Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,6-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)=[CH:2]\[CH3:3].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:1](/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[O:14])=[CH:2]\[CH3:3]
Reactant: C=CC(=O)OC
Reactant: C/C=C/c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C/C=C/c1ccccc1C=CC(=O)OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Under an argon atmosphere, 2-((E)-1-propenyl)bromobenzene (2.1 g, 11.0 mmol), methyl acrylate (4.5 mL, 50 mmol) and triethylamine (1 mL) were added to a solution (15 mL) of palladium (II) diacetate (11 mg, 0.05 mmol) and tris(2-methylphenyl)phosphine (60 mg, 0.2 mmol) in N,N-dimethylformamide, followed by stirring at 80° C. for 1 hour. Next, the reaction solution was filtered through Florisil, and the solvent contained in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane=1/10) to give methyl 2-((E)-1-propenyl)cinnamate (740 mg, yield 34%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:16]([NH:15][CH2:13][CH3:14])=[S:17])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCN=C=S
Reactant: CC(=O)NNc1ccc(N)cc1
Product: CCNC(=S)Nc1ccc(NNC(C)=O)cc1

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (1.65 g, 0.01 mole) and ethyl isothiocyanate (0.87 g, 0.01 mole) were reacted according to procedure (11.). Yield 1.7 g (67%), p.m. 191°-193° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH2:23]OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[N:9]([CH2:16][C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN2C(=O)SC(=Cc3ccc(O)cc3)C2=O)CCCCC1
Yield: 42 %

Procedure:
A solution of compound vii (0.5 mmol), compound iii (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in DMF (3 mL) at 80° C. for 4 hr, poured into water, extracted with ethyl acetate (3×10 mL), dried and concentrated. The residue was purified by chromatography, affording compound 9 in 42% yield. 1H NMR (300 MHz, CDCl3) δ 0.94 (s, 3H), 1.14-1.86 (m, 10H), 3.63 (s, 2H), 5.69 (s, 1H), 6.94 (d, J=8.40 Hz, 2H), 7.43 (d, J=8.40 Hz, 2H), 7.83 (s, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.1141 amu.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[N:16]([CH2:17][CH2:18][CH2:19][OH:20])[C:15]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:14]=2[N:13]=1)(O)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:10])[C:12]2=[N:13][C:14]3[C:15](=[C:21]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:16]2[CH2:17][CH2:18][CH2:19][O:20]1
Reactant: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3(C)c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{2-[1-(2,4-dichlorophenyl)-1-hydroxyethyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 209, 210 mg, 0.500 mmol) and triphenylphosphine (157 mg, 0.600 mmol) in tetrahydrofuran (10 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 342 μL, 0.750 mmol) at room temperature. The mixture was stirred at 40° C. for 12 h, concentrated in vacuo, and purified by column chromatography on NH silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous (97.6 mg, 0.233 mmol, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]([CH3:30])([CH3:29])[C:7]#[C:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N.Cl[Pd]Cl>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]([C:7]1[N:18]([CH2:19][CH2:20][OH:21])[C:10]2[C:9]([CH:8]=1)=[CH:14][C:13]([N+:15]([O-:17])=[O:16])=[CH:12][CH:11]=2)([CH3:30])[CH3:29])[CH3:2]
Reactant: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])ccc1NCCO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A solution of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl}-3,3-dimethyl-pent-4-ynoic acid ethyl ester (600 mg, 1.34 mmol) and PdCl2(650 mg) in CH3CN (30 mL) was heated at reflux overnight. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was dissolved in THF (20 mL) and TBAF (780 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 1 h, the solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (10% ethyl acetate/petroleum) to afford 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J=2.1 Hz, 1H), 8.05 (dd, J=2.1, 9.0 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 6.48 (s, 1H), 4.46 (t, J=6.6 Hz, 2H), 4.00-3.91 (m, 4H), 2.76 (s, 2H), 1.61 (s, 6H), 0.99 (t, J=7.2 Hz, 1H), 0.85 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:19][C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCNCC2)C1
Reaction time: 1 h
Yield: 136.3 %

Procedure:
To a solution of tert-butyl cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (510 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added a 1:1 solution of trifluoroacetic acid (1 mL) in CH2Cl2 (1 mL). After 1 hour, the reaction mixture was diluted with aqueous 1 N NaOH (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane (520 mg). 1H NMR (400 MHz, CDCl3) δ 7.46-7.31 (m, 2H), 7.10-6.98 (m, 2H), 4.54 (d, J=11.8 Hz, 1H), 3.76 (ddd, J=15.7, 11.3, 4.4 Hz, 1H), 3.66-3.46 (m, 2H), 3.09 (dt, J=13.9, 7.0 Hz, 1H), 2.99-2.76 (m, 3H), 2.69-2.21 (m, 2H), 2.17-2.00 (m, 2H), 1.79-1.64 (m, 1H), 1.64-1.49 (m, 1H), 1.50-1.24 (m, 2H), 1.24-1.12 (m, 3H). ESI-MS m/z calc. 293.18, found 294.5 (M+1)+; Retention time: 0.97 minutes (3 minute run).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]1[CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17][N:16]1CC1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C.O.[Pd]>[CH2:1]([O:13][CH2:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOCC1CNCCN1

Procedure:
An 8 g portion of the above piperazine in 130 ml of ethanol and 10 ml of water was hydrogenated with 10% palladium on carbon for 4 hours then filtered and the filtrate evaporated, giving 4.5 g of 2-[(dodecyloxy)methyl]piperazine.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19](C)(C)C)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16]([C@@H:15]1[CH2:23][CH2:24][C@H:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Temperature: 4 °C

Procedure:
0.6 g of tert-butyl cis-4-(4-methoxycarbonylcyclohexyloxy)benzoate (1.79 mmol, 1 eq.) is placed in 2.5 mL of dichloromethane. The reaction medium is cooled to a temperature of 4° C. with stirring in an ice bath. 1 mL of trifluoroacetic acid (13.46 mmol, 7.5 eq.) is added and the ice bath is removed. After stirring for 5 hours at room temperature, the medium is concentrated, taken up in diethyl ether, drained and filtered to give 0.30 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid. M+H+=279.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[NH:2]1.[C:13]([O:16][C:17](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:13][O:16][CH:17]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:12])[NH:2][C:3]1=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccccc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 4H-Isoquinoline-1,3-dione (1.5 g, 9.3 mmol) in 22.5 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (2.0 mL, 18.6 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour, at which point a beige precipitate formed, product. Upon cooling to room temperature, more product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 1.47 g of 4-Methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=2)[C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([NH:22]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:5]([Cl:33])=[CH:4][N:3]=1.Cl>COCCO.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:33][C:5]1[CH:4]=[N:3][C:2]2[NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH:17]=3)[CH2:15][NH:14][C:12](=[O:13])[C:11]3[CH:10]=[C:9]([NH:8][C:6]=1[N:7]=2)[CH:32]=[CH:31][CH:30]=3
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: C1COCCO1
Product: O=C1NCc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Temperature: 150 °C
Yield: 62.5 %

Procedure:
To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4-yl)amino]benzoyl}amino)methyl]phenyl}carbamate (40.0 mg, 0.0819 mmol) in 2-methoxyethanol (0.452 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (100 μL). The resulting mixture was heated at 150° C. in the microwave for 15 min. The cloudy mixture was diluted with Na2CO3 (aq), filtered, washed with water. The crude cake was triturated with MeOH to give the desired product as an off-white powder (18 mg, 62%). LCMS for C18H14ClN5O (M+H)+: m/z=352.0. 1H NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 10.05 (t, J=2.0 Hz, 1H), 9.66 (s, 1H), 9.05 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.62 (t, J=2.0 Hz, 1H), 8.25 (t, J=8.0 Hz, 1H), 8.00 (m, 1H), 7.76 (ddd, J=7.6, 2.0, 1.2, 1H), 7.52 (m, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.02 (m, 1H), 6.90 (m, 1H), 4.32 (s, 2H).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:27][C:28]1[C:33]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1cccnc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A suspension of tert-butyl ({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-fluoropyridin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow oil (yield 87 mg, 41%).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][C:10]#[N:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][OH:13]>CCOCC>[ClH:1].[CH3:12][O:13][C:10](=[NH:11])[CH2:9][CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#CCCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: COC(=N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride is bubbled into a cold (0° C.) solution of 3-phenypropionitrile (5.43 g, 41.4 mmol) in methanol (2.5 mL, 62.1 mmol) for 5 min, and the mixture stirred at rt for 3 h. The solid that formed is suspended in Et2O and filtered to give 7.8 g of the product 242. 1H NMR (CDCl3) δ 12.65 (s, 1 H), 11.65 (s, 1 H), 7.40-7.15 (m, 5 H), 4.24 (s, 3 H), 3.08 (s, 4 H)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](N)Cc1ccccc1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
A sample of the compound from step 4a (790 mg, 4.48 mmole) was dissolved in 30 mL of THF and 6 mL of water, triphenylphosphine (5.0 g, 19.1 mmole) was added, and the reaction mixture was stfired for 24 hours at reflux. The solvent was removed, and the residue was dissolved in 2 N HCl. NaCl was added, and the solution was extracted with ethyl ether. The aqueous layer was adjusted to pH 12 with K2CO3, saturated with NaCl, then extracted with GICl3 and CHCl3 containing 15% isopropanol. The solvent was removed under vacuum to afford 439 mg of the title compound. MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
Reaction SMILES: O[N:2]=[C:3]([C:15](=[O:17])[CH3:16])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].O.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C.[Zn]>[C:19]([NH:2][CH:3]([C:15](=[O:17])[CH3:16])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1ccc(NC(=O)C(=NO)C(C)=O)cc1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)C(NC(C)=O)C(C)=O)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 11.8 of 2-(hydroxyimino)-N-(4-methoxyphenyl)-3-oxobutanamide in 30 ml of acetic acid and 10 ml of acetic anhydride at 20°-30° C. is added 10 g of zinc dust and the mixture is stirred for 1 hour. Water (150 ml) is added, the mixture is stirred for 2 hours, and the zinc is removed by filtration. The solvent is evaporated from the filtrate under reduced pressure and the resulting residue is recrystallized from methanol to give 2-acetylamino-N-(4-methoxyphenyl)-3-oxobutanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9]O.CCCCCC.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:20]1[CH:21]=[CH:22][C:17]([OH:23])=[CH:18][CH:19]=1
Reactant: Oc1ccccc1
Reactant: OCc1cc(I)ccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h

Procedure:
A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer was charged with (2-chloro-5-iodophenyl)methanol (268.5 mg, 1 mmol), anhydrous ZnCl2 (136.3 mg, 1 mmol), dichloromethane (5.0 mL) and n-hexane (29 mL) under argon. After stirring for 10 min at 20 to 25° C., HBr (gas) was bubbled into the mixture for 10 min and a solution of phenol (197.6 mg, 2.1 mmol) in dry dichloromethane (3.0 mL) was added dropwise over 30 min. After bubbling HBr for additional 2 h, the mixture was refluxed for 3 days. The conversion was about 65%. The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2×30 mL), washed with water (2×30 mL), brine (30 mL), concentrated and the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid. Yield: 180 mg (52%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J=8.4 Hz, 2H), 7.03˜7.09 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.76 (s, 1H), 3.95 (s, 2H), 3.82 (s, 2H). MS ESI (m/z): 345 [M+1]+. 13C NMR (CDCl3, 100 MHz): δ 154.1, 141.4, 139.5, 136.6, 134.2, 131.2, 130.9, 130.1, 115.5, 91.67, 38.07.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[C:9]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][S:22][CH2:21]2)=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1>C(O)C.C1COCC1>[F:7][C:8]1[C:9]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][S:22](=[O:2])[CH2:21]2)=[CH:10][C:11]2[O:15][C:14](=[O:16])[NH:13][C:12]=2[CH:17]=1
Reactant: O=c1[nH]c2cc(F)c(NCC3CCCSC3)cc2o1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(F)c(NCC3CCCS(=O)C3)cc2o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.1 %

Procedure:
Alumina-supported sodium metaperiodate [K. T. Liu and Y. C. Tong, J.O.C. 43:2717 (1989)] (5.6 g) was added to a solution of 1.2 g (4.25 mmole) 5-fluoro-6-[(tetrahydrothiopyran-3-yl)methylamino]benzoxazolin-2-one in 200 ml ethanol and 50 ml THF. The mixture was stirred for 20 hours at room temperature. The alumina was filtered off and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with ethyl acetate/THF/methanol (80:20:5), and recrystallized from methanol/diethyl ether to give the title compound (0.28 g, 22% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH3:31])=[CH:26][N:25]=1)([O-])=O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>N1C=CC=CC=1.CC(C)=O>[CH3:31][C:27]1[C:28](=[O:30])[NH:29][C:24]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=2)=[N:25][CH:26]=1.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]
Reactant: Cc1cnc(N[N+](=O)[O-])[nH]c1=O
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: Cc1cnc(NCCCCc2csc(NC(N)=NCC(F)(F)F)n2)[nH]c1=O

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.7 g.) and 2-nitroamino-5-methyl-4(3H)-pyrimidone (0.3 g.) was heated under reflux in pyridine (3 ml.) for 3.5 hours. The mixture was then evaporated to dryness and the residue purified by preparative thin layer chromatography using ethyl acetate/methanol/6:1:1 v/v/v for development. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.). Evaporation of the solvent to dryness gave a red gum which was treated in acetone with excess maleic acid to give 5-methyl-2-(4-[(-2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butylamino)pyrimid-4-one containing 1.75 equivalents of maleic acid. The n.m.r. of this compound in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):1.6 (multiplet, 4H); 1.8 (singlet, 3H); 3.3 (multiplet, 2H); 4.2 (quartet, 2H); 6.6 (singlet, 1H); 7.5 (singlet, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:11].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>C1(C)C=CC=CC=1>[C:10]([C:12]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([Cl:9])[CH:4]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)#[N:11]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 1,2-dichloro-4-fluorobenzene (1.64 g, 10 mmol) in toluene (25 mL) was added tert-butyl 4-cyanopiperidine-1-carboxylate (2.10 g, 10 mmol) and KHMDS (0.5 M in toluene) (2.99 g, 15.00 mmol). The reaction mixture was stirred at 60° C. for 16 hours and cooled to room temperature. After the addition of 1N HCl (25 mL), the reaction mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by Prep-TLC (eluted with ethyl acetate:petroleum ether=1:5) to provide Example 140A. LCMS: 255 [M−100]+.