Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[ClH:23].Cl.[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][NH2:31])[CH2:26]1>O>[ClH:23].[NH:25]1[CH2:29][CH2:28][C@@H:27]([O:30][N:31]=[C:17]2[CH2:16][CH2:15][C@@:14]3([CH3:21])[CH:19]([C@@H:2]([CH3:1])[CH2:3][C@@H:4]4[C@@H:13]3[CH2:12][CH2:11][C@@:9]3([CH3:10])[C@H:5]4[CH2:6][CH2:7][C:8]3=[O:22])[CH2:18]2)[CH2:26]1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Solvent: O
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=NO[C@@H]3CCNC3)CC12
Yield: 70 %

Procedure:
Prepared in 70% yield as described in Example 1 starting from 6α-methylandrostane-3,17-dione (II-ai, Prepn. 19) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (III-e, Prepn. 5). The crude product was dissolved in H2O and freeze-dried to give the title compound I-ax. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.03 (2H, bb), 4.73 (1H, m), 3.30-3.02 (5H, m), 2.45-0.56 (22H, m), 0.87 (3H, m), 0.84 (3H, s), 0.78 (3H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]C(O)=O.[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][N:13]2[CH2:3][CH2:2][Cl:1]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Br)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc(Br)c2c1N(CCCl)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottom flask, 3-chloropropanoic acid (8.44 g, 89.3 mmol, 20 eq.) was added to 5-bromoquinolin-8-ol (1 g, 4.46 mmol, 1 eq.) in 15 mL THF at 0° C. NaBH4 (759 mg, 20 mmol, 4.5 eq.) was added portionwise in 50 minutes at 0° C. The reaction was stirred at 0° C. for 30 minutes then heated to 80° C. for 2 hours. The reaction was cooled down. Reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated to give 5-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinolin-8-ol crude. LCMS-ESI+ (m/z): [M+H]+ calcd for C11H14BrClNO: 291.58. found: 292.0.
Reaction SMILES: Cl[C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(#N)C>[N:24]1([C:2]2([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:16])[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Cc1ccc(C2(Cl)c3ccccc3C(=O)c3ccccc32)cc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Cc1ccc(C2(n3ccnc3)c3ccccc3C(=O)c3ccccc32)cc1
Yield: 41.7 %

Procedure:
36.2 g (0.113 mol) of 9-chloro-9,10-dihydro-9-(4-methylphenyl)-10-oxo-anthracene and 20.4 g (0.3 mol) of imidazole in 400 ml of absolute acetonitrile are heated under reflux for 5 hours. Thereafter, the solvent is distilled off in vacuo and the residue is taken up in 500 ml of methylene chloride. The methylene chloride solution is washed twice with 1,000 ml of water each time and the organic phase is separated off, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The yellow, oily residue is recrystallised from 300 ml of acetonitrile. 16.5 g (40.6% of theory) of 9,10-dihydro-9-imidazol-1-yl-9-(4-methylphenyl)-10-oxo-anthracene of melting point 200°-204° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O/[N:30]=[C:31](\[NH2:42])/[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38]([F:41])([F:40])[F:39]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([O:14]/[N:30]=[C:31](\[NH2:42])/[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38]([F:41])([F:39])[F:40])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N/C(=N\O)c1cccnc1C(F)(F)F
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: N/C(=N\OC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1)c1cccnc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred solution of 3,4-bis(benzyloxy)-5-nitrobenzoic acid (0.759 g, 2 mmol) in dimethylformamide (10 mL) at room temperature was added 1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) in one portion. The resulting yellow mixture was allowed to stir for ninety minutes whereupon (Z)—N′-hydroxy-2-(trifluoromethyl)nicotinimidamide (0.41 g, 2 mmol) was added in one portion. The resulting mixture was stifled at room temperature for two hours and then poured onto water (100 mL). The resulting precipitate was filtered off, washed with water and dried. After recrystallisation from dichloromethane/isopropanol, (Z)—N′-(3,4-bis(benzyloxy)-5-nitrobenzoyloxy)-2-(trifluoromethyl)nicotinimidamide was obtained as a light yellow solid, 0.88 g (78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28](OC)=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:33][CH2:34][CH2:35][OH:36])=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Product: COc1ccc(-n2c(=O)c(C(=O)NCCO)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and 2-aminoethanol (0.03 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (47 mg, 89% yield) as a white solid. 1H NMR (CDCl3) δ 10.18 (s, 1 H), 8.44 (s, 1 H), 7.08-7.02 (m, 4 H), 6.98-6.94 (m, 2 H), 6.91-6.87 (m, 2 H), 6.74 (s, 1 H), 3.90 (s, 2 H), 3.85 (s, 3 H), 3.71 (m, 2 H), 3.53 (m, 2 H); HRMS m/z calcd for C25H23FN3O5: 464.1616 Found: 464.1617.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1>CO>[CH:11]1[CH:12]=[CH:13][C:14]2[C:9](=[CH:8][N:7]=[N:6][C:5]=2[NH:2][NH2:3])[CH:10]=1
Reactant: NN
Reactant: Clc1nncc2ccccc12
Solvent: O
Solvent: CO
Product: NNc1nncc2ccccc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A 2 L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser, and was charged 375 mL of hydrazine hydrate; the solution was then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt was added in portions at a rate to maintain the solution temperature at 0 to 5° C. After addition, the solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and 150 mL of methanol was added, the solution stirred for 3 hrs, and the resulting solid material was filtered, washed with 150 mL of cold methanol, and dried under vacuum at 35° C. Yield 99%.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Li]CCCC.[Br:20]C(F)(F)C(Br)(F)F>C1COCC1>[Br:20][C:7]1[CH:6]=[C:5]([C:4]#[C:3][C:2]([CH3:14])([CH3:13])[CH3:1])[S:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(C)(C)C#Cc1ccc(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(Br)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a of solution of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid (6.5 g, 31.3 mmol, 1.0 equiv) in THF (150 mL) at −78° C. was added n-BuLi (44.9 mL, 1.6 M in heptane, 71.9 mmol, 2.3 equiv) and the resulting solution was stirred at −78° C. for 1 hour. To the solution was then added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (16.2 g, 62.5 mmol, 2.0 equiv) and the solution was allowed to warm to room temperature over 2 hours. The reaction was quenched by addition of sat. aq. NH4Cl solution and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was continued to the next step with no further purification.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1.O.[OH-].[K+]>[F:21][C:3]1[C:2]([N:27]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CC1CNCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1
Reaction time: 13 h
Yield: 63.9 %

Procedure:
A suspension of 3.5 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.6 g of 2-methylpiperazine in 40 cm3 of pyridine is heated at a temperature close to 115° C., with stirring, for 13 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at 60° C. The residue is twice taken up with 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid obtained is taken up in 60 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. The aqueous phase is washed with twice 100 cm3 of trichloromethane, 10.28 g of methanesulphonic acid are added and the aqueous phase is again washed with twice 100 cm3 of trichloromethane. 10 cm3 of 30% aqueous potassium hydroxide solution are added. The precipitate formed is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. 2.7 g of 7-fluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 360°-363° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:33][C:31]=2[NH2:32])[CH2:26][CH2:25]1.Cl.O1CCOCC1>CO>[N:27]1([C:30]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:33][C:31]=2[NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:3]=2[CH3:23])[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(C(F)(F)F)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)quinoline (129 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-7-(trifluoromethyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, s), 8.04 (1H, d, J=8.6 Hz), 7.58-7.72 (2H, m), 7.46-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.30-7.40 (2H, m), 7.17-7.24 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.47 (1H, dd, J=8.6, 2.7 Hz), 6.04 (1H, d, J=0.8 Hz), 3.92 (4H, t, J=4.7 Hz), 3.69-3.80 (4H, m), 3.06 (4H, br. s.), 2.82-3.00 (4H, m), 2.24 (3H, s). Mass Spectrum (ESI) m/e=567.3 (M+1).
Reaction SMILES: CN([CH:4]=[O:5])C.[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:4]=[O:5])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a DMF (0.47 M) solution of 6-bromo-1H-indole (1 eq.) was added at 0° C. phosphorus oxychloride (1.2 eq.). The resulting solution was warmed to RT and stirred at RT for 16 h. The resulting solution was re-cooled to 0° C. and then carefully added NaOH (2 M aq. solution, 2.8 eq.). After stirring at RT for another 2 h, the crude reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→EtOAc) afforded the title compound as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[Na+].N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:15][C@@H:10]([CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([OH:14])=[O:13]
Reactant: [Br-]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@@H](Br)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of O-(phenylmethyl)-L-serine (21.6 g, 0.108 mol) in aqueous sulfuric acid (786 ml, 2.5N) containing sodium bromide (69.3 g, 6.0 eq) was cooled to 0° C. in an ice bath. Sodium nitrite (21 g, 2.7 eq) was added over 10 minutes, and the solution stirred at 0° C. for one hour. The cooling bath was removed, ether (250 ml) was added, and stirring was continued overnight at room temperature. The aqueous layer was extracted repetitively with ether (3×100 ml), and the combined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 25 g of a crude product. The product was purified by column chromatography (83:17; petroleum ether:ethyl acetate) to yield the title compound (10.6 g).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:7]12[CH2:19][C:18](=[O:20])[CH:17]=[C:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[CH2:15]2)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:17]1[C:18](=[O:20])[CH2:19][C:7]2([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][C:14]3[CH:13]=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[C:8]=12
Reactant: BrBr
Reactant: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC12CC(=O)C(Br)=C1c1ccc(O)cc1C2
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
Bromine (0.005 mL, 0.095 mmol) was added to an ice-cold mixture of 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (23 mg, 0.095 mmol) and NaHCO3 (40 mg, 0.48 mmol) in CCl4 (0.3 mL). The resulting mixture was stirred at 0-5° C. for 45 minutes, then diluted with CH2Cl2 (30 mL) and washed with water (30 mL). The aqueous phase was back-extracted with CH2Cl2 (2×10 mL). The combined organics were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and evaporated under vacuum to provide an off-white solid. Recrystallization from hexane/CH2Cl2 afforded 3-bromo-8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as small, white needles.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C=O.[CH:33](O)=O>C(Cl)(Cl)Cl>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH3:33])[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Reactant: O=CO
Agent: C=O
Solvent: ClC(Cl)Cl
Product: CN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
The mixture of Isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg), paraformaldehyde (3 mg) and formic acid (2.2 mg) in chloroform (0.1 mL) was stirred at 65° C. for overnight. After cooling down, the mixture was concentrated under vacuum and filtered through anion exchange cartridge to get rid of formic acid. The crude product was purified by prep TLC with 10% methanol/89% dichloromethane/1% NH4OH to give the product as a clear sticky oil (2 mg, 67% yield).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH2:18][Cl:19]
Reactant: O=C(Cl)OCCl
Reactant: OC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)OC1CCCCC1

Procedure:
A solution of 3.0 g of cyclohexanol and 2.4 ml of pyridine in 30 ml of methylene chloride is cooled to -78° C. and, with stirring, 2.4 ml of chloromethyl chloroformate is added dropwise to the solution. After completion of addition, a cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 4.5 g of colorless oil, which is crystallized from ligroine giving the title compound as colorless crystals melting at 36°-37° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]1)C1C=CC=CC=1>CCO.CC(O)=O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH2:25]1
Reactant: O=C1CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(CCCc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
A solution of 5-[2-benzyloxy-4-((E)-3-phenylpropenyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (74 mg, 0.17 mmol) in 6 mL of EtOH/HOAc (4:2) is hydrogenated at 50 psi over 10% Pd/C (70 mg) for 18 h. The catalyst is filtered, the solvent is removed under reduced pressure and the residual oil purified by preparative HPLC to give the title compound as a solid: (M−1)−=345.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[N:15](OCCC(C)C)=[O:16]>CO>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12](=[N:15][OH:16])[C:13]#[N:14]
Reactant: CC(C)CCON=O
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC(=NO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
Under an ice cooling, sodium methoxide (2.70 g) was dissolved in methanol (100 ml), and 2,4-dichlorophenylacetonitrile (9.30 g, 50 mmol) and isoamyl nitrite (5.85 g) were added thereto. The mixture was stirred for 18 hours at a room temperature. The solvent was distilled off, and the residue was crystallized by adding diethyl ether (100 ml) to the residue. The resulting crystal was separated by filtration and azeotropically dried with benzene to give the title compound (9.68 g, 90%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=O)[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:14])[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(=O)NCC1C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=S)NCC1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 146.6 %

Procedure:
2.5 g of ethyl 4-methyl-2-oxopyrrolidine-3-carboxylate and 3.4 g of phosphorus pentasulfide were added to 50 ml of benzene and stirred at 50° C. for 1 hour. After cooling, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography to thereby give 2.1 g of the title compound as an oily product.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.C([N:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[NH:25]1[CH2:30][CH2:29][CH:28]([O:31][C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: c1ccc(OCCOc2nccnc2OC2CCNCC2)cc1
Yield: 35.5 %

Procedure:
The title compound was prepared according to the procedure described in Example 49 starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (250 mg, 1.00 mmol; from Example 1, Step 1) and N-Boc-4-hydroxypiperidine (234 mg, 1.16 mmol) to give 112 mg (35%) of the title product. HRMS m/z calcd for C17H23N3O3(M)* 315.1583, found 315.1570.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][C:17]([OH:19])=[O:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 6 h

Procedure:
4-Chloro-3-nitrobenzotrifluoride (10 grams), glycine (7 grams), and potassium carbonate (10 grams) were mixed in a mixture of 40 ml. each of water and dimethyl sulfoxide. The mixture was heated to 80°-100°C. and held for 6 hours, then poured into 600 ml. of water, acidified, and chilled to 5°C. The mixture was filtered, yielding N-(2-nitro-4-trifluoromethylphenyl)-glycine. The product was dissolved in 5 percent sodium bicarbonate and reprecipitated by acidification. It was separated and recrystallized from a mixture of ethanol and water, m.p., 167°-170°C.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2nc(CO)c(C)o2)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxymethyl-2-(4-methylphenyl)-5-methyl-1,3-oxazole (3 g) in 30 ml of dichloromethane was cooled to 0° C., and thionyl chloride (1.75 g) added dropwise. The reaction was stirred for 1 hour at room temperature, then washed twice with dilute sodium bicarbonate solution, the organic layer separated, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 4-chloromethyl-2-(4-methylphenyl)-5-methyl-l,3-oxazole, which was used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1OC[C@@H]1CO1
Yield: 72 %

Procedure:
A solution of methyl 2-hydroxy-5-methylbenzoate (0.166 g, 1 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (0.26 g, 1 mmol) and caesium carbonate (0.39 g, 1.2 mmol) in dimethylformamide (5 mL) was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by flash chromatoghrphy on silica gel (eluent:ethyl acetate/n-heptane), yielding the titled compound (0.16 g, 72%) as colourless oil.