Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)P(N(C)C)(N(C)C)=O.[CH2:12]([N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[CH2:31][CH2:32][CH2:33][CH2:34]I.O>O1CCCC1>[CH2:12]([N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]2([CH2:34][CH2:33][CH2:32][CH2:31]2)[C:20]1=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCc2ccccc2N1Cc1ccccc1
Reactant: ClCCCCI
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C1N(Cc2ccccc2)c2ccccc2CC12CCCC2
Temperature: -22 °C
Reaction time: 16 h

Procedure:
To diethylamine (0.96 ml, 0.0092 mol) in 4 ml tetrahydrofuran at 0° C. was added butyllithium (5.8 ml of 1.6 M in hexane, 0.0092 mol) and the mixture stirred for 10 minutes at 0° C., then warmed to room temperature, thus forming a solution of lithium diethylimide. The solution was cooled to -22° C., hexamethylphosphoramide (4 ml) and then, over a 5 minutes period, 1-benzyl-3,4-dihydro-2(1H)-quinolone (1.0 g, 0.0042 mol) in 6 ml tetrahydrofuran were added, and the resulting mixture warmed to 15° C. over 1 hour, then recooled to -55° C., at which point a solution of 1-chloro-4-iodobutane (0.95 g, 1.03 molar equivalents) in 10 ml tetrahydrofuran was added over 5 minutes. After stirring 16 hours at -55° C., water (5 ml) was added and the mixture warmed to room temperature, poured into 30 ml H2O and extracted 3×15 ml ether. The organic layers wre combined, washed 4×20 ml H2O, dried (MgSO4) and stripped to dryness (1.32 g) and radially chromatographed on a thick layer plate of silica gel with CHCl3 as eluant to produce present title product, 0.48 g; mass spectra includes molecular ion at 291.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22]CC)=O)=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C(O)(=O)CC([CH2:32][C:33](O)=O)(C(O)=O)O.[NH2:38][OH:39]>O1CCCC1.C(O)C.[OH-].[Na+]>[CH2:32]([C:19]1[C:20]([OH:22])=[N:38][O:39][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: NO
Reactant: CCOC(=O)CCc1ccc(OCCc2cccc(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1c(O)noc1-c1ccc(OCCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed solution of ethyl 3-(4-(2-(3-methoxyphenyl)ethoxy)phenyl)propionate (75 mg) in tetrahydrofuran (1 ml) and ethanol (0.5 ml), 0.041 ml of hydroxylamine (50% aqueous solution) and 0.277 ml of 2.5N aqueous sodium hydroxide were added, and the reaction solution was stirred overnight at room temperature. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., ethyl acetate/hexane (25:75)) to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=[O:24].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:15]2[CH:20]=[C:19]([CH:18]=[CH:17][N:16]=2)[C:21]([NH2:22])=[O:24])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccnc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccnc(Oc2ccc(C=O)c3ccccc23)c1
Temperature: 70 °C

Procedure:
To a solution of 4-hydroxy-1-naphthaldehyde (500 mg, 2.9 mmol) and 2-chloro-4-cyanopyridine (402 mg, 2.9 mmol) in DMF (4 mL) was added K2CO3 (2.01 g, 14.52 mmol). The reaction was heated for 1 h at 70° C. in a microwave. The mixture was diluted with EtOAc (100 mL), washed with water (2×50 mL) and the aqueous phase extracted with EtOAc (2×50 mL). The organic phase was washed with water (100 mL), 1M NaOH (3×60 mL), brine (50 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, NH4OH:MeOH:DCM, 0.2:2:98) to give the title compound: RT=3.02 min; m/z (ES+)=293.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]=O)[C:9]=2[CH:10]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:4]2[C:9]([CH:10]=1)=[C:8]([CH2:11][N:32]1[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]1)[CH:7]=[CH:6][CH:5]=2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc2c(C=O)cccc2n1S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2c(CN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 130 °C
Yield: 80 %

Procedure:
2-Methyl-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (94 mg, 0.3 mmol, Intermediate 47) was dissolved in THF (dry) (4 mL) before boc-piperazine (87.7 mg, 0.5 mmol) was added followed by acetic acid (188 mg, 3.1 mmol) and sodium triacetoxyborohydride (199 mg, 0.9 mmol) was added. The reaction mixture was heated in microwave for 720 s at 130° C. The solvent was evaporated, added water and DCM. Separated the phases and extracted the aqueous phase with DCM twice. The combined organic phases were dried (MgSO4) and the solvent was evaporated. The crude product was purified by preparative HPLC (30-60). Isolated 110 mg, as an oil, yield 80%. MS (ESI+) for C25H31N3O4S m/z 470 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH:6]2[CH2:12][CH2:13][C:14]([NH:16][C:17]1C=CC(C(F)(F)F)=C[N:18]=1)=[O:15].NC1[S:38][CH:39]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])N=1>>[CH2:45]([O:44][C:42]([C:40]1[N:18]=[C:17]([NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH:6]2[C:7]3[C:3](=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[F:11])[C:4](=[O:35])[N:5]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[S:38][CH:39]=1)=[O:43])[CH3:46]
Reactant: O=C(CCC1c2c(F)ccc(F)c2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)c1csc(N)n1
Product: CCOC(=O)c1csc(NC(=O)CCC2c3c(F)ccc(F)c3C(=O)N2Cc2ccc(F)cc2)n1

Procedure:
The product from Example 18, Part A (100 mg, 0.29 mmol) and ethyl 2-amino-1,3-thiazole-4-carboxylate were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (80 mg, 55%). 1H (300 MHz, CDCl3) δ 10.31 (s, 1H), 7.77 (s, 1H), 7.28 (m, 2H), 7.12 (m, 1H), 6.99 (m, 3H), 5.21 (d, J=15 Hz, 1H), 4.65 (m, 1H), 4.32 (q, J=7 Hz, 2H), 4.12 (d, J=15 Hz, 1H), 2.57 (m, 2H), 2.14 (m, 1H), 2.08 (m, 1H), 1.35 (t, J=7 Hz, 3H). MS: m/z (MH+) 504.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:13]=[CH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH:13]3[O:27][CH:12]3[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(Cl)s2)CC2OC2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.85 g (2.9 mmol) methyl 1-[(5-chloro-thiophen-2-yl)-carbonylamino]-cyclopent-3-ene-1-carboxylate and 20 ml methylene chloride is combined with 0.92 g 70% meta-chloroperbenzoic acid at 0° C. and stirred for 3 h at room temperature. The mixture is washed with sat. Sodium hydrogen carbonate solution and concentrated.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:5]=21.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[C:25]([NH:29][C:30](=[O:32])[CH3:31])=[CH:26][CH:27]=[CH:28][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(N)cccc32)cc(Br)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(NC(C)=O)cccc32)cc(Br)c1OC
Temperature: 0 °C
Yield: 93.1 %

Procedure:
2,7-Diamino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (10) (45 mg, 0.1 mmol) was taken in pyridine (2 ml) at 0° C., charged with acetic anhydride (11 mg, 0.11 mmol) and stirred further at 0° C. under LC-MS control. The reaction mixture was diluted with water (10 ml) under stirring, stirred further at room temperature for 2 h, the precipitates were collected by filtration, washed with water and dried to get the title compound (46 mg, 93%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:13]([CH3:28])=[C:12]2[CH2:29][C:30]([NH2:32])=[O:31])C.[OH-].[Na+].O.Cl>CO>[NH2:32][C:30](=[O:31])[CH2:29][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:13]=1[CH3:28]
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)O)ccc21
Yield: 77 %

Procedure:
A mixture of 590 mg (1.3 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1.5 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The precipitate was filtered and recrystallized from MeOH. There was obtained 430 mg (77% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid, mp, 163-165° C.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][N:12]([CH3:23])[CH2:13][C:14]([CH3:22])([CH3:21])[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]([CH3:10])([CH3:9])[C:6]#[C:5]/[CH:4]=[CH:3]/[CH2:2][N:18]1[CH2:19][CH2:20][CH:15]([C:14]([CH3:22])([CH3:21])[CH2:13][N:12]([CH3:11])[CH3:23])[CH2:16][CH2:17]1
Reactant: CN(C)CC(C)(C)C1CCNCC1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(C)(C)C1CCN(C/C=C/C#CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
12 g (6.10-2 mole)of 1-bromo-6,6-dimethyl-2-hepten-4-yne (E/Z=3/1) in solution in 20 ml of N,N-dimethylformamide was added drop-wise to a mixture of 10 g (5.4×10-2 mole) of N,N,β,β-tetramethyl-4-piperidineethanamine and 14.9 g of potassium carbonate in 150 ml of N,N-dimethylformamide. The mixture was stirred for 48 hours at room temperature then poured into water. This was extracted several times with ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. The residual oil obtained was purified by silica column chromatography, eluting with a 9/1 (v/v) methylene chloride/methanol mixture. After evaporation of the solvents under reduced pressure, 10.3 g (yield: 56%) of (E)-1-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N,N,β,β-tetramethyl-4-piperidineethanamine was obtained. The corresponding (Z)-2-butene-dioate was obtained from this in ethanol. M Pt=185°-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-L-valine (1.26 g) and morpholine (0.479 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.711 g) in DMF (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.90 g) at room temperature. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate/hexane, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.53 g).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[H][H]>[Pd].CO>[F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(NCC(F)F)CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Yield: 88.6 %

Procedure:
(2,2-Difluoro-ethyl)-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine (625 mg, 2.31 mmol) was charged to 30 ml methanol and 200-400 mg 10% palladium on carbon was added. The suspension was hydrogenated at 30 psi hydrogen for 2.5 hours and followed by NMR. The reaction was filtered through a ¼″ pad of celite and the pad washed with 4×10 ml portions of methanol. The resulting solution was clarified through a 45 micron frit to yield a yellow solution that was evaporated to yield N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (492 mg, 89% yield) as a white solid. 1H-NMR (CDCl3) δ 6.88 (m, 1H), 6.44 (m, 2H), 5.82 (m, 1H), 3.00 (m, 2H), 2.66 (m, 5H), 2.04 (m, 2H), 1.27 (m, 2H). LC/MS (ESI+)=241 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:15](OCC)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])[CH3:28]>>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH:33]/[C:15](=[C:6]1\[C:5](=[O:25])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:26]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)ccc21)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Product: COc1ccc2c(c1)NC(=O)/C2=C(\Nc1cccc(CN(C)C)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-methoxy-2-indolinone and 3-(dimethylaminomethyl)-aniline
Reaction SMILES: [ClH:1].[C:2]([NH:6][CH2:7][C:8]([CH2:14]O)([N+:11]([O-:13])=[O:12])[CH2:9][OH:10])([CH3:5])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[ClH:1].[OH:10][CH2:9][C:8]1([N+:11]([O-:13])=[O:12])[CH2:7][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:14]1
Reactant: CC(C)(C)NCC(CO)(CO)[N+](=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)N1CC(CO)([N+](=O)[O-])C1
Yield: 70 %

Procedure:
The product of example 2 was ring closed by dissolving 0.243 g (1 mmol) of the product in 10 ml of tetrahydrofuran (THF) and 0.262 g (1 mmol) of triphenylphosphine at room temperature. Diethylazodicarboxylate (0.174 g, 1 mmol) was slowly added dropwise. Color instantly appeared and a white solid precipitated. The solid was filtered from the solution and dried to yield a product (70% of theoretical yield) of 3-hydroxymethyl-3-nitro-1-tertiarybutylazetidine hydrochloride as determined by 1H-nmr.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].O.Cl>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(-c2ncccc2F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ncccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a mixture of methyl 2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzoate (Preparation 36, 240 mg, 0.85 mmol) in ethanol (5 mL) was added 2M LiOH in water (2.1 mL, 4.23 mmol). The reaction was stirred at room temperature for 1 hour before neutralising with 2M HCl (aq). The resulting precipitate was collected, washed with water and dried to afford the title compound as a white solid (160 mg, 70%).
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[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:20][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[NH:8]1
Reactant: CCCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(=O)[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(ethyl propionyl)piperidine. (1.8 g, 6.01 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 75 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(ethyl propionyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 121.1-122.0° C.; 1H NMR (300 MHz) δ9.44 (s, 2H), 5.68 (m, 2H), 4.19 (s, 1H), 3.56 (s, 1H), 2.2-1.2 (m, 17H), 0.88 (t, 3H); 13C NMR (75 MHz) δ137.1 (s), 122.8 (s), 48.34 (s), 47.94 (s), 31.4 (s), 28.8 (s), 28.4 (s), 27.9 (s), 22.4 (s), 17.6 (s), 17.1 (s), 13.97 (s) ppm. FT-IR (neat): 3435, 3192, 2924, 1586, 1431, 1030, 673. Elemental Analysis. for C13H26NCl: C, 67.34%; H, 11.33%; N, 6.04%. Found: C, 67.44%; H, 11.23%; N, 5.98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[N:21]1(C(OCC)=O)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH2:11][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1ccc(CC(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(CC(CCCN2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
50 g (0.17 mol) of 4,5-bis(4-fluorophenyl)pentyl chloride, 32.5 g (0.21 mol) of ethyl piperazine-1-carboxylate, 46.9 g (0.34 mol) of powdered potassium carbonate and 2.8 g of potassium iodide were reacted in 580 ml of methyl isobutyl ketone and the mixture was worked up, by a process analogous to that described in Example 3d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[CH2:25]([NH:32][CH2:33][CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH2:25]([N:32]([CH2:33][CH3:34])[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNCc1ccccc1
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
[4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.200 g, 0.577 mmol) was dissolved in DMF (10 ml), N-benzyl-N-ethylamine (0.086 g, 0.635 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.204 g, 0.635 mmol) and N-ethyl-N,N-diisopropylamine (0.157 g, 1.212 mmol) was added. The solution was stirred over night at room temperature. Water (100 ml) was added and the water phase was extracted with diethyl ether (3×20 ml). The organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 30/70 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the solvent was removed by evaporation to give 0.137 g of methyl 2-{[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-ethyl]thio}benzoate (yield 51.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.[N:17]([Sn](C)(C)C)=[N+:18]=[N-:19]>C1(C)C=CC=CC=1>[C:11]1([C:3]2[CH:4]=[C:5]([CH2:8][C:9]3[NH:19][N:18]=[N:17][N:10]=3)[CH:6]=[CH:7][C:2]=2[NH2:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: N#CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from (4-amino-3-cyclohex-1-enyl-phenyl)-acetonitrile (as prepared in the previous step, 103 mg, 0.485 mmol) and azidotrimethylstannane (105 mg, 0.510 mmol) in toluene (4 mL) according to the procedure in Example 52, step (c) and then further purified by preparative TLC (10% MeOH—CHCl3) to afford 40 mg (39%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C14H17N5, 256.1 (M+H), found 256.1.