Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:52])[CH3:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:52][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH3:51]
Reactant: CCS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)cc(SCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g), ethylmercaptan (0.08 ml) and potassium carbonate (0.25 g) in acetonitrile (10 ml) was heated at 70° C. for 2 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (2 ml) was added to the solution, followed by stirring at room temperature for 21 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.2 g, 48%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:41])=[C:11]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]4([N:26]([CH:28]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]5)[CH3:27])[CH2:25][CH2:24]4)[CH2:19]3)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:42]2[CH2:44][CH2:43]2)[CH:7]=1)=[O:5])C.[Li+].[OH-]>C(O)C.O>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([N:26]([CH3:27])[C:23]2([CH:20]3[CH2:21][CH2:22][N:18]([C:11]4[C:12]([F:17])=[CH:13][N:14]5[C:9]([C:10]=4[CH3:41])=[C:8]([CH:42]4[CH2:43][CH2:44]4)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]5=[O:16])[CH2:19]3)[CH2:25][CH2:24]2)[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(N3CCC(C4(N(C)C5CCN(C(=O)OC(C)(C)C)CC5)CC4)C3)c(F)cn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
To a solution of 8-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (15 g, 24 mmol) in ethanol (200 mL) was added the solution of LiOH (10 g, 238 mmol) in water (100 mL) in a round bottom flask. The solution was heated at 60° C. for one hour. The resulting solution was partitioned between dichloromethane (400 mL) and saturated aqueous NH4Cl (200 mL) and well shaken. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to yield a yellow solid (14 g). This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([CH2:26][CH3:27])[N:23]([CH3:28])[C:22]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>[Cu](I)I.CS(C)=O>[CH2:26]([C:24]1[N:23]([CH3:28])[C:22]2[CH:29]=[C:18]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:19]=[CH:20][C:21]=2[N:25]=1)[CH3:27]
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: CCc1nc2ccc(Br)cc2n1C
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (5 g), 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (6.54 g), potassium carbonate (9.46 g), N,N′-dimethylethylenediamine (2.91 ml), copper iodide (1.3 g) and DMSO (100 ml) was stirred at 150° C. for 4 h. After cooling, the mixture was poured into 28% NH3 solution at 0° C. The precipitate was collected by filtration and dissolved in EtOAc/THF. The resulting solution was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was treated with activated carbon in MeOH, and recrystallized from MeOH/water to give the title compound (3.44 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[CH:11][C:4]=2[CH:3]=1.[H-].[Na+].[Br-].[Li+].Br[CH2:25][CH:26]=[CH2:27]>COCCOC.CN(C=O)C>[CH2:27]([N:6]1[C:7](=[O:8])[C:2]([Br:1])=[CH:3][C:4]2[CH:11]=[N:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[C:5]1=2)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1[nH]c2c(cnn2-c2ccc(F)cc2F)cc1Br
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(Br)cc2cnn(-c3ccc(F)cc3F)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.05 g, 3.22 mmol) in DME (10 mL) and DMF (0.9 mL) at 0° C. was treated with NaH (116 mg, 4.8 mmol). After stirring for 20 min at RT, lithium bromide (1.67 g, 19.32 m mol) was added and the reaction mixture was allowed to stir for 1 h at RT before addition of 3-bromoprop-1-ene (0.28 ml, 3.22 mmol). The mixture was allowed to stir at 40° C. for 18 h. The mixture was quenched with brine and extracted with 2×30 mL EtOAc. The combined EtOAc layers were washed with brine, dried and concentrated. Purification on the ISCO (40 g column, 10-80% EtOAc in Hexanes) afforded 7-allyl-5-bromo-1-(2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one as a tan amorphous solid. MS (ESI, pos.ion) m/z: 365.9/367.9 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[NH2:35][C:36]1([C:47]2[N:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([NH:35][C:36]1([C:47]2[N:48]=[CH:49][CH:50]=[CH:51][N:52]=2)[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.111 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (31.8 mg, 0.111 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added PyBOP (69.2 mg, 0.133 mmol) and then triethylamine (0.046 ml, 0.332 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate. Yield: 40 mg (53%). LCMS: (ES+) m/z observed=584.2 (M+H)+ of 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH2:14][CH3:15])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C.C(O)(=O)C.O>[CH2:1]([O:3][C:4]1[C:5]([CH2:14][CH3:15])=[CH:6][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(NC(C)=O)cc1CC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(NC(C)=O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(4-Ethoxy-3-ethyl-phenyl) acetamide [3.1 g, Reference Example 33(e)] was dissolved in acetic anhydride (5 mL), a solution of nitric acid in acetic acid (0.5 mL of 95% nitric acid, in 4 mL) was added and the mixture was stirred overnight at ambient temperature. The mixture was diluted with water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane/ethyl acetate 9/1) to give N-(4-ethoxy-5-ethyl-2-nitrophenyl)acetamide (3.0 g) as a bright yellow solid. LC-MS (Method E): RT=3.27 minutes, 253 (M+H)+. (h) 1-Ethoxy-2-ethyl-4-nitrobenzene
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:13]=1[C:24]([NH2:26])=[O:25])=[O:10])(=O)C>[Pd].O1CCCC1.CN(C)C=O.CCOCC>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[C:13]([C:24]([NH2:26])=[O:25])=[C:12]([NH:11][C:9]([NH:8][CH2:7][CH2:6][CH2:5][OH:4])=[O:10])[S:16][N:15]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)OCCCNC(=O)Nc1snc(-c2ccc(N)cc2)c1C(N)=O
Agent: [Pd]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCO
Yield: 99 %

Procedure:
3-[({[4-(aminocarbonyl)-3-(4-aminophenyl)isothiazol-5-yl]amino}carbonyl)amino]propyl acetate (10.0 g) and 10% palladium on carbon (3 g) in tetrahydrofuran (400 mL) and dimethylformamide (100 mL) was hydrogenated at 80 psi over 24 hr. in metal bomb. The catalyst was removed by filtration through celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give a yellow solid, which was stirred in ether (100 mL) and collected by filtration to give the title compound as a light yellow solid (8.8 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)sc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-phenylthiazole to obtain 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-thiazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-chloroform to give colorless prisms, m.p.128-129° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:3][C@:4]([CH2:9][OH:10])([CH3:8])[C:5]([OH:7])=[O:6].[CH3:24][CH2:25]O.Cl>O1CCOCC1>[CH2:24]([O:6][C:5](=[O:7])[C@@:4]([CH2:9][OH:10])([CH3:8])[CH2:3][C@H:2]([NH2:1])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)[CH3:25]
Reactant: CCO
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
(2S,4R)-4-Amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methylpentanoic acid (0.3 g, 957 μmol) was combined with EtOH (6 mL) and 4 M of HCl in 1,4-dioxane (718 μL), and stirred overnight. The solvents were evaporated and the product was azeotroped with toluene (2×) to yield the title compound (295 mg), which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl.CCOC(C)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][O:22][S:39]([CH3:38])(=[O:41])=[O:40])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:30]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethanol (895 mg, 2.44 mmol) in DCM (20 mL) is added Et3N (0.47 mL, 3.41 mmol). The reaction mixture is cooled down to 5° C. before adding methanesulfonylchloride (0.23 mL, 2.92 mmol) and stirring is continued at rt for 2 h. The mixture is then diluted with EtOAc and the org. solution is washed with sat. aq. NaHCO3 followed by brine, is dried over MgSO4, filtered and concentrated to give methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester as a brown oil (1.07 g); LC-MS: tR=1.19 min; [M+H]+=489.89.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][N:14]1[C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25](OCC)=[O:26])[N:24]=[C:13]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1.CCN(CC)CC>C(O)C>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH:40][C:25]([C:23]2[N:24]=[C:13]3[C:12]4([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]4)[CH2:15][N:14]3[C:21](=[O:31])[C:22]=2[OH:30])=[O:26])=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Reactant: NCc1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 10-(((benzyloxy)carbonyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (5.00 g, 11.70 mmol), (4-fluorophenyl)methanamine (2.67 mL, 23.39 mmol) and Et3N (3.26 mL, 23.39 mmol) in ethanol (78 mL) was stirred at 90° C. for 16 h, cooled and concentrated. The resulting pale yellow foam was dissolved in ethyl acetate and washed with 1N HCl. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was taken up in hot ethyl acetate and hexane was added until the solution became slightly cloudy. After cooling, the title compound was collected by filtration as a white solid (4.8203 g, 81% yield). 1H NMR (500 MHz, DMSO-D6) δ: 10.25 (s, 1H), 7.52 (s, 1H), 7.34-7.40 (m, 8H), 7.15-7.21 (m, 2H), 5.72 (s, 1H), 4.91 (s, 2H), 4.40 (d, 2H, J=6.4 Hz), 4.15 (s, 2H), 2.48-2.52 9 m, 2H), 2.02-2.08 (m, 2H), 1.94-1.98 (m, 2H), 1.63-1.70 (m, 2H). LCMS (M+H)=507.42.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-chlorophenyl)-5-(pent-1-enyl)pyridine (Example 145) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.80 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 19 H), 2.26 (m, 2 H), 3.23 (m, 1 H) 3.41 (m, 1 H), 4.34 (m, 2 H), 7.05-7.45 (m, 4 H). FAB-MS: calculated for C23H32NOCl 374; found 374 (M+H, 100%). Rf0.26 (10% ethyl acetate/n-hexane). mp 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N+:3]=1[O-:33]
Reactant: FC(F)(F)c1ccc2oc(-c3ccnc(Cl)c3)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)cc1Cl
Temperature: 50 °C
Yield: 90.2 %

Procedure:
To a mixture of 0.40 g of 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.53 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred while ice-cooling for 30 minutes, then stirred at room temperature for three hours, and then stirred while heating at 50° C. for 1.5 hours. To the mixture, 0.53 g of 65% m-chloroperbenzoic acid and 2 ml of chloroform were added and stirred while heating at 60° C. for five hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 0.38 g of 2-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 22”).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([O:26]CC)=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2.FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH2:22][CH:21]4[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)CC1CC1c1ccc(OCCc2ccc3c(n2)NCCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.3 %

Procedure:
The product of step 7 (380 mg, 1 mmol) was dissolved in 5 ml methanol and 2.5 ml 1 N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, acidified with 1 ml trifluoroacetic acid, and concentrated. The residue was purified on HPLC using acetonitrile gradient 15-50% in 30 min to yield 210 mg desired product as an yellow oil. FAB-MS:(MH+)=355. H MNR(CDCl3) δ 0.78 (m, 1H), 0.86 (m, 1H), 1.21 (m, 1H), 1.70 (m, 1H), 2.35 (m, 2H), 3.12 (t, 2H), 3.63 (t, 2H), 4.22 (t, 2H), 4.26 (t, 2H), 6.65 (d, 1H), 6.79 (d, 2H), 7.0 (d, 2H), 7.6 (d, 1H). Anal Calcd. for C20H22N2O4 plus 1 CF3COOH and 0.2 H2O: C, 55.98; H, 5.00; N, 5.93. Found: 55.90; H, 5.28; N, 5.24.
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH2:3][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6]>C(O)C.[Pt](=O)=O>[NH2:1][C:2](=[O:22])[CH2:3][CH:4]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)[C:5]([OH:7])=[O:6]
Reactant: NC(=O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: NC(=O)CC(C(=O)O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A suspension of benzyl 4-amino-2-(4-bromophenyl)-4-oxobutanoate (1.53 g, 4.22 mmol) and platinum(IV) oxide (30 mg) in ethanol (100 mL) was stirred under an hydrogen atmosphere for 2 h. After replacement of hydrogen with nitrogen the crude reaction mixture was filtered through a thin pad of celite and the filtrate evaporated to dryness to give the title compound as a cream coloured solid (1.14 g, 100%). LC/MS: 2.36 min; z/e 272 and 274, calcd (M+1) 272 and 274. 1H NMR (400 MHz: DMSO-d6): 7.50 (2H), 7.30 (1H), 7.20 (2H), 6.80 (1H), 3.90 (1H), 2.80 (1H), 2.40 (1H).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[F:6][C:7]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(F)ccc1C(C)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(F)c([N+](=O)[O-])cc1C(C)=O
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In nitrogen atmosphere, conc. sulfuric acid 36 mL was added to 1-(4-fluoro-2-methoxyphenyl)ethanone 5.50 g, followed by heating to homogeneity. Cooling the same with salt-ice, potassium nitrate 3.47 g was added little by little, followed by an hour's stirring. The reaction liquid was poured in ice water, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals, 6.47 g of the title compound was obtained.
Reaction SMILES: [CH:1]1[C:13]([NH2:14])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH:1]1[C:13]([NH:14][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: CCCCCC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Yield: 7.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine (0.13 g, 0.55 mmol), hexanoyl chloride (0.076 mL, 0.55 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-ylhexanamide (14 mg). MS (ES) m/z 325.1; HPLC purity 100% at 210-370 nm, 11.0 min.; 98.9% at 250 nm, 11.0 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2289.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[C:4]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1>C(OCC)(=O)C.C(=O)([O-])O.[Na+].[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: C[C@H](Nc1c(Cl)c(N)nn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(N)nn(C)c1=O)c1nc2ccc(F)cc2n1-c1ccccc1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
6-Amino-5-chloro-4-[(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamino]-2-methyl-2H-pyridazin-3-one (0.13 g, 0.315 mmol) in ethyl acetate (10 mL) and sat. aq sodium hydrogen carbonate (1 mL) was hydrogenated over 10% palladium on carbon (40 mg) at room temperature and pressure for 24 h. The reaction mix was filtered, evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-5% (9:1 MeOH/0.880 NH3) in DCM). Fractions containing the product were evaporated and freeze dried to give 344 as a white solid, (77 mg, 64%). LCMS (Method C): RT 3.57 min [M+H]+ 379.05. 1H NMR δ (ppm DMSO-d6): 7.76 (1H, dd, J=8.82, 4.84 Hz), 7.63-7.62 (5H, m), 7.14 (1H, ddd, J=9.9, 8.9, 2.5 Hz), 6.87 (1H, dd, J=8.88, 2.51 Hz), 6.47 (1H, d, J=7.48 Hz), 5.44 (1H, s), 5.18 (2H, s), 4.62 (1H, dq, J=6.95 Hz), 3.40 (3H, s), 1.41 (3H, d, J=6.63 Hz)