Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[CH:10][C:11]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[OH:12])[CH2:6]2.C[I:24].[C:25]([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[I-:24].[OH:12][C:11]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH:10]=[C:5]1[CH2:4][CH:3]2[N+:2]([CH3:25])([CH3:1])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1
Reactant: CN1C2CCC1CC(=CC(O)(c1cccs1)c1cccs1)C2
Reactant: CI
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C[N+]1(C)C2CCC1CC(=CC(O)(c1cccs1)c1cccs1)C2
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A solution of 2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-1,1-di-thiophen-2-yl-ethanol (10 mg, 0.03 mmol) in CH3CN (1 mL) and CH2Cl2 (0.5 mL) was mixed with methyliodide (0.038 mL, 0.6 mmol) and K2CO3 (0.1 g, 0.7 mmol). The mixture was stirred overnight at r.t. and filtered. Separation via a reverse-phase HPLC then afforded the title compound (10 mg, 96%): LCMS (ES) m/z 346 (M+H)+; 1H-NMR(CDCl3) δ 1.28 (m, 1H), 2.04 (m, 2H), 2.29 (m, 1H), 2.51 (m, 2H), 2.64 (m, 1H), 3.30 (s, 6H), 4.07 (m, 1H), 4.38 (m, 1H), 5.93 (s, 1H), 6.62 (m, 1H), 6.85 (m, 1H), 6.98 (m, 1H), 7.03 (m, 1H), 7.11 (m, 1H), 7.46 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].C([O:41][C:42]([N:44]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.Cl.[C:52](OC(=O)C)(=O)C>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:42]([N:44]1[CH2:50][CH2:49][CH2:48][N:47]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]3[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:46][CH2:45]1)(=[O:41])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCN(c2cc(-c3ccccc3C)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Temperature: 150 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
A mixture of 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 17; 100 mg) and 1-(t-butoxycarbonyl)homopiperazine (95.0 mg) was stirred at 150° C. for 5 hours. While the resulting residue was chilled on an ice bath, a 3 mol/L ethyl acetate solution of hydrogen chloride (1 mL) was added, and then the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation to obtain a residue, and then the residue was dissolved in tetrahydrofuran (1 mL). While the resulting solution was chilled on an ice bath, triethylamine (0.2 mL) and acetic anhydride (0.1 mL) were added, and then the mixture was stirred for 1 hour. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water, and was then dried on anhydrous sodium sulfate. The solvent was removed by distillation to obtain a residue, and then the residue was purified on a silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (42.7 mg, 36%).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.FC(F)(F)C([O-])=[O:11].[Cl:15][CH2:16][C@H:17]([OH:20])C[NH3+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>ClCCl>[Cl:15][CH2:16][CH:17]1[O:20][C:4](=[O:11])[NH:3][C@@H:6]1[CH3:7]
Reactant: CCN(CC)CC
Reactant: [NH3+]C[C@@H](O)CCl
Reactant: O=C([O-])C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H]1NC(=O)OC1CCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (370 μl, 2.65 mmol) was added slowly to a mixture of (R)-3-chloro-2-hydroxypropan-1-aminium 2,2,2-trifluoroacetate (210 mg, 0.88 mmol) in dichloromethane (2.0 mL) at 0° C. The mixture was stirred for 15 minutes. A mixture of triphosgene (89 mg, 0.30 mmol) in dichloromethane (15 mL) was added drop wise via addition funnel. The mixture was allowed to warm to room temperature for 14 h, and then diethyl ether (2.0 mL) was added and the mixture was cooled to −78° C. The solids were filtered and the filtrate was concentrated under reduced pressure to about 1 mL. The mixture was then added to a plug of silica gel and washed slowly with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and dried under vacuum to afford crude (4R)-5-(chloromethyl)-4-methyloxazolidin-2-one that was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1.[CH3:31]I.Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11](=[C:29]([NH:28][C:23]2[CH:22]=[C:21]([Cl:20])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[S:30][CH3:31])[C:12]#[N:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of 4-chlorophenylsulfonylacetonitrile (1.00 g, 4.6 mmol) in dry acetone (10 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 3,5-dichlorophenyl isothiocyanate (0.99 g, 4.9 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 4 h, and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 45 min. Then pH was adjusted to 1 with 1N aqueous HCl. The precipitate was filtered off and washed with water to give 1.86 g (93%) of a crude product. Recrystallisation from ethyl acetate/heptane (1:1) gave 1.42 g (72%) of the title compound contaminated with 4-chlorophenylsulfonylacetonitrile. Mp 128-131° C. 1H NMR (200 MHz, CDCl3): δ=2.25 (s, 3H), 7.20 (d, 2H), 7.30 (t, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 9.80 (br s, 1H); EI SP/MS: 434 (M+), 436 (M+2).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 22 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (1.9 g) and 6-bromo-1-phenyl-1-hexanone (1.7 g) were reacted and treated in the same manner as in Example 172 to give 0.56 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-oxo-6-phenylhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C.O>C(#N)C.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.[Cu]I>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
To a solution of methyl 4-iodobenzoate (20 g, 76 mmol), propargyl alcohol (5.55 g, 99.0 mmol) and triethylamine (20 mL) in acetonitrile (200 mL) was added dichlorobis(triphenylphosphine)palladium(II) (1.55 g, 2.21 mmol), followed by CuI (454 mg, 2.38 mmol). The reaction mixture was stirred at room temperature for 24 h. Water was added and the aqueous solution was washed with EtOAc (3×). The organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]=[O:14].S(=O)(=O)(O)O>O1CCCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17]=1[O:18][CH3:19])[CH:13]([OH:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 2 h

Procedure:
25 ml of 2M phenyl lithium solution (in benzene/ether (7:3)) are added dropwise within 15 minutes to 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuran and the mixture is stirred at 0° for 1 hour and at 20° for 2 hours. The mixture is subsequently treated with 150 ml of 2N sulfuric acid and extracted three times with 150 ml of ether. The combined ether phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromatographed on 180 g of silica gel with methylene chloride. There is obtained 3,4-dimethoxy-5-nitrobenzhydrol as an amorphous solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-methylpiperidine (130.86 mg, 1.32 mmol, 3.00 equiv), DIEA (170.28 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:7). This resulted in 60 mg (36%) of methyl 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: Clc1ccc(Br)cc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(Br)ccc1Cl)OCC
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 9.88 g 5-bromo-2-chloro-benzylbromide in 6.10 ml triethylphosphite is stirred for 3 h at 130° C. Then a further 1.50 ml triethylphosphite are added, and the mixture is stirred for a further 3 h at 160° C. After cooling to ambient temperature the mixture is purified on silica gel (dichloromethane/methanol 1:0->9:1).
Reaction SMILES: C[OH:2].[Mg].[CH:4]([C:7]1(CCC(OC)=O)[NH:11][CH:10]=[CH:9][S:8]1)([CH3:6])[CH3:5].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH:4]([C:7]1[S:8][CH:9]=[C:10]([CH2:18][CH2:19][C:20]([O:21][CH3:22])=[O:2])[N:11]=1)([CH3:5])[CH3:6]
Reactant: COC(=O)CCC1(C(C)C)NC=CS1
Reactant: C1CCOC1
Reactant: CO
Agent: [Mg]
Product: COC(=O)CCc1csc(C(C)C)n1

Procedure:
A solution of 225 mg (1 mmol) of (E)-ethyl 3-(2-isopropyl-4-thiazolyl) propenoate in 10 ml of freshly distilled (from calcium hydride) methanol and 1 ml of dry THF was treated with 49 mg (2 mmol) of magnesium turnings. The mixture was stirred for 20 min, during which the magnesium was consumed. The resulting solution was poured over cold aqueous HCl, basified to pH 8 with NaHCO3, extracted with ethyl acetate, dried over Na2SO4, and concentrated. Silica gel chromatography using 10% ethyl acetate in hexane provided a mixture of the desired compound and methyl 3-(2-isopropyl-4-thiazolinyl)propanoate.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\Cl.C(N)CCC.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1]/[CH:2]=[CH:3]\[C:15]#[C:14][CH:13]([O:16][CH2:17][CH3:18])[O:12][CH2:10][CH3:11]
Reactant: Cl/C=C\Cl
Reactant: C#CC(OCC)OCC
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCN
Product: CCOC(C#C/C=C\Cl)OCC
Temperature: 25 °C
Reaction time: 4.2 h
Yield: 53 %

Procedure:
Neat cis-1,2-dichloroethylene (4.5 ml, 60 mmol) followed by butylamine (8.0 ml, 81 mmol) was added to a solution of copper iodide (0.90 g, 4.73 mmol) and palladium tetrakis(triphenylphosphine) (1 g, 0.86 mmol) in 40 mL of dry benzene stirring at 25° C. under argon. Immediately thereafter, a solution of 3,3-diethoxy-propyne (5 g, 39 mmol) in 10 mL of benzene was added via cannula. The reaction vessel was wrapped in foil to shield it from light, and the reaction mixture was stirred for 4.2 h at 25° C. The dark brown reaction mixture was filtered by suction through a coarse frit and diluted to approximately 180 ml with diethylether. The solution was washed with 75 mL of water and 120 mL saturated brine, and the organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was flash chromatographed in SiO2 using 5%, then 10%, and then 15% diethyolether/pentane as eluent to provide the desired product as clear liquid (3.9 g, 55%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]2[N:12]([N:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=2)[C:13]([I:16])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[C:13]([I:16])[N:12]2[N:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(I)n2nc(C(F)(F)F)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(I)n2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
The compound of Example 92 (4.57 g) was dissolved in tetrahydrofuran (50.0 mL). While this solution was chilled in an ice bath, 1.0 mol/L tetran-butyl ammonium fluoride/tetrahydrofuran solution (12.0 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, water was added and the reaction mixture was extracted with ethylacetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (hexane:ethyl acetate=2:1) afforded the title compound as a pale yellow powder (3.26 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7]C(O)=O.C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[C:19](=[O:23])[NH:16][CH:7]=[CH:6]2
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2c(=O)[nH]ccc2c1
Temperature: 210 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 3-methoxy cinnamic acid (11.04 g, 62 mmol), triethylamine (12.52 g, 124 mmol) in acetone (80 mL) was added ethyl chloroformate dropwise at 0° C. After stirring at this temperature for 1 h, aqueous NaN3 (6.40 g, 100 mmol in 35 mL H2O) was added dropwise and the reaction mixture was stirred for 16 h at the ambient temperature. Water (100 mL) was added to the mixture and the volatile was removed in vacuo. The resulting slurry was extracted with toluene (3×50 mL) and the combined organic layers were dried over MgSO4. This dried solution was added dropwise to a heated solution of diphenylmethane (50 mL) and tributylamine (30 mL) at 190° C. The toluene was distilled off as added. After complete addition, the reaction temperature was raised to 210° C. for 2 h. After cooling, the precipitated product was collected by filtration, washed with hexane (2×50 mL), dried to yield a white solid (5.53 g, 51%), MS m/z 176 (M++H).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].Cl[C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][C@@H:18]3[CH2:20][C@H:15]2[CH2:16][N:17]3[C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([CH3:33])[C:24]=2[CH3:34])[CH3:22])=[O:13])=[CH:8][CH:7]=1>C1COCC1.CN1CCCC1=O.[Cl-].[Na+].O>[CH2:1]([C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][C@@H:18]3[CH2:20][C@H:15]2[CH2:16][N:17]3[C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH3:32])=[C:25]([CH3:33])[C:24]=2[CH3:34])[CH3:22])=[O:13])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(Cl)nc2)c(C)c1C
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2ccc(CC)nc2)c(C)c1C
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Fe(acac)3 (5 mg) followed by EtMgBr (0.73 mL, 1N in THF) is added to a solution of the amide obtained in Example 4 (129 mg) in 3 mL of THF and 0.3 mL of N-methylpyrrolidinone at room temperature under N2. The dark purple reaction mixture is stirred at room temperature for 50 min and then diluted with brine and extracted 3 times with EtOAc (10 mL). The combined extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by preparative thin layer chromatography, developing 2 times with 25-1 CHCl3-MeOH (25-1) to afford the desired product. LC/MS: 422 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=S.Cl.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([OH:38])[CH:26]([NH:29][C:30](=[O:37])[CH:31]([NH2:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH3:28].O1[C:43]2C=CC=[CH:47][C:42]=2N=C1C(C(NC(=O)C(NC1C2C=CC=CC=2S(=O)(=O)N=1)CC(C)C)CC)=O>>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([OH:38])[CH:26]([NH:29][C:30](=[O:37])[CH:31]([NH:36][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[N:4][CH2:3][C:2]([F:14])([F:13])[F:1])[CH2:32][CH:33]1[CH2:34][CH2:47][CH2:42][CH2:43][CH2:35]1)[CH2:27][CH3:28]
Reactant: CCC(NC(=O)C(CC(C)C)NC1=NS(=O)(=O)c2ccccc21)C(=O)c1nc2ccccc2o1
Reactant: FC(F)(F)CNC(=S)N1CCOCC1
Reactant: CCC(NC(=O)C(N)CC(C)C)C(O)c1nc2ccccc2o1
Agent: Cl
Product: CCC(NC(=O)C(CC1CCCCC1)NC(=NCC(F)(F)F)N1CCOCC1)C(O)c1nc2ccccc2o1

Procedure:
Proceeding as described in Example 5 above, but substituting (morpholin-4-yl-carbothioyl)carbamic acid ethyl ester with morpholine-4-carbothioic acid (2,2,2-trifluoroethyl)amide and 2-amino-4-methylpentanoic acid [1-(benzoxazol-2-ylhydroxymethyl)propyl]amide hydrochloride with 2-amino-3-cyclohexylpropionic acid [1-(benzoxazol-2-ylhydroxymethyl)propyl]amide hydrochloride (prepared by reacting L-cyclohexyalanine with 2RS-amino-1-benzoxazol-2-yl-1-butanol as described in Example 1, step 2 above) provided N-[1-(benzoxazol-2-yl-hydroxy-methyl)-propyl]-3-cyclohexyl-2-{[N-(2,2,2-trifluoroethyl)-morpholine-4-carboximidoyl]-amino}-propionamide, Mol. Wt.: 553.62. MS: 552.5 (M−1), 554.7 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH2:4][CH2:3]1.C1(CCO)C=CC=CC=1.[H][H]>[Rh]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)CCC/C=C\CC1=CCCC1=O
Agent: Cl[Rh]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: OCCc1ccccc1
Product: COC(=O)CCCCCCC1CCCC1=O

Procedure:
A solution of 8.8 g. of 7-(5-oxo-1-cyclopentenyl)-cis-5-heptenoic acid, methyl ester and 6.6 g. of tris-(triphenylphosphine) rhodium (I) chloride in 800 ml. of 1:1 benzene-ethanol is hydrogenated at 25° and atmospheric pressure until 1 equivalent of hydrogen was absorbed. The solvents are evaporated and the resulting residue dissolved in 1:1 ethyl acetate-hexane and flushed through a silica column. The crude product is then rechromatographed on silica with 15% ethyl acetate in hexane to obtain 7.2 g. of the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](CO)([OH:16])[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:13][C:14](=[O:16])[CH2:15]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reaction time: 3.5 h
Yield: 81.2 %

Procedure:
A solution of EXAMPLE 283E (3.60 g, 9.5 mmol) in THF (100 mL) and water (25 mL) was cooled to 0° C. in an ice bath and treated with sodium periodate (2.42 g, 11.3 mmol). The ice bath was removed, and the mixture stirred for 3.5 h. The mixture was diluted with EtOAc (200 mL), washed with brine (3×), then dried (MgSO4). Solvent removal and drying under vacuum provided the product as a tan solid (2.68 g).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
Place t-butylamine (4.32 mL, 41.1 mmol), triethylamine (8.15 mL, 58.7 mmol) and dichloromethane (75 mL) in a 3-neck round bottom flask. Cool this stirring solution to 0° C. and add a solution of 4-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) in dichloromethane (50 mL). Add additional dichloromethane (25 mL) and stir the reaction overnight, allowing it to warm to ambient temperature. Evaporate the reaction in vacuo. Suspend the resulting white solid in ethyl acetate and filter it. Concentrate the filtrate in vacuo and purify the resulting residue by flash chromatography (silica gel; 50%-80% gradient CH2Cl2 in hexanes) to provide 9.85 g of 4-bromo-N-tert-butyl-benzenesulfonamide (86%).