Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[O:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccncc3o2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cccc(-c2nc3ccncc3o2)c1
Yield: 31.2 %

Procedure:
A suspension of 2-(3-nitrophenyl)oxazolo[5,4-c]pyridine (1.20 g, 5 mmol), iron powder (1.40 g, 25 mmol) and NH4Cl (2.14 g, 40 mmol) in CH3OH:H2O (4:1, 60 mL) was refluxed for 6 hrs. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was poured into water. The precipitate was collected by filtration, and washed with water (20 mL×3) to afford 3-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as a white solid (0.330 g, yield: 31%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C1COCC1.O>[Cl:15][C:14]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([NH:21][C:20]2[CH:22]=[CH:23][C:24]([F:25])=[C:18]([C:17]([F:27])([F:16])[F:26])[CH:19]=2)[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1C(F)(F)F
Temperature: 2.5 °C
Yield: 27.5 %

Procedure:
Potassium carbonate (2.76 g, 20 mmol) was added to a solution of cyanuric chloride (II) (1.84 g, 10 mmol) in THF (30 mL) and the mixture cooled to 0-5° C. in an ice bath. 3-Trifluoromethyl-4-fluoroaniline (XVI) (1.79 g, 10 mmol) was added dropwise with stirring. The mixture was stirred for 16 h, diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extract was rinsed with brine (20 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography (silica gel; EtOAc/hexane (1:4)) to afford 4,6-dichloro-N-(3-trifluoromethyl-4-fluorophenyl)-1,3,5-triazine-2-amine (XVII) as an off-white solid (0.9 g, 19% yield): m.p. 114-117° C.; 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.86 (m, 2H), 7.65 (bs, 1H), 7.27 (t, 1H); ESI/MS 326 (M+H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][CH2:12][C:13]([CH3:16])([NH2:15])[CH3:14])[CH2:8]2.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].O>C1COCC1>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[N:11]1[CH2:12][C:13]([CH3:16])([CH3:14])[NH:15][C:17]1=[O:18])[CH2:4]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(N)CNC1C2CC3CC(C2)CC1C3
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CN(C2C3CC4CC(C3)CC2C4)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.8 %

Procedure:
N1-Adamantan-2-yl-2-methyl-propane-1,2-diamine (250 mg) was dissolved in dry THF (6 mL) under argon and carbonyldiimidazole (182 mg) was added. The resulting mixture was allowed to stir at RT for 48 hours. The mixture was poured into water/0.5 M HCl and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography using (a gradient of 10 to 70% ethyl acetate in heptane as an eluent. The fractions containing the desired material were combined and evaporated to leave 1-adamantan-2-yl-4,4-dimethyl-imidazolidin-2-one as a white solid (256 mg). MS (EI): 248.3 (M+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][N:2]=[CH:1]3)=[CH:6][CH:7]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ccncc3c2)CC1

Procedure:
The product from step (a) above (300 mg, 1.1 mmol) and 1-BOC-piperazine (307 mg, 1.6 mmol, Aldrich) was reacted under the conditions of Example 132b to give the title compound as yellow amorphous solid, which was used for the next step. MS (ESI, pos. ion) m/z: 314 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]([NH:18][CH2:19][CH3:20])=[S:17]>C(Cl)Cl>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[C:2](=[O:3])[C:1](=[O:5])[N:18]([CH2:19][CH3:20])[C:16]1=[S:17]
Reactant: CCNC(=S)Nc1c(C)cccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCN1C(=O)C(=O)N(c2c(C)cccc2C)C1=S
Yield: 45.7 %

Procedure:
Oxalyl chloride (7.62 g; 0.06 mol) was added dropwise to the stirring solution of N-(2,6-dimethylphenyl)-N′-ethylthiourea (10.4 g; 0.05 mol) in methylene chloride (200 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. Ethanol (100 mL) was added and the mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with 2N hydrochloric acid (500 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ether/hexane to give 6.0 g of 1-(2,6-Dimethylphenyl)-3-ethyl-2-thioxo-4,5-imidazolidinedione, m.p. 103–105° C. Mass spectrum; FAB (M+H)+ m/z 263. 1H-NMR (DMSO-d6; 300 MHz): δ 7.31–7.27 (m, 1H), 7.18 (d, 2H), 3.94 (q, 2H), 2.08 (s, 6H), and 1.25 ppm (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:42][CH2:43]3)[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous white substance (315 mg, 75%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[N:22]1([CH2:2][CH2:3][CH2:4][C:5]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH:8]=[CH:7][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1(CCCCl)CC=CCC1c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCN2CCCCC2)CC=CCC1c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (6.35 g, 20.7 mmol) was dissolved in 50 ml of dimethylformamide (DMF) to which piperidine (10 equiv, 15 ml) was added. The contents were stirred under N2 at 50° C. for 16 hrs. The reaction was allowed to cool to ambient temperature, whereupon the DMF was removed on the rotovap at 3 mm pressure. To the residue was added 200 ml of ethyl ether and the organic material was washed three times with 100 ml of water. The organic fraction was dried over MgSO4, filtered and concentrated in vacuo to afford after distillation (155°-160° C./0.1 mm) ethyl 1-[3-(1-piperidinyl)propyl]-6-phenyl-3-cyclohexene-1-carboxylate as a clear viscous oil (6.61 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[O:22]=[C:23]1[C:28]2=[CH:29][NH:30][C:31]([CH:32]=O)=[C:27]2[CH2:26][CH2:25][O:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:32][C:31]2[NH:30][CH:29]=[C:28]3[C:23](=[O:22])[O:24][CH2:25][CH2:26][C:27]=23)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[N:4]=[C:5]([Br:13])[N:6]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=12.CC(O)CC>O>[Br:2][C:3]1[N:4]=[C:5]([Br:13])[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:1])[C:7]=12
Reactant: N
Reactant: Clc1nccn2c(Br)nc(Br)c12
Solvent: CCC(C)O
Solvent: O
Product: Nc1nccn2c(Br)nc(Br)c12
Reaction time: 8 h

Procedure:
20 M of NH3 in H2O(10 mL) was added to a suspension of 1,3-Dibromo-8-chloro-imidazo[1,5-a]pyrazine (1.726 g, 0.007425 mol) in 2-Butanol (7.49 mL, 0.0817 mol). The mixture was heated in an oil bath set at 90° C. overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography using 1→6% MeOH in DCM to obtain the title compound as a yellow solid. MS (ES+): m/z 294.83 (85) [MH+]. HPLC: tR=1.58 min (Open Lynx polar—5 min). 1H NMR (400 MHz, CD3OD):δ=7.10 (d, J=5.05 Hz, 1H), 7.43 (d, J=5.05 Hz, 1H)
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH:23]=[CH:22]4)=[O:30])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1ccc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-cyclohexylphenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>CC(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[C:16]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:15]([OH:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4cccc(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling the 6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.29 (s, 9H), 1.46–1.76 (br m, 8H), 2.19 (m, 2H), 2.47 (s, 3 Hz), 2.56–2.70 (m, 7H), 2.87 (d, 1H, J=17.5 Hz), 3.80 (d, 1H, J=16.2 Hz), 3.90 (d, 1H, J=16.2 Hz), 7.12 (m, 2H), 7.28 (m, 3H), 10.92 (s, 1H). Anal. Calcd. For C30H38N4O3.0.4 AcOH: C, 70.24; H, 7.58; N, 10.64. Found: C, 70.27; H, 7.42; N, 10.59.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]([O:36]C)=[O:35])=[CH:7][CH:6]=1)#[N:4].O>O1CCOCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH2:33][C:34]([OH:36])=[O:35])=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1 M, 7.27 mL, 7.27 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetate (example 31, 1.76 g, 3.64 mmol) in 1,4-dioxane (15 mL) and the mixture is stirred at room temperature for 1 h. Water (80 mL) is added and the mixture is extracted twice with diethyl ether. The organic phase is discarded and the aqueous phase is acidified with aqueous hydrogen chloride (1 M) and extracted three times with diethyl ether. The combined organic layers are washed with water and saturated aqueous sodium chloride, and concentrated under reduced pressure. Yield: 1.69 g; ESI mass spectrum [M+H]+=470; Retention time: 0.88 min (Z018_S04).
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25]([C:28](=O)[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1>>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH2:18][C:19]1[N:23]2[N:24]=[C:25](/[C:28](=[N:6]/[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])/[CH3:29])[CH:26]=[CH:27][C:22]2=[N:21][CH:20]=1
Reactant: CS(=O)(=O)NN
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\NS(C)(=O)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 60 %

Procedure:
The title compound was prepared from methanesulfonohydrazide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 60% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.63 (s, 1H), 8.85 (dd, 1H), 8.30 (d, 1H), 8.09 (d, 1H), 7.94 (d, 1H), 7.75 (m, 3H), 7.47 (q, 1H), 4.58 (s, 2H), 3.10 (s, 3H), 2.26 (s, 3H). LCMS (method A): [MH]+=413, tR=4.57 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[C:14]([CH3:20])[CH:13]=2)=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32](/[CH:36]=[CH:37]/[C:38]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[O:39])=[CH:31][C:30]=2[CH3:46])=[N:26][CH:27]=1>CN(C=O)C>[OH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32](/[CH:36]=[CH:37]/[C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH2:18][C:15]4[CH:16]=[CH:17][C:12](/[CH:11]=[CH:10]/[CH2:9][O:8][C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:13][C:14]=4[CH3:20])[CH2:42][CH2:41]3)=[O:39])=[CH:31][C:30]=2[CH3:46])=[N:26][CH:27]=1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(C)c1Oc1ccc(O)cn1
Reactant: Cc1ccc(OC/C=C/c2ccc(CCl)c(C)c2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(OC/C=C/c2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(C)c4)CC3)c(C)c2)cc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
To a solution of (E)-3-[4-(chloromethyl)-3-methylphenyl]prop-2-en-1-yl 4-methylphenyl ether (0.180 g) and (E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}-1-(piperazin-1-yl)prop-2-en-1-one (0.222 g) in DMF (2 mL) was added KHCO3 (0.063 g) at room temperature under an Ar atmosphere. The mixture was heated at 100° C. for 3 hours, and then cooled to room temperature, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (AcOEt) to afford (2E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-3,5-dimethylphenyl}-1-(4-{2-methyl-4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.286 g) as a colorless powder.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)CCO)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution (30 ml) of ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl) (methyl)amino]benzoate (2.33 g, 6.90 mmol) in tetrahydrofuran was added tetrabutyl ammoniumfluoride (1.0 M toluene solution, 10.4 ml, 10.4 mmol) at room temperature and the mixture was stirred overnight. After concentration of the reaction mixture under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3:2-1:4, v/v) to give the title compound (1.11 g, 72%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH:19]([N:32]1[CH2:35][CH:34]([NH2:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]1([CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:32]2[CH2:35][CH:34]([NH:36][C:16]([C@@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:18])[CH2:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Product: O=C(NC1CN(C(c2ccccc2)c2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 1-benzhydryl-3-azetanamine [see J. Med. Chem. (1977), 21(1), 78-82]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 60:40, then 50:50, by volume, hexane:ethyl acetate to afford (2S)-N2-(1-diphenylmethyl-3-azetidinyl)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide as a white foam.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH2:19][C:20]#[N:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([CH2:19][C:20]([NH2:1])=[NH:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: N#CCC1(c2ccc(Br)cc2)CCCC1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a suspension of NH4Cl (1.21 g, 43.65 mmol) in toluene (30 mL) was added dropwise a solution of trimethyl aluminium (1.64 g, 43.65 mmol, 2M in toluene) at 0° C. and stirred for 2 h at room temperature prior to the addition of a solution of [1-(4-bromophenyl)-cyclopentyl]-acetonitrile (228) (2.0 g, 7.57 mmol) in toluene (10 mL). The resulting solution was heated to 80° C. for 16 h. The cooled reaction mixture was poured into a slurry of silica gel (10 g) in CHCl3 (20 mL), followed by vigorous stirring for 30 min. The silica gel was filtered off and the cake was rinsed in turn with methanol. The solvent was evaporated and the crude product was taken up in 10% methanol in dichloromethane (200 mL) and stirred for 30 min. The solid suspension was removed by filtration and the filtrate was evaporated. The crude product was triturated in diethyl ether and the solid was collected by filtration and dried under vacuum to afford HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (1.78 g, 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[CH3:13][N:14]([CH3:16])[NH2:15]>>[CH3:13][N:14]([CH3:16])[NH:15][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([Cl:1])=[C:3]([Cl:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: CN(C)N
Product: CN(C)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of 1,2,4-trichloro-5-nitrobenzene with 1,1-dimethylhydrazine as described in Example I gave the desired product, m.p. 138°-143° C.
Reaction SMILES: C[N:2](C)C=O.C(Cl)(=O)C(Cl)=O.[F:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:26])([F:25])[F:24])[C:14]=1[C:29]([N:31]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][C:33]([OH:35])=O)=[O:30]>C(Cl)Cl>[F:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:25])([F:24])[F:26])[C:14]=1[C:29]([N:31]([CH2:32][C:33]([NH2:2])=[O:35])[C:36]([O:38][CH3:39])=[O:37])=[O:30]
Reactant: COC(=O)N(CC(=O)O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)N(CC(N)=O)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
Dimethyl formamide (6 μL, 0.067 eq) and oxalyl chloride (130 μL, 1.2 eq) were added to a stirred solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine in anhydrous methylene chloride (2.5 mL) at 0° C. under a dry nitrogen atmosphere. After 5 minutes, the reaction was warmed to room temperature. After 13/4 hours, the organics were removed. The residue was dissolved in anhydrous ether (30 mL) at 0° C. and ammonia gas was bubbled in for 1 minute. The reaction was immediately quenched with hexane (30 mL). The solid was collected by suction filtration and suspended in ethyl acetate (75 mL). The ethyl acetate phase was washed with water (2×25 mL), dried with magnesium sulfate, and the ethyl acetate was removed. The solid was combined with that from another run and recrystallized in chloroform:petroleum ether to provide the title compound as a white solid (325 mg, 54% combined yield), m.p. 199°-202° C.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]1[C:35]2([CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[O:31]1[C:35]2([CH2:40][CH2:39][C:38](=[CH:20][C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32]1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Product: O=C(C=C1CCC2(CC1)OCCO2)OCc1ccccc1
Temperature: 95 °C
Reaction time: 48 h
Yield: 92.1 %

Procedure:
Benzyl (triphenylphosphoranylidene)acetate (47.30 g, 115.2 mmol) was added to a solution of 1,4-dioxaspiro[4,5]decan-8-one (10.0 g, 64.02 mmol) in toluene (300 ml) at room temperature, and the mixture was stirred at 95° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was diluted with ether and hexane, the resultant precipitate was removed by filtration, and the filtrate was concentrated. The residue was chromatographed on silica gel column (hexane:ethyl acetate=9:1) to give the title compound as a colorless oil (17.0 g, yield 92%).