Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:22])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 60 °C
Yield: 51.2 %

Procedure:
To a solution of 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg, 2.3 mmol) and ammonium acetate (1.8 g, 23 mmol) in methanol (9 mL) was added sodium cyanoborohydride (720 mg, 11.5 mmol). After heating at 60° C. for 15 hours, the mixture was cooled and treated with concentrated hydrochloric acid until pH=1. The organics were removed under reduced pressure and the resulting precipitate was collected by filtration, dissolved in ethyl acetate and methanol, and washed with saturated aqueous sodium carbonate. The phases were separated and the organic phase was concentrated to yield 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine (260 mg, 52% yield) as a light brown solid. 1H-NMR (DMSO-d6): δ 10.90 (s, 1H), 7.34 (m, 1H), 7.27 (d, 1H), 6.97 (dd, 1H), 3.90 (t, 1H), 2.54 (m, 2H), 2.04-1.89 (m, 2H), 1.66 (m, 1H), 1.50 (m, 1H); MS m/z 221 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCCOc1cccc2ccccc12
Product: COC(=O)c1cc(OCCOc2cccc3ccccc23)cc(OCCOc2cccc3ccccc23)c1

Procedure:
Using this procedure, reaction of 3,5-dihydroxybenzoic acid methyl ester with 1-(2-bromoethoxy)naphthalene gave 3,5-bis[2-(1-naphthalenyloxy)ethoxy]benzoic acid methyl ester, mp 132°-137°, Anal. Calcd for C32H28O6 : C, 75.58; H, 5.55. Found: C, 75.19: H, 5.44.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[CH:21]>C(N(CC)CC)C.CCOC(C)=O.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>[CH3:17][CH:18]([CH3:22])[CH2:19][C:20]#[C:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2
Reactant: C#CCC(C)C
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.0 g, 10.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (1.03 g, 1.07 mmol) and CuI (203 mg, 1.07 mmol) in triethylamine (30 mL), was added 4-methylpent-1-yne (2.23 g, 27.8 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜10% EtOAc in petroleum ether) affording the title compound (2.2 g) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.90-3.86 (m, 1H), 3.77-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.33 (d, 2H), 2.05-1.94 (m, 2H), 1.86 (m, 1H), 1.76-1.71 (m, 1H), 1.60-1.54 (m, 2H), 1.02 (d, 6H); LCMS: 283 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]2/[C:7](=[C:16](\[CH3:19])/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[O:10][CH2:11][C:5]=2[CH:4]=1.N1C(C)=CC=CC=1C.[Br-].[Li+].CS(OS(C)(=O)=O)(=O)=O.[CH2:41]([C:43]1[NH:44][C:45]2[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][C:46]=2[N:47]=1)[CH3:42].[OH-].[Li+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:41]([C:43]1[N:47]([CH2:2][C:3]2[CH:21]=[CH:20][C:6]3/[C:7](=[C:16](\[CH3:19])/[C:17]#[N:18])/[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[O:10][CH2:11][C:5]=3[CH:4]=2)[C:46]2[CH:48]=[C:49]([CH3:53])[CH:50]=[C:51]([CH3:52])[C:45]=2[N:44]=1)[CH3:42]
Reactant: CCc1nc2cc(C)cc(C)c2[nH]1
Reactant: C/C(C#N)=C1\c2ccc(CO)cc2COc2ccccc21
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2c(C)cc(C)cc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(/C)C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
[step 1] (Z)-2-(8-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (150 mg, 0.54 mmol) was dissolved in THF (5.5 mL), and the solution was added with 2,6-lutidine (0.378 mL, 3.25 mmol), lithium bromide (282 mg, 3.25 mmol) and methanesulfonic anhydride (236 mg, 1.35 mmol), followed by stirring at room temperature for 16 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. The obtained residue and 2-ethyl-4,6-dimethylbenzimidazole (123 mg, 0.71 mmol) were dissolved in DMF (3.0 mL) and the solution was added with lithium hydroxide (24 mg, 0.98 mmol) at 0° C., followed by stirring at room temperature for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-6/4) to give (Z)-2-[8-(2-ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (219 mg, 93%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH2:12]([N:14]([CH2:20][CH3:21])[C:15](=[O:19])[CH2:16][N+:17]#[C-:18])[CH3:13]>CO>[CH2:12]([N:14]([CH2:20][CH3:21])[C:15]([C@H:16]1[C@H:8]([C:7]2[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=2)[O:9][CH:18]=[N:17]1)=[O:19])[CH3:13]
Reactant: [C-]#[N+]CC(=O)N(CC)CC
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C(=O)[C@@H]1N=CO[C@H]1c1ccc(F)cc1

Procedure:
To a stirred and cooled (0° C.) solution of KOH (0.26 g, 3.92 mmol) in MeOH (36 mL) was added successively 4-fluorobenzaldehyde (0.443 g, 3.56 mmol) and N,N-diethyl-2-isocyanoacetamide (0.50 g, 3.57 mmol). The solution was stirred for 16 h (0° C. to RT) and then concentrated. The residue was partitioned between CH2Cl2 (20 mL) and brine (20 mL). The organic layer was separated and the desired product was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and evaporated. A pale crude yellow solid was obtained the (±)-trans-N,N-diethyl-5-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxamide, SLA 19142, as a brown oil (0.86 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:40])[N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:39]=[CH:38][C:37]5[O:36][CH2:35][O:34][C:33]=5[CH:32]=4)[CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=[O:6].C(N(CC)CC)C.[C:52](Cl)(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.O.O.[C:63]([OH:68])(=[O:67])[C:64]([OH:66])=[O:65]>C1COCC1.C(O)(C)C.O>[C:63]([OH:68])(=[O:67])[C:64]([OH:66])=[O:65].[C:52]([N:14]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:40])[N:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]3[CH:39]=[CH:38][C:37]4[O:36][CH2:35][O:34][C:33]=4[CH:32]=3)[CH2:28][CH2:29]2)=[CH:17][CH:16]=1)[C:11]1[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1)(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccc(Nc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N(C(=O)c2ccccc2)c2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 3,4-dichloro-N-(6-{4-[3-oxo-3-(4-piperonylpiperazin-1-yl)propyl]phenylamino}-pyridin-3-yl)benzamide (250 mg, 0.395 mmol) in THF (5 mL) were added triethylamine (0.132 mL, 0.949 mmol) and benzoyl chloride (0.0550 mL, 0.474 mmol), and the resulting solution was stirred for 7 hours at room temperature. Water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield 0.300 g of a free form. To this free form were added isopropanol (5 mL) and oxalic acid dihydrate (100 mg, 0.793 mmol), and the resulting solution was dissolved under heat. The solvent was evaporated, and the resulting solid was recrystallized from isopropanol, to thereby yield 80.0 mg of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:19])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[C:12]([CH3:18])[CH:11]=[CH:10]2)(=O)=O.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+]>CN(C=O)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>[Br:19][C:8]1[C:7]([CH:22]=[CH2:23])=[C:16]([CH3:17])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([CH3:18])=[N:13]2
Reactant: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2nc(C)ccc2c1Br
Temperature: 80 °C
Yield: 87.7 %

Procedure:
PdCl2(PPh3)2 (207 mg, 0.30 mmol) was added to a mixture of 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (5A) (1.13 g, 2.95 mmol), tributyl(vinyl)stannane (0.95 mL, 3.25 mmol) and lithium chloride (375 mg, 8.85 mmol) in DMF (30 mL). The reaction mixture was flushed with argon, heated at 80° C. for 4 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 5B (678 mg, 88%). LCMS-ESI+ (m/z): 262.1, 264.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][C:5]1([C:18](=[O:32])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH:21]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:30][N:28]([CH3:29])[C:27](=[O:31])[O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:18]([C:5]2([CH2:4][CH2:3][N:2]([CH3:33])[CH3:1])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[O:32])[CH:21]=1
Reactant: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1

Procedure:
Crude tert-butyl 4-(2-(dimethylamino)ethyl)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)piperidine-1-carboxylate from step C was treated with 1:1 TFA:CH2Cl2 (1.5 mL) for 45 min. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (30×100 mm C18 column, 0-50% MeOH:H2O (0.1% TFA), 12 min., 45 mL/min.) and lyophized to give impure title compound (173 mg) as the TFA salt. MS (ES+) [M+H]+=363.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH2:37])[CH2:33][N:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH:37][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:33][N:34]([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=391.5 ([M+H]+), was produced in analogy with example 1, steps 3 and 4. Thus, commercially available 11-phenylundecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(11-phenyl-undecanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:67]([NH2:71])([CH2:69][CH3:70])[CH3:68]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH:71][C@H:67]([CH2:69][CH3:70])[CH3:68])[N:7]=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(C(C)=O)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C(C)=O)n1
Yield: 17 %

Procedure:
Dissolve 2-acetyl-6-chloro-isonicotinic acid methyl ester (300 mg, 1.4 mmol), palladium (II) acetate (16 mg, 0.07 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg, 0.07 mmol) and cesium carbonate (781 mg, 2.1 mmol) in anhydrous toluene (3 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.16 mL, 1.68 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes) to give the title compound as a solid (17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[C:23](=[O:29])[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[C:23](=[O:29])[N:24]([CH3:30])[S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)NS(C)(=O)=O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-[(methylsulfonyl)carbamoyl]-1,4-oxazepane-4-carboxylate (246 mg) in DMF (3 mL) were added potassium carbonate (109 mg) and methyl iodide (0.049 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (174 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=[N:23][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[C:21]([C:25]([OH:27])=[O:26])[CH:22]=[N:23][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1cncc(C(=O)O)c1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2cncc(C(=O)O)c2)C1
Yield: 48 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 5-aminopyridine-3-carboxylic acid, the title compound was isolated in 48% yield (98% purity by HPLC). MS(ESI+): 334.5; MS(ESI−): 332.4.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: CON
Reactant: Cc1ccccc1C=O
Agent: Cl
Product: CON=Cc1ccccc1C
Yield: 96 %

Procedure:
Reaction of 2-methylbenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (96% yield). HPLC indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.44 (3H, s, CH3), 4.01 (3H, s, OCH3), 7.19–7.28 (3H, m, aromatics), 7.73 (1H, m, aromatic), 8.36 (1H, s, CH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](=[O:31])N(OC)C)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:31])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccn2)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 2-bromopyridine (0.89 g, 5.62 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.81 mL, 1.6 M in THF, 5.62 mmol). The reaction was stirred for 30 minutes prior to the addition of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.77 g, 2.81 mmol) as a solution in 5 mL of THF. The reaction was then stirred at room temperature for 30 minutes and then 1 hour at 60° C. The reaction was then quenched by adding a saturated solution of sodium bicarbonate and then extracted with 2×50 mL ethyl acetate. The combined organic layers was dried on magnesium sulfate and concentrated under vacuum to afford an orange oily solid which was purified via silica gel chromatography (gradient: ethyl acetate/hexane; 0:1 to 3:5) to afford the title compound as a white solid (290 mg). 1H NMR (400 MHz, CDC3) δ 8.70 (d, J=6.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.86 (t, J=7.6 Hz, 1H), 7.46 (t, J=6.2 Hz, 1H), 4.25-4.13 (m, 2H), 4.09-4.00 (m, 1H), 2.94 (t, J=12.6 Hz, 2H), 1.91 (d, J=11.6 Hz, 2H), 1.69-1.65 (m, 2H), 1.50 (s, 9H). LRMS m/z ES+=290.8 (M+H), retention time 1.78.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:41][O:42][CH:43]1[CH2:46][CH:45]([NH2:47])[CH2:44]1>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:47][CH:45]4[CH2:46][CH:43]([O:42][CH3:41])[CH2:44]4)=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: COC1CC(N)C1
Product: COC1CC(NC(=O)Nc2ccc(-c3cc(-c4cc(F)ccc4S(C)(=O)=O)nc(N4CCOC[C@@H]4C)n3)cc2)C1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) 3-methoxycyclobutanamine (22 mg, 0.213 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (37 mg, 30%)
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[ClH:1].[CH2:36]([O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCBr
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: Cl
Product: CCCCCCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 34 %

Procedure:
Using methods analogus to those previously described, hydrochloride 11 (0.4 mmol) is reacted with 1-bromoheptane to afford the title compound 59 (0.14 mmol, 34%) as a glass, which can be pulverized to an off-white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.49 (s, 1 H), 7.37 (m, 2 H), 7.27 (m, 1 H), 6.51 (s, 1 H), 6.45 (s, 1 H), 6.43 (s, 1 H), 4.05 (m, 1 H), 3.98 (m, 1 H), 3.88 (t, J=6.5 Hz, 2 H), 2.96 (hept, J=7 Hz, 1 H), 2.84 (m, 1 H), 2.6 (3H obscured by solvent), 2.36 (m, 1 H), 2.16 (m, 2 H), 2.01 (s, 3 H), 1.85-1.75 (m, 4 H), 1.58 (m, 1 H), 1.5-1.26 (m, 18 H), 0.89 (t, J=6.6 Hz, 3 H); MS (CI) m/z 555.5 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.NN>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1cccnc1-2

Procedure:
Following the procedure described in Example 608, Part C, 3.45 g (19 mmole), of 4-azafluoren-9-one, 6.8 g (0.213 mole) of hydrazine in 50 ml of diethyleneglycol were combined and heated to 205° over a 30-minute period. TLC showed no remaining starting material. Identical workup yielded 2.33 g of pure 4-azafluorene, RF-0.46 (hexane ethylacetatetriethylamine, 29.75:69.46:0.79).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20](O)=[O:21])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[CH2:19][C:20]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)Cc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Product: Clc1ccc(-c2c(Cc3nc4ccccc4o3)cnn2-c2ccccc2)cc1

Procedure:
A mixture of 31.3 g of (5-p-chlorophenyl-1-phenyl-pyrazol-4-yl)-acetic acid, 10.9 g of o-aminophenol and 400 ml of polyphosphoric acid is heated at 175° for 2 hours. After cooling and the customary working up, 5-p-chlorophenyl-1-phenyl-4-(benzoxazol-2-ylmethyl)-pyrazole is obtained; m.p. 137°-139°.