Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=3)[N:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41](=[O:43])[CH3:42])[N:39]=3)[N:36]=2)=[CH:3][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(C)(O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: CC(=O)Nc1cn2nc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(C(C)(C)O)cc4)c3)ccc2n1
Temperature: 90 °C
Yield: 6.5 %

Procedure:
A glass microwave reaction vessel was charged with a mixture of N-(5-bromo-2-chloropyridin-3-yl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide from Step 2 (250 mg, 616 μmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide from Step 3 (223 mg, 739 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (32 mg, 43 μmol, Strem Chemical, Inc., Newburyport, Mass.), sodium carbonate (131 mg, 1.2 mmol), and dioxane (3 mL). Ar was bubbled in for 1 minute, and the vessel was sealed and heated at 90° C. for 12 h. After cooled down to room temperature, the black suspension was filtered through a Celite® (diatomaceous earth) pad, and the filtercake was washed by MeOH-DCM (50%). The filtrate was concentrated in vacuo. Purification by silica gel chromatography (10 to 20% MeOH/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 40 to 90% CH3CN/H2O, 0.1% TFA, over 10 min) (Phenomenex, Torrance, Calif.) provided N-(6-(6-chloro-5-(4-(2-hydroxypropan-2-yl)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (20 mg, 65% yield) as a yellow solid. MS (ESI positive ion) m/z: 501 (M+1). 1H NMR (400 MHz, MeOH-d6): δ ppm 1.51 (s, 6H), 2.22 (s, 3H), 7.66 (d, J=8.53 Hz, 2H), 7.71 (d, J=9.54 Hz, 1H), 7.78 (d, J=9.03 Hz, 2H), 7.98 (d, J=9.54 Hz, 1H), 8.43 (s, 1H), 8.56 (d, J=2.01 Hz, 1H), 8.78 (d, J=2.51 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][C:38]([C:44]#[N:45])=[CH:39][CH:40]=4)[CH:35]=3)[S:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:46]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][C:38]([C:44]#[N:45])=[CH:39][CH:40]=4)[CH:35]=3)[S:22]([N:25]([CH3:46])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
t-Butyl N-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate obtained in Reference Example 42 (172 mg) was dissolved in 0.7 ml of tetrahydrofuran, 139 mg of triphenylphosphine, 32 μl of methanol and 83 μl of diethyl azodicarboxylate was added to the solution at 0° C., and then the mixture was stirred at room temperature for 40 minutes. The reaction solution was evaporated, and the resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (85:15) as the eluent to give 153 mg of t-butyl N-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]-N-methylcarbamate.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:28](C1CC(=O)N(O)C1=O)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29].CN(C=O)C>ClCCl>[CH3:6][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:28]([O:30][CH2:31][CH:32]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]3[C:44]2=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:29])=[CH:15][CH:16]=1)=[O:2])[CH3:7]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Reaction time: 10 h

Procedure:
Boc-para-aminophenylalanine (2.6 mmol; 0.72 g) was dissolved in 12 ml of dichloromethane (DCM) (from Dow Chemical, Midland, Mich.) containing 3.85 mmol of triethylamine (TEA) (from Aldrich, Milwaukee, Wis.; distilled before use). 1.3 Grams (3.85 mmol) of Fmoc-N-hydroxysuccinimide was added and the solution was left at room temperature for 10 hours. The solution was evaporated to dryness in vacuo. The residue was dissolved in 100 ml ethyl acetate and washed with 50 ml of 5% NaHCO3. The solution was filtered and the NaHCO3 wash was repeated two more times. The precipitate from the three NaHCO3 washes was then extracted with a mixture of three parts (v/v) ethyl acetate to one part saturated KHSO4. The organic layer was isolated and concentrated in vacuo. After removal of most of the ethyl acetate by vacuum the product was precipitated with petroleum ether. The product was recrystallized twice using an ethyl acetate-petroleum ether mixture to yield 0.83 g (64%) with a melting point of 118-120° C. Thin layer chromatography was performed according to well-known procedures and displayed a spot with Rf=0.28. [α]D21 =-6.29 (c1.7, DMF).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:6]=[CH:5][N:4]=1.Br[C:23]1[N:28]=[C:27]([C:29]2[N:33]3[N:34]=[C:35]([N:38]4[CH2:42][CH2:41][CH2:40][C@@H:39]4[C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=4)[CH:36]=[CH:37][C:32]3=[N:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[F:49][C:45]1[CH:44]=[C:43]([C@H:39]2[CH2:40][CH2:41][CH2:42][N:38]2[C:35]2[CH:36]=[CH:37][C:32]3[N:33]([C:29]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)[N:28]=4)=[CH:30][N:31]=3)[N:34]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(Br)n4)n3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2cccc(-c3cnc4ccc(N5CCC[C@@H]5c5cccc(F)c5)nn34)n2)n1
Temperature: 110 °C

Procedure:
In step 14-1, 2-(methylthio)-4-(tributylstannyl)pyrimidine (4.3 g, 13.2 mmol) and Pd(PPh3)4 (196 mg, 0.17 mmol) were added to a solution of (R)-3-(6-bromopyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (14-1) (1.5 g, 3.4 mmol) in toluene (35 mL). The mixture was degassed using N2 for 15 minutes and then heated at 110° C. for 2 hours. All the solvents were removed. The resulting mixture was purified by column chromatography (silica gel, EtOAc/CH3OH, 0 to 10% gradient) to give (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (14-2) as a light-yellow foam. LC/MS: 484.2 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCSCCCN(C)C)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1

Procedure:
A mixture of 7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-[9-(3-dimethylaminopropylthio)nonyl]thiochroman (50 mg, 0.09 mmol), hydrobromic acid (0.13 ml, 48% aqueous solution) and acetic acid (0.15 ml) was heated for 8 hours. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to give the title compound (60 ml, crude product) as a colorless oil. This compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].[CH3:11][N:12]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]1B(O)O.[F-].[K+].[Br-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:13]2[N:12]([CH3:11])[C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[C:3]([F:10])[CH:4]=1
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Nc1cc(F)c(Br)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1c(F)cc(N)cc1F
Yield: 200.8 %

Procedure:
A mixture of 4-bromo-3,5-difluoroaniline (0.782 g, 3.78 mmol), tris(dibenzylidene-acetone)dipalladium (0.096 g, 0.105 mmol), N-methyl-5-cyanopyrroleboronic acid (1.12 g, 7.46 mmol), and potassium fluoride (0.789 g, 13.6 mmol) in THF (10 mL) was stirred under nitrogen. Tri-tert-butylphosphine (10% solution in hexane, 0.621 mL, 0.210 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/tetrahydrofuran, filtered through a plug of silica gel, the solvent evaporated and the residue purified by silica gel column chromatography (hexane/ethylacetate, 70/30) to afford the title compound (1.77 g, 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH2:3][CH2:2]1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O.O>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[N:8]=[CH:9][NH:10][CH:11]=3)[CH2:5][CH2:6]2)=[CH:14][CH:15]=1)(=[O:22])[CH2:20][CH3:21]
Reactant: c1nc(C2CCNCC2)c[nH]1
Reactant: CCC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(N2CCC(c3c[nH]cn3)CC2)cc1
Reaction time: 3 h

Procedure:
3 g (0.019 mole) of 4-(4-piperidyl)-1H-imidazole and 2.88 g (0.019 mole) of para-fluoropropiophenone are stirred in 70 cm3 of dimethylformamide for 5 minutes. 4 g (0.037 mole) of disodium carbonate and 0.2 g (0.0012 mole) of potassium iodide are added and the solution is brought to 160° C. for 3 hours. After being cooled, the solution is poured into 200 cm3 of water and stirred for 1 hour. The precipitate formed is drained, washed with water, dried and recrystallized in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[CH2:16]([O:18][C:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:35][CH2:34][C@H:33]([NH2:36])[C:32]1=[O:37])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:30][N:31]1[CH2:35][CH2:34][C@H:33]([NH:36][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[C:32]1=[O:37])=[O:20])[CH3:17]
Reactant: CCOC(=O)n1c(CN2CC[C@H](N)C2=O)cc2ncccc21
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: CCOC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3cc4ccc(Cl)cc4s3)C2=O)cc2ncccc21

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylic acid ethyl ester hydrochloride as starting material. The crude product is purified by column chromatography eluting with 60% EtOAc/CH2Cl2 to provide the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1ccc(OCc2ccccc2)cc1F
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 4-benzyloxy-2-fluoro benzaldehyde (Compound 8, 16 g, 69.6 mmol) in methanol (100 mL) and dichloromethane (100 mL) was treated with sodium borohydride (5.26 g, 139 mmol). After 2 h at ambient temperature, the volatiles were evaporated in vacuo, the residue was diluted with water and dilute aqueous hydrochloric acid and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (15 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C(C)c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)c2ccccc2)ccc1C(=O)O
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl 2-methyl-4-(1-phenylethyl)benzoate (1.6 g, 5.4 mmol) in dichloromethane 9 mL, and 3 mL trifluoroacetic acid was added. The mixture was stirred 0.5 hour. Thin layer chromatography showed full conversion. The reaction mixture was concentrated to give 2-methyl-4-(1-phenylethyl)benzoic acid (1 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:18]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:19])[CH3:2]
Reactant: ONC1CCCCC1
Reactant: CCOc1ccccc1C=O
Product: CCOc1ccccc1C=[N+]([O-])C1CCCCC1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2-ethoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 89% yield as a solid, m.p. 54.8° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[N:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Reactant: Nc1ccncc1
Product: CC1CC(=O)c2c(C(=O)Nc3ccncc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 4-aminopyridine, General Procedure B provided the title compound:
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:45]=[CH:44][C:18]([C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][S:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[C:27]([N+:41]([O-:43])=[O:42])[CH:26]=3)(=[O:24])=[O:23])=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>ClCCl.O>[N+:41]([C:27]1[CH:26]=[C:25]([S:22]([NH:21][C:19](=[O:20])[C:18]2[CH:44]=[CH:45][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH:2]=[O:1])[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][C:28]=1[NH:31][CH2:32][CH2:33][S:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([O-:43])=[O:42]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(N2CCC(CCC3OCCCO3)CC2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCCC1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1

Procedure:
A solution of Example 203C (250 mg, 0.4 mmol), in dichloromethane (5 mL), TFA (1.5 mL), and 1 drop water was stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with water, saturated NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane 0.5-1.0% methanol to provide the desired product. MS (APCI) m/e 597 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 9.80 (s, 1H), 8.87 (d, 1H), 8.67 (t, 1H), 8.47 (s, 1H), 8.15 (dd, 1H), 7.63 (d, 2H), 7.40 (m, 2H), 7.24-7.34 (m, 4H), 6.87 (d, 2H), 6.82 (m, 2H), 3.87 (d, 2H), 3.58 (m, 4H), 3.21 (t, 2H), 2.86 (m, 2H), 2.50 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.55 (s, 4H) 1.31 (m, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1CC(=O)N(C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and acetyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (70%) 1H NMR (400 MHz, CDCl3) δ 6.98-7.43 (m, 10H), 6.06 (m, 1H), 5.29 (m, 1H), 4.38 (m, 2H), 3.70-4.02 (m, 2H), 3.03-3.27 (m, 1H), 2.89 (s, 2H), 2.80 (s, 1H), 2.58-2.78 (m, 3H), 2.50 (br s, 1H), 1.92 (s, 3H), 1.81 (m, 1H), 1.75 (m, 3H). Mass Spectral Analysis m/z=394.3 (M+H)+ tR=3.43 min (99%)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.Cl>ClCCCl>[CH3:3][CH2:2][C:1]([C:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: c1ccc2ccccc2c1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Product: CCC(=O)c1cccc2ccccc12
Temperature: 47.5 °C
Yield: 79 %

Procedure:
The foregoing 1,2-dichloroethane solution of a propionyl chloride.aluminum chloride complex was added dropwise to a solution consisting of 128.2 g (1.0 mol) of naphthalene and 300 mL of 1,2-dichloroethane at 35 to 40° C. over one hour. After completion of addition, the resulting mixed liquid was heated at 45 to 50° C. for 2 hours and after cooling to room temperature, was poured into, ice water. 200 mL of concentrated hydrochloric acid was further added thereto, and the mixture was stirred and mixed. The product as formed in this reaction mixture was extracted with chloroform together with 1,2-dichloroethane, dried over magnesium sulfate, and concentrated in vacuo. A concentrated liquid was distilled in vacuo to obtain 145.3 g (yield: 79%, boiling point: 139 to 142° C./4 mmHg) of 1-propionaphthone as a pale yellow oil.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:48][C:49]1[CH:50]=[C:51]2[C:56](=[O:57])[NH:55][C:53](=[O:54])[C:52]2=[CH:58][C:59]=1[Cl:60]>CC1CCCO1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:55]2[C:56](=[O:57])[C:51]3[C:52](=[CH:58][C:59]([Cl:60])=[C:49]([Cl:48])[CH:50]=3)[C:53]2=[O:54])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Reactant: O=C1NC(=O)c2cc(Cl)c(Cl)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)C1
Reaction time: 8 h

Procedure:
To a round bottomed flask was added trans 3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.0 g, 4.62 mmol, prepared from WO2008065021), triphenylphosphine (1.52 g, 5.76 mmol) and 2-methyltetrahydrofuran (120 mL). Diisopropyl azodicarboxylate (1.23 mL, 6.25 mmol) was added over two minutes via syringe followed by 4,5-dichlorophthalimide (1.35 g, 6.25 mmol). The reaction was stirred overnight and evaporated. The reaction was repeated and the combined material was purified by column chromatography (160 g SiO2, EtOAc in hexane) to give cis 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-5,6-dichloro-isoindole-1,3-dione, a yellowish solid (2.0 gm, 52% yield)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([S:21][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCCBr
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCSCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Potassium carbonate (5 g) and 1-bromo-5-chloropentane (4.9 g) were added to a solution of benzylmercaptan (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 70-80° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3 g of 5-benzylthiopentyl chloride.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])CO)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH2:27][CH2:28][S:29][CH3:30])[CH2:25][OH:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH2:27][CH2:28][S:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CSCC[C@@H](CO)NC(=O)OC(C)(C)C
Product: CSCC[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 42 %

Procedure:
The same reaction procedure as in Reference Example 12 was repeated except that (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanol used in Reference Example 12 was replaced by 7.53 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl) amino]-4-(methylthio)butanol, whereby 3.22 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxy-5-(methylthio)pentanamide was obtained in a yield of 42%.