Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Li]C(C)(C)C.[B:16](OC)([O:19]C)[O:17]C.Cl>C(OCC)C>[CH3:10][C:3]1[CH:4]=[C:5]([S:8][CH3:9])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: CSc1ccc(Br)c(C)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CSc1ccc(B(O)O)c(C)c1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 52.4 %

Procedure:
Add 1-bromo-2-methyl-4-methylsulfanyl-benzene (608 mg, 2.80 mmol) to diethyl ether (60 mL) and cool to −78° C. under a nitrogen blanket. Add t-BuLi (3.4 mL, 5.78 mmol) over a 15 minute period, stir for 2 minutes, add trimethyl borate ((MeO)3B, 340 μL, 2.99 mmol) over 2 minutes, stir for 15 minutes at −78° C. and then let warm to room temperature. Quench the reaction with saturated aqueous NH4Cl (7 mL), stir for 15 minutes, add 1M aqueous HCl (6 mL), stir for another 2 minutes and separate. Dry with Na2SO4, filter (wash the drying agent with ethyl acetate (3×20 mL)), and concentrate. Chromatograph the crude material on a SiO2 column with 20% ethyl acetate in hexanes to 5% methanol in ethyl acetate to give 267 mg of the title compound (52%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[NH:13][C:12]2=[O:28])=[CH:2]1>CCCCCC.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[NH:13][C:12]2=[O:28])[CH2:2]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=N[C@@H]1Cc1c[nH]c2ccccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1CC1CNc2ccccc21

Procedure:
The procedure of Example 9 was followed in which 3(R)-[(1H-indol-3-yl)methyl]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was reduced to give the tile compound. The analytical sample was obtained after silica gel chromatography using hexane-ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:18][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([F:10])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-fluorobenzonitrile (15.6 g, 100 mmol) was dissolved in triflic acid (75 mL) at 0° C., then NBS (17.8 g, 100 mmol) was added. The reaction was warmed up to room temperature and stirred overnight. The reaction mixture was poured into ice and extracted with DCM (2×). DCM layers were washed with NaHCO3 and brine. The DCM was dried over Na2SO4 then filtered and concentrated. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10-20% ethyl acetate/hexane solvent system to yield 3-bromo-2-chloro-6-fluorobenzonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.C1(C(C2C=CC=CC=2)=CC[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:19][CH2:18]2)C=CC=CC=1.F[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>CN(C)C(=O)C.C(Cl)Cl>[OH:45][CH:44]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:43]1[CH:46]=[CH:47][C:40]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:32])[CH2:21][CH2:22]2)=[CH:41][CH:42]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(O)c3ccccc3)cc2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Potassium carbonate (10.6 g, 76.5 mmol) was added to a solution of Example 2 Part A compound (15.0 g, 69.6 mmol) and 4-fluorobenzaldehyde (Aldrich) (8.61 g, 69.6 mmol) in N,N-dimethylacetamide (100 mL) and the reaction was stirred at 125° C. for 24 h, then cooled to RT. The reaction was dissolved in CH2Cl2 (500 mL) and washed with water (4×180 mL) and brine (2×200 mL), then dried over MgSO4. Evaporation gave a solid mass. The crude product was triturated with EtOAc (10 mL), then washed with EtOAc (10 mL) and filtered to give title compound (17.8 g, 80%) as a white solid (mp 211-214° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]4[O:16][C:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:18][N:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15]([CH3:23])([CH3:22])/[CH:16]=[CH:17]/[C:18](OC)=[O:19])[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+]>O1CCCC1>[CH3:22][C:15]1([CH3:23])[CH:16]=[CH:17][C:18](=[O:19])[N:14]1[C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COC(=O)/C=C/C(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C=CC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Methyl (2E)-4-{[4-(4-cyanophenyl)-1,3-thiazol-2-yl]amino}-4-methylpent-2-enoate (0.15 g, 0.46 mmol), prepared in the previous step, was dissolved in tetrahydrofuran (2 mL) and sodium methoxide (53 mg, 1.0 mmol) was added. The mixture was stirred for 2 h, quenched with saturated NH4Cl, diluted with ethyl acetate, washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone/hexane) afforded the title compound (0.105 g, 78%) as a white solid. HRMS: calcd for C16H13N3OS+H+, 296.08521; found (ESI, [M+H]+), 296.0867; Analytical HPLC: purity 99.0% at 210-370 nm, 9.8 min; 97.8% at 304 nm, 9.8 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([F:18])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[C:4]([F:18])[CH:3]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(F)cc1N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cc(F)c(C(=O)N2CCOCC2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of (4-amino-2-fluoro-5-methoxyphenyl)(morpholino)methanone (260 mg, 1.02 mmol), BBr3 (1.28 g, 5.10 mmol), and CH2Cl2 (15 mL) was stirred at 0° C. for 2 h. The reaction was quenched by water at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. Silica-gel column chromatography afforded the title product as yellow solid (200 mg, 81%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:27][CH2:26][C:20]1([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: NC1(CO)CCCCC1
Product: O=C(NC1(CO)CCCCC1)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (1-aminocyclohexyl)methanol (CAN 4313-56-8) as starting materials and isolated (55 mg, 53%) as a white solid; MS (ESI, m/z): 373.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[C:9]([I:15])[CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18].N1C=CN=C1>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([I:15])[C:10]3[NH:14][C:17](=[O:18])[NH:13][C:11]=3[CH:12]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(I)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (15 g, 45.6 mmol, 1.0 eq), DMAP (2.9 g, 22.7 mmol, 0.5 eq) and carbonyl diimidazole (11.0 g, 68.4 mmol, 1.5 eq) in THF (200 mL) was refluxed for 3 h. The reaction was cooled to room temperature, purified by flash column chromatography to give a solid, which contained some imidazole and DMAP. The solid was triturated with THF (2×) and filtered to afford 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one. LC-MS: 354.0 [M−H]−1H NMR (400 MHz, DMSO-d6) δ 10.9 (br s, 2H), 7.24 (d, J=1.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 2.37 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:41])=[C:22]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:23][O:24][C:25]2[C:33]3[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=3[CH:28]=[CH:27][CH:26]=2)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:42][C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:5][CH:6]=2)=[CH:39][CH:38]=[C:37]([Cl:40])[C:22]=1[CH2:23][O:24][C:25]1[C:33]2[N:32]=[C:31]([O:34][CH3:35])[N:30]([CH3:36])[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccncc1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)cccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5ccncc5)nc4)c3Cl)cccc2n1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 7.7 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (90 mg) and 4-aminopyridine (14.3 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.7 mg) and 1-hydroxybenzotriazole (26.4 mg) at ambient temperature, and after standing for 1 day, the mixture was stirred for 8 hours at 50° C. To the mixture was added water, and extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 12:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(4-pyridylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (7.8 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33](I)[CH:32]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH3:39][O:40][C:41]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH2:30][C:31]5[CH:32]=[C:33]([C:47]6[CH:46]=[CH:45][CH:44]=[C:43]([C:41]([O:40][CH3:39])=[O:42])[CH:48]=6)[CH:34]=[CH:35][CH:36]=5)=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(I)c5)cc4)C(=O)O3)ccc2O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccc(-c2cccc(COCCOc3ccc(CCN4C[C@@H](c5ccc6c(c5)COC(C)(C)O6)OC4=O)cc3)c2)c1
Temperature: 85 °C

Procedure:
A mixture of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-{2-[(3-iodobenzyl)oxy]ethoxy}phenyl)ethyl]-1,3-oxazolidin-2-one {Example 6 i)} (150 mg), 3-(methoxycarbonyl)phenylboronic acid (47 mg), tetrakis(triphenylphosphine)palladium (0) (6 mg) and 2N sodium carbonate (7 mL) in dimethoxyethane (10 mL) was heated at 85° C. for 1 h. The solution was then diluted in EtOAc, washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 40 g) eluting with CH2Cl2-MeOH (200:1) to give the title compound (128 mg). LCMS RT=3.99 min.
Reaction SMILES: [CH2:1]([C:11]12C[CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23].[I-].C([Al+][CH2:28][CH3:29])C>C1(C)C=CC=CC=1>[CH2:4]([CH:5]1[CH2:6][CH:7]2[CH2:28][CH:29]1[CH:9]=[CH:8]2)[CH2:3][CH2:2][CH2:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCC12C=CC(CC1)C2
Reactant: CC[Al+]CC
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: C=CCCCC
Product: CCCCCCCCCCC1CC2C=CC1C2
Reaction time: 1 h

Procedure:
50 ml dry toluene cosolvent, 7 ml decylnorbornene, 0.8 ml of the 1-hexene solution, and 0.9 of the diethylaluminum iodide solution were charged to a dry, nitrogen-purged 7 oz. bottle. 1.1 ml of the MoCl5 solution was charged last, and the bottle was shaken. After 1 hour the reaction was shortstopped using a mixture of 0.1 ml ethanolamine and 0.5 ml Solution A. No antioxidant was added. The polymer cement was coagulated using excess Solution A in a Waring blender. About 4.5 grams of a solid, ring-opened 5-decyl-2-norbornene/1-hexene copolymer was recovered by filtering and vacuum drying.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.I[CH2:18][C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:18][C:19]([NH2:21])=[O:20])[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 101.9 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-piperazine (0.438 g, 1.94 mmol), Iodoacetamide (0.401 g, 2.17 mmol), Cesium Carbonate (0.956 g, 2.93 mmol) and Acetonitrile (20 mL, 400 mmol) were combined and stirred at 60° C. for 20 hours. The mixture was cooled to room temperature. Water was added to the mixture and the product was extracted into ethyl acetate three times. The extracts were dried over sodium sulfate, filtered and concentrated to yield a yellow solid, 2-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-acetamide (558 mg, 100%). LCMS: m/z=283.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, 2H), 7.26 (br s, 1H), 7.17 (m, 2H), 2.94 (s, 2H), 2.60 (m, 2H), 2.50 (s, 6H).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[ClH:1].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12]3[S:28][C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=4[C:16](=[O:18])[C:11]=3[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CN(CC2CCCCC2)CCC1=O
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1c2c(sc3ccc(F)cc13)CCN(CC1CCCCC1)C2
Reaction time: 2 h
Yield: 37.9 %

Procedure:
A mixture of 6.68 g of the product of Step B and 2.51 g of p-fluoro-thiophenol were added in two portions with stirring over 20 minutes to 80 g of polyphosphoric acid heated to 100° to 120° C. and the mixture was held at 110° C. for two hours to form a yellow solution which was poured into 500 ml of water. The resulting suspension was adjusted to a pH of 8 by addition of sodium carbonate and the yellow precipitate formed was recovered by filtration. The product was washed with water and dissolved in 250 ml of dichloromethane. The solution was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and ethanol and 10 ml of a solution of 10% hydrogen chloride in ethanol were added thereto. The mixture was filtered and the pale cream colored product was washed with a little ethanol and dried under reduced pressure to obtain 2.73 g (39 % yield) of 2-cyclohexylmethyl-8-fluoro-1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride melting at 243° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(=O)([O-])O.[Na+]>ClCCl>[CH2:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:3]=2)=[O:25])[CH2:13][CH2:14]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 30 %

Procedure:
To a stirred solution of 0.34 g (1 mmol) of N-(3-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-2-oxo-acetamide (Example 11) and 0.16 ml (2 mmol) of pyridine in 10 ml of dichloromethane 0.16 ml (2 mmol) of methanesulfonyl chloride in 2 ml of dichloromethane is added dropwise below 10° C., and the reaction mixture is stirred at room temperature for 10 hours. Then 50 ml of 8% sodium hydrogencarbonate solution is added to the mixture, the organic layer is separated and the water phase is extracted three times with 10 ml of dichloromethane. The combined organic layers are dried over sodium sulfate, concentrated, the residue is treated with diethylether and the crystals are filtered to yield 0.25 g (30%) of the title compound. Melting Point: 128-130° C. (diethylether)
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[NH4+]>C1COCC1>[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=1[CH:14]([C:7]1[O:6][CH:10]=[CH:9][N:8]=1)[OH:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)c2ncco2)c(Cl)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6M in hexane, 7.4 ml) was added to a solution of oxazole (0.78 ml) in THF (100 ml) which had been cooled to -70° C. The mixture was stirred at that temperature for 1 hour. A solution of 2-chloro-4-nitrobenzaldehyde (2 g) in THF (5 ml) was added and the mixture was stirred at -70° C. for 3 hours. A saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to give 1-(2-chloro-4-nitrophenyl)-1-(2-oxazolyl)methanol (1.45 g), m.p. 158°-160° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:33])[NH:14][C:15](=[O:32])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:33])[NH:14][C:15](=[O:32])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1cc(C2=C(c3cn(C4CCNCC4)c4ccccc34)C(=O)NC2=O)c2occc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1NC(=O)C(c2cc(O)cc3ccoc23)=C1c1cn(C2CCNCC2)c2ccccc12
Temperature: 190 °C
Yield: 82.9 %

Procedure:
Combine 3-(5-methoxybenzofur-7-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]pyrrole-2,5-dione (0.125 g, 0.24 mmol) and pyridine hydrochloride (2.2 g, 18-fold excess by weight) under nitrogen. Attach a heating mantle and heat to 190° C. for 45 min. Let cool to 20° C., then extract with ethyl acetate versus water. Wash with brine, dry organic layer over magnesium sulfate, filter and concentrate. Purification by column chromatography (5% methanol: dichloromethane) gives 0.085 g (70%) product. High Res. Mass Spec (m/z): Calcd 518.2080 found 518.2080.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][N+:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+:22]([O-])=O)[CH3:21])=[CH:15][CH:14]=1.[CH3:25][C:26]([OH:28])=[O:27]>>[C:26]([OH:28])(=[O:27])[CH3:25].[CH3:21][CH:20]([NH2:22])[CH2:19][CH:16]1[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1
Reactant: CC(=Cc1cc[n+](C)cc1)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(=O)O
Product: CC(N)CC1CCN(C)CC1

Procedure:
A mixture of 1-methyl-4-(2-nitro-propenyl)-pyridinium tosylate (66) and Pt2O (10 wt %) in AcOH was agitated under 50 psi of H2 (gas) for a time sufficient for reaction completion. The mixture was filtered through Celite and the solvent removed by rotary evaporation to afford compound 67.