Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[CH:3]1([C:6]2[NH:10][N:9]=[C:8]([NH:11][C:12]3[C:13]([F:33])=[C:14]([NH:22][C@H:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:24][OH:25])[C:15]([F:21])=[CH:16][C:17]=3[N+:18]([O-])=O)[CH:7]=2)[CH2:5][CH2:4]1.C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:18][C:17]1[CH:16]=[C:15]([F:21])[C:14]([NH:22][C@H:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:24][OH:25])=[C:13]([F:33])[C:12]=1[NH:11][C:8]1[CH:7]=[C:6]([CH:3]2[CH2:5][CH2:4]2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of saturated ammonium chloride (4 ml) was added slowly to a suspension (R)-2-(3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluoro-4-nitrophenylamino)-2-(4-fluorophenyl)ethanol (Method 105, 0.250 g, 0.577 mmol) and zinc dust (0.189 g, 2.88 mmol) in MeOH/THF (10 ml, 1:1). The mixture was stirred at 25° C. for 5 minutes. Saturated ammonium acetate solution (5 ml) was added and the mixture was stirred for another 30 minutes. Zn dust was removed by filtration and the cake was washed with EtOAc (15 ml). The organic layer was separated and dried over sodium sulfate. After removal of solvent, the product was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][NH:7][NH2:8].[C:12](#[N:15])[CH:13]=[CH2:14].OCC[N+](C)(C)C.[ClH:23].[OH-].[Na+]>>[ClH:23].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][N:7]1[CH2:14][CH2:13][C:12]([NH2:15])=[N:8]1
Reactant: C=CC#N
Reactant: COc1cccc(CNN)c1
Agent: C[N+](C)(C)CCO
Agent: Cl
Agent: [Na+]
Product: COc1cccc(CN2CCC(N)=N2)c1

Procedure:
A mixture of 3-methoxybenzylhydrazine (15.2 g), acrylonitrile (10.6 g) and 20 drops of 50% methanolic solution of choline base was heated at 110° in an oil bath for 1 hour. A 25% hydrochloric acid solution (35 ml) was added and the mixture was refluxed for an additional hour. After cooling, the mixture was basified with sodium hydroxide pellets. The precipitate was isolated, washed with water and dried. A solution of the dried product in ethanol was treated with ethereal hydrochloric acid to give 1-(3'-methoxybenzyl)-3-amino-2-pyrazoline hydrochloride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][N:29]5[CH2:34][CH2:33][NH:32][CH2:31][C:30]5=[O:35])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[C:36](Cl)(=[O:38])[CH3:37].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[C:36]([N:32]1[CH2:33][CH2:34][N:29]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:15]3[C:16](=[O:19])[C:17]4[S:18][C:10]([C:7]5[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=5)=[CH:11][C:12]=4[N:13]=[CH:14]3)=[CH:27][CH:26]=2)[C:30](=[O:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: O=C1CNCCN1Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(Cc2ccc(CCn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of the compound (30 mg) obtained in Example 38, acetyl chloride (4.7 mg), triethylamine (19 mg) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (20 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C@@:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:1][C@@:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@](N)(CO)C(=O)O
Product: C[C@@](CO)(NCc1ccccc1)C(=O)O
Yield: 50.2 %

Procedure:
(S)-2-amino-3-hydroxy-2-methylpropanoic acid (1.2 g, 10 mmol) was reacted with benzaldehyde (1.06 g, 10 mmol) according to the procedure as described in Example 46, Step A to give the title compound as a gray solid (1.05 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14](OC)=[O:15])[N:13]=1.[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:26]([NH:34][C:14]([C:12]1[N:13]=[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:15])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Product: O=C(NCCc1ccccc1)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 42.6 %

Procedure:
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.10 g, 298 μmol) and phenethylamine (0.5 ml; 3.98 mmol) to provide the title compound as an off-white solid (0.054 g; 42%). LCMS: m/z=425 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[Cl-].[Li+].CCOC(C)=O>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>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:14][CH:13]=[CH2:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1cc(Br)ccc1C#N
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(OC)c1
Temperature: 130 °C

Procedure:
To a 50 mL flask containing a stir bar were added 2-methoxy-4-bromobenzonitrile (0.30 g, 1.4 mmol), palladium tetrakis (82 mg, 0.071 mmol), allyltri-n-butyltin (0.88 mL, 2.8 mmol), and lithium chloride (0.120 g, 2.83 mmol). The resulting mixture was then dissolved in anhydrous toluene (16 mL); the flask was placed in an oil bath and heated at 130° C. LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The flask was taken out of the oil bath and cooled to room temperature. To the flask was poured EtOAc (40 mL) and the mixture was transferred into a reparatory funnel and washed with aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then dissolved in DCM and absorbed into silica gel. The silica gel was then loaded onto a silica column for separation with the solvent systems of hexanes/EtOAc (1/0.3); this gave 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile. LC-MS (IE, m/z): 174 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:24]=[O:25])[C:10]([CH3:14])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)n(Cc2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccccc2)c(C)c1C=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Dissolve 1-benzyl-3,5-dimethyl-1H-pyrazole (3.088 g, 16.6 mmol) in N,N-dimethylformamide (12.8 mL) and heat the mixture to 95° C., then add phosphorus oxychloride (13.4 mL) dropwise. Stir the mixture for 3 hr. at 95° C. then cool and add ice water very slowly. Adjust the mixture to approximately pH=4 using 5 N sodium hydroxide, extract the black mixture with diethyl ether 3 times, dry (sodium sulfate) and filter to give the title preparation as a yellow solid (2.65 g, 75%). 1H-NMR (400 MHz, DMSO-d6) δ 2.282 (s, 3H); 2.433 (s, 3H); 5.233 (s, 2H); 7.13 (m, 2H); 7.21-7.34 (m, 3H); 9.800 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12]>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>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH:11]=[CH2:12])[C:6]#[N:7]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)cc1C

Procedure:
0.75 g (0.65 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to a solution of 5.1 g (0.026 mol) of 4-bromo-3-methylbenzonitrile and 8.3 g (0.026 mol) of vinyltributyltin in 250 mL of toluene under argon, and the reaction was heated at reflux overnight. The mixture was filtered through a layer of celite and evaporated. The residue was flash chromatographed on silica gel with heptane:EtOAc (1:1) as eluant. Yield: 4.0 g (100%).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][CH2:9][O:10]CC(O)=O)[CH:6]=[CH:5][N:4]=[CH:3]1.C[Si](C)(C)N1C=CN=C1.C[Si]([O:28]C(=O)C(Cl)C)(C)C>>[N:2]1([CH2:7][CH2:8][C:9]([OH:10])=[O:28])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: O=C(O)COCCCn1ccnc1
Reactant: CC(Cl)C(=O)O[Si](C)(C)C
Agent: C[Si](C)(C)n1ccnc1
Agent: Cl
Product: O=C(O)CCn1ccnc1

Procedure:
The 6-(imidazol-1-yl)-3-oxa-hexanoic acid-hydrochloride used as the starting material is prepared in the following manner: 1-trimethylsilylimidazole (b.p.20 : 117°-120° C.) is reacted with chloropropionic acid-trimethylsilyl ester (b.p.1013 : 172°-175° C.) with simultaneous saponification of the esters to form 3-(imidazol-1-yl)-propionic acid (m.p.: 148°-150° C.). Reaction with trimethylchlorosilane in ethanol leads to the corresponding ethyl ester-hydrochloride from which the free 3-(imidazol-1-yl)-propionic acid-ethyl ester (oil) was obtained with 2N sodium hydroxide solution. The 1-(imidazol-1-yl)-3-propanol (oil) obtained after reduction with lithium aluminium hydride is allowed to react with ethyl bromoacetate in dimethyl formamide in the presence of sodium hydride to form 6-(imidazol-1-yl)-3-oxa-hexanoic acid ethyl ester (oil) which is subsequently saponified with 3N hydrochloric acid to form the desired acid.
Reaction SMILES: F[C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[NH:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:14]1[C:5]2[C:6](=[O:11])[NH:7][C:8]3=[CH:9][CH:10]=[CH:2][C:3]([C:4]=23)=[CH:12][CH:13]=1
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2cccc3ccc(-c4ccc[nH]4)c1c23
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
A mixture of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (250 mg, 0.504 mmol) and 3-R-hydroxy pyrrolidine (Aldrich, 870 mg, 9.99 mmol) in DMF (5 mL) was treated with NaH (Aldrich, 120 mg, 5.04 mmol). The mixture was stirred at approximately 110° C. for 2.5 hours and then at room temperature overnight. The reaction mixture was poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, with 0-100% ethyl acetate in hexanes and then 0-100% THF in ethyl acetate) to give 6-fluoro-5-[(R)-3-hydroxy-pyrrolidin-1-yl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow-green solid. (Yield 6 mg, 5%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]([CH3:35])[CH2:33][NH2:34])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:34][CH2:33][CH:32]([C:27]2[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=2)[CH3:35])=[O:8])=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
4-Chloro-2-(2,4-difluoro-benzenesulfonylamino)-benzoic acid was coupled with (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=12.04 min. MS (ESI−): mass calcd. for C22H17Cl3FN2O3S2, 532.00; m/z found, 531/533 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.41 (s, 1H), 8.00 (ddd, J=8.6, 8.6, 6.0, 1H), 7.61 (d, J=2.0, 1H), 7.42 (d, J=8.2, 1H), 7.32 (d, J=2.1, 1H), 7.11 (d, J=8.4, 1H), 7.08 (dd, J=8.2, 2.1, 1H), 7.03-6.97 (m, 1H), 6.97 (dd, J=8.4, 2.0, 1H), 6.92-6.86 (m, 1H), 6.02-5.95 (br m, 1H), 3.76-3.68 (m, 1H), 3.41-3.31 (m, 1H), 3.11-3.01 (m, 1H), 1.32 (d, J=7.0, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.ClCCl.N1C=CN=C1.[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)Cl)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: NC(=O)Cc1coc2cc(O)ccc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(CC(N)=O)coc2c1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 77.6 %

Procedure:
To a solution of 2-(6-hydroxy-benzofuran-3-yl)-acetamide (0.23 g, 1.20 mmol) in a mixture of dry dichloromethane (20 mL) and DMF (6 mL) was added imidazole (0.34 g, 5.05 mmol), followed by tert-butyldiphenylchlorosilane (1.31 mL, 5.05 mmol) at room temperature and the mixture was stirred for two days. The solution was quenched with methanol and stirred for 10 min. The solvent was evaporated in vacuo and the residue was purified by column chromatography (methanol:dichloromethane; 5:95) to give the 2-[6-(tert-butyl-diphenyl-silanyloxy)-benzofuran-3-yl]-acetamide as a white solid (0.40 g, 78%). 1H NMR (DMSO-d6, 400 MHz) 1.06 (s, 9H), 3.38 (s, 2H), 6.74 (dd, J=1.8, 8.4 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.42-7.54 (m, 7H), 7.64 (s, 1H), 7.70 (m, 4H), 7.80 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:14]1[C:15]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]3)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Temperature: 70 °C
Yield: 23.8 %

Procedure:
A mixture of 6-bromo-1-chloro-naphthalen-2-ol (11.2 g, 43.5 mmol), benzothiophene-2-boronic acid (15.1 g, 85.0 mmol) in three portions, palladium (II) acetate (0.76 g, 3.43 mmol) in three portions, potassium carbonate (30.1 g, 224 mmol) in three portions, tetrabutylammonium bromide (14.0 g, 43.5 mmol) in water (65 mL) and THF (40 mL) was heated at 70° C. for 8.5 hours. The reaction mixture was allowed to cool to ambient temperature and then poured into excess 2N hydrochloric acid. It was extracted with chloroform. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography using 100% chloroform, 30–50% 1,2-dichloroethane in hexane and 20–30% 1,2-dichloroethane in hexane (Biotage apparatus) eluent. Drying at 60° C. in vacuo for 20 minutes yielded 6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-ol as a beige-yellow solid (3.22 g, 23.9%) MP: 220–1° C.; Mass spectrum (−ES, [M−H]−) m/z 309/311. 1H NMR (500 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.26 (d, 1H, J=1.73 Hz), 8.11 (d, 1H, J=8.85 Hz), 8.05 (dd, 1H, J=8.85 and 1.83 Hz), 7.95–8.01 (m, 2H), 7.87–7.92 (m, 2H), 7.33–7.43 ppm (m, 3H). Elemental Analysis for C18H11ClOS: Calcd: C, 69.56; H, 3.57; N, 0.00; Found: C, 69.58; H, 3.83; N, 0.00.
Reaction SMILES: B(F)(F)F.CCOCC.[I:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([O:17][CH:18]([C:27]#[N:28])[C:19]2([CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:22][O:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]([CH:18]1[C:19]2([CH:23]3[CH2:24][CH2:25][CH2:26]3)[CH2:22][O:21][C:15]([C:14]3[CH:13]=[CH:12][C:11]([I:10])=[CH:30][CH:29]=3)([O:16][CH2:20]2)[O:17]1)#[N:28]
Reactant: N#CC(OC(=O)c1ccc(I)cc1)C1(C2CCC2)COC1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: N#CC1OC2(c3ccc(I)cc3)OCC1(C1CCC1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Boron trifluoride etherate (1 ml) was added to a stirred solution of 1-cyano-1(3-cyclobutyloxetan-3-yl)methyl 4-iodobenzoate (2.3 g, 5.8 mmol) in dry dichloromethane (30 ml) at -70° C. under a nitrogen atmosphere. The solution was allowed to warm to room temperature and was stirred overnight. Triethylamine (1 ml) was added, the solution was evaporated to dryness to leave a gum which was partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous potassium carbonate and evaporated. The residue was chromatographed on basic alumina, eluting with hexane:dichloromethane (4:1 v/v) to give 3-cyano-4-cyclobutyl-1(4-iodophenyl)-2,6,7-trioxabicyclo[2.2.2]octane as a white solid (1.05 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>C(O)(=O)C.O>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[NH:14][C:15](=[O:16])[NH:1]2)([O-:13])=[O:12]
Reactant: NC(N)=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c([N+](=O)[O-])cccc2[nH]1
Yield: 64.6 %

Procedure:
A mixture of 2-amino-6-nitro-benzoic acid (60 g, 329 mmol) and urea (257.3 g, 4285 mmol) in acetic acid (1.65 lit.) was heated to reflux for 24 h. The acetic acid was evaporated under reduced pressure and the residue obtained was diluted with water (2.5 lit). The solid product separated out was filtered and washed with water. The product was collected and dried in an air oven to give 44 g of the product as a yellow solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 11.58 (br. s, 1H); 11.55 (br.s, 1H); 7.76 (t, J=8.4, 1H); 7.41 (d, J=7.8, 1H); 7.32 (d, J=8.4, 1H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([NH:27][S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3].[C:38](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[C:25]([N:27]([S:28]([CH:31]2[CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH3:38])=[O:26])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)NS(=O)(=O)C2CC2)C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)N(C)S(=O)(=O)C2CC2)C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide (8 mg, 0.014 mmol; Example 177, Step B) in DMF (1.0 mL) was added potassium carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 μL, 0.017 mmol) at rt. The reaction was stirred for 1 hour. After this time more iodomethane (1.1 μL, 0.017 mmol) and potassium carbonate (2.9 mg, 0.021 mmol) was added and the reaction was stirred at rt for 60 hours. After this time the reaction was partitioned between EtOAc (20 mL) and 1.0 M LiCl (5 mL). The separated organic layer was washed with 1.0 M LiCl (5 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>C(#N)C.C(Cl)Cl>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Reaction time: 1 h

Procedure:
Piperazine (24.46 g) is dissolved in acetonitrile (200 ml) and anhydrous potassium carbonate (10.47 g) is added. Then 2-chloronitrobenzene (10.0 g) is added dropwise. After stirring 1 hr at 20°, the reaction mixture is diluted with methylene chloride, washed with water, and saturated aqueous potassium carbonate. After drying over anhydrous sodium sulfate, the reaction mixture is concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 7.75, 7.49, 7.14, 7.04, 3.03 and 1.93δ.