6.30 g, 37.2 mmol) was added to a solution of 2-chloro-5-(methoxymethyl)pyrimidine (5.90 g, 37.2 mmol) from step A of this example in DMF (35 ml). Potassium carbonate (6.68 g, 48.4 mmol) was added and the mixture stirred at RT overnight. The mixture was diluted with 120 ml of brine, extracted with EtOAc (150 ml×3), the organic layers combined, dried over Na2SO4, filtered and the volatiles removed in vacuo. Purification by silica gel chromatography eluting with EtOAc:Hexanes (0-70% then 70% EtOAc in hexanes) afforded the title compound (9.7 g, 90%). MS (ESI) ink 292.4 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.[C:13]([O:18][CH3:19])(=[O:17])[C:14]([CH3:16])=O.C(O)C>O>[CH3:19][O:18][C:13]([C:14]1([CH3:16])[NH:2][CH2:3][CH2:4][S:5]1)=[O:17]
Reactant: NCCS
Reactant: COC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)NCCS1
Yield: 70.5 %

Procedure:
A mixture of 36.6 g of cysteamine hydrochloride, 32.6 g of triethylamine, 32.9 g of methyl pyruvate and 500 ml of ethanol was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a residue which was, after addition of water, extracted with ethyl acetate. The extract was vacuum distilled to give 36.6 g (yield 70.4%) of 2-methylthiazolidine-2-carboxylic acid methyl ester with a boiling point of 76° C./2 mmHg.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:5][CH:4]=1.[N:21]#[C:22][NH2:23].CC(C)([O-])C.[K+].BrN1C(=O)CCC1=O>CO>[C:22]([N:23]=[S:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[CH:19][CH:20]=1)[CH3:1])#[N:21]
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CO
Product: CS(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1 h

Procedure:
A solution of 2-(4-(methylthio)benzyl)isoindoline-1,3-dione (preparation 6a, 3.60 g, 12.71 mmol), cyanamide (694 mg, 16.5 mmol) and potassium tert-butoxide (1.71 g, 15.25 mmol) in methanol (30 mL) is treated with N-bromosuccinimide (3.39 g, 19.06 mmol). The mixture is stirred for 1 h and concentrated under reduced pressure. Saturated aqueous Na2S2O3 solution is added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate to ethyl acetate/methanol 4:1). Yield: 2.43 g (59% of theory); ESI mass spectrum: [M+H]+=324; r.t. HPLC: 0.52 min (X001_004).
Reaction SMILES: [Cl:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[OH:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[C:57]([C:58]3[N:62](C4CCCCO4)[N:61]=[CH:60][CH:59]=3)=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][N:50]=2)[CH2:45]1>C1COCC1.O>[Cl:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:53](=[O:54])[C:52]2[CH:56]=[C:57]([C:58]3[NH:62][N:61]=[CH:60][CH:59]=3)[C:49]([N:46]3[CH2:47][CH2:48][C@@H:44]([OH:43])[CH2:45]3)=[N:50][CH:51]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cnc(N2CC[C@@H](O)C2)c(-c2ccnn2C2CCCCO2)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline (16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt.H2O, 11.9 g, 77.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25° C. and then at 65° C. for 16 h. After cooling the RM to 35° C., further EDCI.HCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35° C. then again at 65° C. for 16 h. After cooling the RM to 35° C., water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35° C. for 1 h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1) to afford the title compound as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C:12]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH:13]=1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1
Reactant: OC1=Cc2ccccc2C=Cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (5 ml) in dry dichloromethane (75 ml) at -78° C. under nitrogen was added, dropwise. dimethyl sulphoxide (8.75 ml), and the solution stirred at -78° C. for 15 minutes. A solution of 5-hydroxy-dibenzo[a,e]cyclooctene (11.1 g) in dichloromethane (75 ml) was added over 5 minutes at -78° C. and the solution stirred for 15 minutes, then triethylamine (30 ml) was added and the mixture allowed to warm to room temperature. The mixture was washed with water (100 ml), 1N hydrochloric acid (50 ml) water (100 ml), brine (50 ml) then dried and evaporated to give the crude ketone which was recrystallised from ethyl alcohol/hexane (10.0 g), mp 112°-6 ° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:9][OH:10])=[CH:5][CH:4]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27].O.CCOCC>N1C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[CH2:9][O:10][C:25](=[O:28])[CH2:26][CH3:27])=[CH:21][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)OCC(Oc1ccc(C(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
2-(4-Trifluoromethyl-phenoxy)-2-(3-trifluoromethyl-phenyl)-ethanol, 125, (0.01 mol) was dissolved in pyridine (20 mL) and the solution was cooled to 0° C. Propionyl chloride (0.015 mol) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ether were added. The organic phase was washed with dilute hydrochloric acid, dried and concentrated. The residue was chromatographed to afford the title compound 135.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Sn+2].[O-]S(C(F)(F)F)(=O)=O.[CH2:18]([O:21][CH2:22][CH2:23][CH:24]([NH:33][CH2:34][C@@H:35]([OH:52])[C@@H:36]([NH:44]C(=O)OC(C)(C)C)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:21][CH2:22][CH2:23][CH:24]([NH:33][CH2:34][C@@H:35]([OH:52])[C@@H:36]([NH2:44])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[CH:19]=[CH2:20]
Reactant: C=CCOCCC(NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)c1cccc(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOCCC(NC[C@@H](O)[C@@H](N)Cc1ccccc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
Step R (5): Tin (II) triflate (1.2 g, 2.89 mmol) was added to a 0° C. solution of tert-butyl (2S,3R)-4-(3-(allyloxy)-1-(3-methoxyphenyl)propylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate from Step R (4) (700 mg, 1.45 mmol) in dry DCM (30 mL). The reaction was warmed to rt and stirred for 16 h. The reaction was neutralized with saturated NaHCO3 and the product was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 320 mg (57% yield) of the title compound. LC-MS (M+H)+=385.42; 1H NMR (300 MHz, CDCl3) δ ppm 2.05-2.80 (m, 4H) 2.78-3.54 (m, 4H) 3.63-3.97 (m, 6H) 4.99-5.30 (m, 2H) 5.65-5.94 (m, 1H) 6.76-7.33 (m, 10H) 7.53-7.74 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([F:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[C:28]12([CH2:38][NH2:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>CS(C)=O.C(OCC)(=O)C.CCCCCC>[C:28]12([CH2:38][NH:39][CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:21](=[C:22]([F:24])[CH:23]=[C:15]4[O:14][CH2:13]3)[NH:20][C:19](=[O:25])[CH2:18]5)[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(F)c4c(c3O2)CC(=O)N4)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1Cc2c(c(F)cc3c2OC(CNCC24CC5CC(CC(C5)C2)C4)CO3)N1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-fluoro-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.5 mmole) and 1-adamantylmethylamine (1.6 g, 10 mmole) were combined in 30 ml of dry DMSO and heated at 80°-90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 500 ml of 1:1 ethyl acetate/hexane and washed with 250 ml of saturated aqueous sodium bicarbonate and with two 250 ml portions of water, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel using 0.5% methanol/CHCl3 as eluant to give 0.70 g of the free base of the title compound as a colorless oil. This was crystallized from ethanol with the addition 4N isopropanolic HCl to give 0.54 g of the (S) enantiomer of the title compound as a fluffy white solid hydrochloride, m.p. >260° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1C=CC=C[CH:10]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C=C>CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:20])[CH:9]=[CH2:10]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Agent: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate salt, crude 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester was deprotected after 2 hours. Flash column chromatography with 0.5% TFA17% MeOH/CHCl3 gave 2.46 g (87%) of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt as a colorless foam.