Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:17][C:18]1[CH:19]=[C:20]([O:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:27]2[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[N:26]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(Oc2cccc(Cl)c2)n[nH]1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(Cl)c2)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 86.4 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and phenyl isocyanate (0.15 g, 1.3 mmol) were added to a solution of 3-(3-chlorophenyloxy)-5-methylpyrazole (0.25 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-phenyl-3-(3-chlorophenyloxy)-5-methylpyrazole-1-carboxamide (0.34 g, yield: 84.5%). 1H-NMR (CDCl3, TMS, ppm): δ 2.66 (d, J=0.8 Hz, 3H), 5.78 (q, J=0.8 Hz, 1H), 7.05-7.11 (m, 1H), 7.14-7.21 (m, 3H), 7.28-7.39 (m, 3H), 7.52-7.56 (m, 2H), 8.91 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CC([O-])=O.[Na+].C(O)C>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([O:21][N:22]=[C:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 4-piperidinone (2.5 mmol) in 25 mL of DCM, was added 69b (0.43 g, 2 mmol). The mixture was stirred at room temperature for 2 h. NaOAc (0.27 g, 2 mmol) and ethanol (10 mL) were added and the reaction mixture was heated at 70° C. for 2 h. The solution was allowed to cool down to room temperature and the ethanol was evaporated. The residue was extracted with ethyl acetate, washed with water, dried and concentrated to give 0.59 g of 69c.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]>>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[O:12][CH2:4]1
Reactant: C[S+](C)C
Reactant: O=Cc1ccccc1Br
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: Brc1ccccc1C1CO1

Procedure:
Following the procedure of Example 7 and employing 42.0 g of 57% of sodium hydride in mineral oil, 200 g (0.1 mol) of trimethylsulfonium iodide and 70.4 g (0.50 mol) of o-bromo-benzaldehyde there is obtained o-bromostyrene oxide.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:43][N:41]1[C:40](=[O:44])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([CH3:1])=[CH2:35])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:5][C:6]3=[O:28])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)N1
Reactant: Cn1cc(Br)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)N1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
(S)-4-(2-methylallyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one (38 mg, 0.08 mmol), 5-bromo-1-methylpyridin-2(1H)-one (23 mg, 1.5 equiv.), Pd(PPh3)2Cl2 (2 mg, cat. amount), 2M aq Na2CO3 (500 μL, excess), and 1,4-Dioxane (4 mL) were mixed. The mixture was evacuated and refilled with nitrogen gas (3×), before being heated to 90° C. overnight. After being cooled down, the mixture was concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-1-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-4-(2-methylallyl)-4-phenyl-1,3-diazepan-2-one (16 mg, 44%). LC-MS Method 1 tR=1.76 min., m/z 456 (M+1); 1H NMR (CD3OD) δ 7.90 (s, 1H), 7.80 (dd, 1H), 7.47 (d, 2H), 7.39 (t, 2H), 7.30 (d, 3H), 6.96 (d, 2H), 6.61 (d, 1H), 5.32 (q, 1H), 5.02 (d, 1H), 3.61 (s, 3H), 2.59-2.45 (m, 2H), 1.49 (d, 3H), 1.15 (s, 3H).
Reaction SMILES: [ClH:1].[C:2](#[N:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([OH:10])[CH3:9]>>[ClH:1].[CH2:8]([O:10][C:2](=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH3:9]
Reactant: CCCCC#N
Reactant: CCO
Agent: Cl
Product: CCCCC(=N)OCC
Temperature: 0 °C
Reaction time: 144 h

Procedure:
Hydrogen chloride gas was bubbled into a tared solution of valeronitrile (92.0 g, 1.08 mole) in absolute ethanol (64 ml, 1.08 mole) in a 1-liter round bottom flask cooled to 0° C. The flask was weighed periodically and hydrogen chloride gas bubbling was continued until the weight gain was greater than 39 g (1.08 mole). The mixture was then stoppered and stored at 0° C. for 6 days. Ether (650 mi) was then added (cold) and the mixture was stored at -30° C. for 24 hours. The resulting solid was collected on a buchner funnel, transferred quickly to a large beaker, triturated quickly with cold ether, and collected again on a buchner funnel. The solid was then dried in vacuum to give the title F compound as a free flowing white solid (95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.CS(C)=O.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCC(CO)c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)CCC(C=O)c1ccc(Cl)c(Cl)c1

Procedure:
2-(3,4-Dichlorophenyl)-4-(dimethyamino)-butanol (1.40 g) was reacted with oxalyl chloride/DMSO under standard swern oxidizing conditions in DCM (80 mL) to afford (1.60 g crude) as a oil which was contaminated with tetrabutyammonium cation after aqueous extraction from DCM; MS: m/z 260 (M+); 1H NMR (CDCl3) δ 9.57 (d), 7.44 (d), 7.33 (d), 7.07 (dd), 3.66 (t), 2.35-2.03 (m), 2.22 (s).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16]Br)[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:16][N:22]3[C:21](=[O:23])[C:20]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]4[C:18]3=[O:28])[C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(CBr)c(=O)oc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1
Yield: 48.7 %

Procedure:
7-acetoxy-3-bromomethylcoumarin (630 mg) was stirred overnight with potassium phthalimide (432 mg, 2.33 mmol) in DMF (100 mL). The reaction solvent was evaporated and the reaction partitioned between CH2Cl2 and water, then washed several times with water, then with aqueous NaHCO3. The organic layer was dried with brine, then with anhydrous sodium sulfate and evaporated. The crude product was recrystallized in acetic acid to give 7-acetoxy-3-phthalimidomethylcoumarin (375 mg, >95% purity), an off-white solid. 1H NMR (CDCl3): δ7.73-7.97 (m, 4H), 7.53 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.03 (dd, J=7.5, 2.1, 1H), 4.82 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([CH2:12]O)[CH:3]=1.CN1CCN(C)C1=O.C([Mg]Cl)(C)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:8]([CH3:9])[CH2:12]2
Reactant: CNC(=O)c1ccc(Br)cc1CO
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: CN1Cc2cc(Br)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A 150 mL sealed tube was charged with 4-bromo-2-(hydroxymethyl)-N-methylbenzamide (3.34 g, 13.7 mmol) and 1,3-dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0° C. and Isopropylmagnesium chloride (15.3 ml, 30.5 mmol) was added slowly. The tube was capped and the reaction mixture was stirred at room temperature for 30 minutes. This was recooled to 0° C. and N,N,N,N-tetramethylphosphorodiamidoyl chloride (2.64 ml, 17.8 mmol) was added in one portion; this mixture was stirred at room temperature for 4 hours. The tube was placed in a 150° C. oil bath for 1 hour. The mixture was then diluted with EtOAc (100 mL), then washed with 1M aqueous HCl. The aqueous layer was extracted with ethyl acetate (3×100 mL) and then the combined organics were washed with water (100 mL) and brine (100 mL), dried with MgSO4, filtered, then concentrated to give a yellow oil. This was purified by column chromatography, eluting with 1-4% MeOH/DCM to give 5-bromo-2-methylisoindolin-1-one (1.774 g, 57.3% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:41]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[NH2:41][C:10]1[CH:11]=[C:12]([C@@H:15]([O:37][C:38](=[O:40])[CH3:39])[CH2:16][N:17]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c(N)c1

Procedure:
Acetic acid (R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester in a mixture of THF and toluene is stirred under hydrogen in the presence of PtO2 at room temperature for 15 hours. The mixture is filtered through celite and the filtrate is concentrated in vacuo. ES+ MS m/e 549 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([CH2:9][C:10](OC)=[O:11])#[N:8]>>[N:1]1([C:10](=[O:11])[CH2:9][C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COC(=O)CC#N
Product: N#CCC(=O)N1CCOCC1
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A nitrogen inerted reactor equipped with reflux condenser, nitrogen inlet and mechanical stirring is charged with morpholine (1.2 mol), methyl cyanoacetate (1.0 mol) and MtBE (52 mL). The homogeneous solution is heated to ca. 55° C. and stirred at that temperature for 12 to 18 hours. MtBE (33 mL) is added over ca. 15 minutes, and the solution is slowly cooled below 50° C. where nucleation becomes evident. Additional MtBE (66 mL) is added over a 1-hour period. During this time, the reaction is allowed to cool to near ambient temperature. After complete MtBE addition, the reaction is cooled with stirring to ca. 0° C. The resulting precipitate is collected via filtration and the cake is washed with additional MtBE (ca. 40 mL). The solid is dried under vacuum at ca. 45° C. to provide 3-morpholin-4-yl-3-oxo-propionitrile (139 g). This material is used in subsequent steps without further purification.
Reaction SMILES: Br.C([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)OC1=O)=[O:16])=[O:6])C>C(O)(=O)C>[O:16]=[C:15]1[NH:17][CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([OH:4])=[O:6]
Reactant: CCOC(=O)CCCCCCCNC(=O)n1cc(-c2ccccc2)oc1=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)c[nH]c1=O

Procedure:
A mixture of 800 ml of glacial acetic acid and 80 ml of 63 percent hydrobromic acid is poured over 37.4 g (0.1 mole) of N-ethyoxycarbonylheptyl-2-oxo-5-phenyl-4-oxazolin-3-ylcarboxamide and the mixture is heated under reflux for 2 hours and evaporated as completely as possible in vacuo. The residue is stirred with water. The crude product which is precipitated is separated and washed with a little water. After drying, the compound is purified by column chromatography (silica gel//CHCl3 /methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14](Cl)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:17][NH2:18]>>[CH3:17][NH:18][C:14](=[O:15])[CH2:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1
Reactant: CN
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1OC
Product: CNC(=O)Cc1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 16, react 3,4,5-trimethoxybenzeneacetyl chloride with methylamine to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C1C=CN=C(C2C=[CH:17][CH:18]=[CH:19]N=2)C=1.C1(B(O)O)CC1.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:17]1([N:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]2=[O:8])[CH2:18][CH2:19]1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: O=c1cc(I)cc[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: O=c1cc(I)ccn1C1CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of 4-iodopyridin-2(1H)-one (0.2425 g, 1.10 mmol, 1.0 equiv), Cu(OAc)2 (0.2146 g, 1.18 mmol, 1.07 equiv), bipyridine (0.1832 g, 1.17 mmol, 1.07 equiv), cyclopropylboronic acid (0.2122 g, 2.47 mmol, 2.25 equiv) and Na2CO3 (0.2638 g, 2.49 mmol, 2.27 equiv) in dichloroethane (10 mL) was stirred at 70° C. for 18 h. The reaction mixture was quenched with satd aq NH4Cl, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.2309 g (81%) of 1-cyclopropyl-4-iodopyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1)CCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1

Procedure:
Prepared in an analogous manner to Example 6 according to Procedure B from (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine and 5-(tributylstannyl)-1-methylimidazole; δH [2H6]DMSO 9.98(1H,s), 8.62(1H,s), 8.55(1H,s), 8.20(1H,s), 8.15(1H,s), 7.99(1H,dd), 7.83(2H,m), 7.70(2H,m), 7.28(6H,m), 5.70(2H,s), 3.70(3H,s); m/z (M+1)+432.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1.CC1(C)COB(C2N(C)N=CC=2)OC1>O1CCOCC1.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>[CH3:16][N:17]1[C:21]([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)=[CH:20][CH:19]=[N:18]1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1nccc1B1OCC(C)(C)CO1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-3-thiophenecarboxylic acid (875 mg, 4.23 mmol) in dioxane/H2O (5:1, 21 mL) was added K2CO3 (205 mg, 14.8 mmol), tetrakistriphenylphosphine Pd(0) (297 mg, 0.26 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (988 mg, 4.75 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 5 h, additional tetrakistriphenylphosphine Pd(0) (108 mg, 0.1 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (989 mg, 4.75 mmol) were added. After 12 h, the reaction solution was then partitioned between H2O—CHCl3, and the aqueous phase was washed several times with CHCl3. The aqueous phase was then adjusted to pH 3 with 2.5M HCl and the aqueous phase extracted with CHCl3. The combined organics were dried (Na2SO4), concentrated under vacuum and dried under high vacuum overnight and used without further purification: LC-MS (ES) m/z=209 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:20][CH2:19][CH2:18][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(CCO[Si](C)(C)C(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoazepan-3-ylcarbamate was prepared from compound (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and (2-bromoethoxy)(tert-butyl)dimethylsilane according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 25% ethyl acetate/hexanes, to provide compound (2f) in 48% yield.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13])#[N:2].[SH2:14].[Na].Cl.C(N(CC)CC)C>O1CCOCC1.O>[NH2:2][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:13])=[S:14]
Reactant: S
Reactant: COC(=O)c1ccc(C#N)c(C)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(N)=S)c(C)c1
Temperature: 55 °C

Procedure:
To a solution of methyl 4-cyano-3-methylbenzoate (36 mg, 0.205 mmol) in 1,4-dioxane (0.5 mL) and water (0.500 mL), was added sodium hydrogen sulfide (0.019 mL, 0.616 mmol) and triethylamine hydrochloride (170 mg, 1.233 mmol). The reaction mixture was heated at 55° C. overnight. The reaction was allowed to cool and water was added. The mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo to give the product as a yellow solid. LCMS calc.=210.1; found=210.2 (M+1)+. 1H NMR (500 MHz, CDCl3) 7.86 (s, 1H); 7.84 (d, J=8.1 Hz, 1H); 7.42 (d, J=7.9 Hz, 1H); 7.16 (s, 2H); 3.93 (s, 3H); 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[I:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:27][NH:26][C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([I:19])=[CH:29][CH:28]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (5.0 g, 18.6 mmol), 4-iodobenzhydrazide (CAS 3915-95-2, 4.88 g, 18.6 mmol) and 1-hydroxybenzotriazole hydrate (2.85 g, 18.6 mmol) were placed in a 250 mL round bottomed flask. Anhydrous THF (120 mL) was added and the mixture was cooled to −20° C. N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (5.35 g, 27.9 mmol) was added, followed by Et3N (3.9 mL, 28.0 mmol). The reaction mixture was stirred at −20° C. for h and room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc, which was washed with 5% aqueous NaOH, water, brine and dried over Na2SO4. The extracts were filtered and the filtrate was concentrated to provide a brown solid, which was purified by flash chromatography (80% EtOAc in hexanes) to afford the title compound (7.3 g, 77%), which was used directly in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9](=[O:11])[CH3:10])C=CC=CC=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[C:35]([O:36][CH2:37][CH2:38][F:39])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>O1CCCC1>[CH3:8][C:9]([CH:10]=[CH:30][C:29]1[C:28]([O:27][CH2:26][CH2:25][F:24])=[C:35]([O:36][CH2:37][CH2:38][F:39])[CH:34]=[CH:33][CH:32]=1)=[O:11]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(OCCF)c1OCCF
Solvent: C1CCOC1
Product: CC(=O)C=Cc1cccc(OCCF)c1OCCF
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
To a stirred, cold (0° C.) solution of 5.2 grams (0.016 mole) 1-triphenylphosphoranylidene-2-propanone in 50 ml of dry tetrahydrofuran was added dropwise a solution of 3.4 grams (0.015 mole) of 2,3-di(2-fluoroethoxy)benzaldehyde in 25 ml of dry tetrahydrofuran. After complete addition the reaction mixture was allowed to warm to room temperature and was then heated at reflux for three hours. The mixture was cooled to room temperature and stirred for approximately 18 hours. The solvent was removed by evaporation under reduced pressure leaving a residue. This residue was partitioned between diethyl ether and water. The organic phase was washed with an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a brown residue. This residue was purified by column chromatography on silica gel, eluting with acetone:n-heptane (20:80), to yield 2.3 grams of 3-(methylcarbonylethenyl)-1,2-di(2-fluoroethoxy)benzene as a solid, mp 71°-72° C.