Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[C:9]2([CH2:12][N:11]([C:13]([C:15]3[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[C:19]([F:30])[C:18]([F:31])=[CH:17][CH:16]=3)=[O:14])[CH2:10]2)[O:8]1.[N-:32]=[N+:33]=[N-:34].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:32]([CH:7]([C:9]1([OH:8])[CH2:10][N:11]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:31])=[C:19]([F:30])[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:14])[CH2:12]1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CC1OCCO1)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 22 h
Yield: 73.7 %

Procedure:
6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (25 mg, 0.042 mmol, 74% yield): MS (EI) for C21H19F3IN5O4: 590 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[CH:4]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A 0.5 M solution of 1-bromomethyl-3-chloro-benzene (102.7 mg, 0.5 mmol) in acetone was added to a suspension of 4-hydroxy-benzaldehyde (67.2 mg, 0.55 mmol), K2CO3 (207.3 mg, 1.5 mmol) and KI (10.8 mg, 0.065 mmol) in acetone (7 ml). The reaction mixture was stirred for 2 hours at 70° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:38]3[CH:39]=[CH:40][N:41]=[C:37]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCc1ncc[nH]1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-undecylimidazole (500 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from diethyl ether-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-undecyl-1-imidazolyl)oxazole as pale yellow prisms (100 mg, 13%). Melting point 53-54° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[N:18]1([C:24]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC(OC(=O)N2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (65 μL) is dissolved in pyridine (2 mL), treated with morpholine-4-carbonyl chloride (500 μL) and stirred for 6 hours at 50° C. Morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 12 hours at 80° C. Again morpholine-4-carbonyl chloride (500 μL) is added and the mixture is stirred for 12 hours at 80° C. The mixture is partitioned between ethylacetate and hydrochloric acid (1 M). The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][NH:13][OH:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]=[C:17]=[O:18].C(OCC)C.O>O1CCCC1>[OH:14][N:13]([CH2:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:17]([NH:16][CH3:15])=[O:18]
Reactant: ONCc1ccc(-c2ccccc2)o1
Reactant: CN=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N(O)Cc1ccc(-c2ccccc2)o1
Yield: 89.2 %

Procedure:
To a solution of N-(5-phenylfur-2-yl)methyl hydroxylamine (0.5 g, 2.64 mmol) in tetrahydrofuran (30 mL) was added methylisocyanate (0.24 mL, 3.97 mmol) dropwise at room temperature under nitrogen while stirring. The reaction was stirred for 20 h and ethyl ether (100 mL) and water (100 mL) was added. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo, to give a solid (0.58 g). Purification by chromatography (silica gel, 2% methanol in dichloromethane) gave the desired product (0.28 g), mp 135°-139° C.; NMR (300 MHz, DMSO-d6): 2.63 (3H, d, J=5.4 Hz), 4.53 (2H, s), 6.38 (1H, d, J=3.3 Hz), 6.87 (1H, d, J =3.3 Hz), 7.03 (1H, q, J=5.4 Hz), 7.24-7.30 (1H, m), 7.38-7.45 (2H, m), 7.38-7.45 (2H, m), 7.62-7.68 (2H, m), 9.40 (1H, s); MS (CI-NH3): M+H=247; Analysis Calculated for C13H14N2O3 : C, 63.40; H, 5.73, N, 11.38; Found C, 63.29; H, 5.76; N, 11.34.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1.[C:24]([C:26]1[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1)#[N:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CO.ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:31]([C:29]3[O:30][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[O:32])=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 54 %

Procedure:
The procedure of Example 4, step (c) was followed using 50.2 mg (0.158 mmol) of 1-methyl-4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine (as prepared in the previous step), 20 mg of 10% palladium on carbon (50% by weight water), 22.8 mg (0.166 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 29.0 μL (0.332 mmol) of oxalyl chloride, and 57.8 μL (0.332 mmol) of DIEA. Chromatography on a 5-g silica SPE column with 0.5-3% MeOH-dichloromethane afforded 34.8 mg (54%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): o 9.59 (br s, 1H), 8.33 (d, 1H, J=8.9 Hz), 7.21, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.78 (d, 1H, J=2.7 Hz), 6.74 (dd, 1H, J=8.9, 2.7 Hz), 3.35-3.55 (m, 4H), 2.95-3.05 (m, 4H), 2.72-2.75 (m, 4H), 2.67 (br s, 3H), 1.83-1.87 (m, 2H), 1.45-1.65 (br m, 1H), 1.43-1.53 (m, 2H) and 1.07 (d, 3H, J=6.2 Hz), Mass spectrum (ESI, m/z): Calcd. for C23H29N5O2, 408.2 (M+H), found 408.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:15]1([C:14]2[N:4]3[N:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reactant: C1CCNC1
Solvent: CCO
Product: c1ccc(-c2nnc3c4ccccc4c(N4CCCC4)nn23)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5 g), pyrrolidine (5 ml), ethanol (35 ml) and catalytic amounts of KI, is poured in a pressure resistant vessell and heated to 100° C. for 8 hours. The reaction mixture is then cooled, the solvent is evaporated off and the residue is thoroughly washed with a small amount of water and crystallized from ethanol yielding the compound of the title in 82% yield. M.p. 208°-09° C.
Reaction SMILES: O.NN.[CH3:4][N:5]1[C:9]([CH3:10])=[CH:8][N:7]([N:11]=CC2C=NC=CC=2)[C:6]1=[O:19]>CO>[NH2:11][N:7]1[CH:8]=[C:9]([CH3:10])[N:5]([CH3:4])[C:6]1=[O:19]
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)n1C
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cn(N)c(=O)n1C

Procedure:
2 g of hydrazine hydrate are added to a solution of 2 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-2,3-dihydroimidazol-2-one in 12 ml of methanol and the suspension is boiled under reflux for 6 hours, then concentrated by evaporation and chromatographed on silica gel. 1 g of pyridine-3-carbaldehyde hydrazone and 0.7 g of the title compound having a melting point of 115°-119° are thus obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc(C(=O)CBr)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of 2-bromo-1-[3-(methyloxy)phenyl]ethanone (2.4 g, 10.5 mmol) in THF (80 mL) and water (20 mL) was added sodium azide (1.703 g, 26.2 mmol), and the reaction mixture was stirred at room temperature for 60 hours. Water (40 mL) was added, and the aqueous mixture was extracted with EtOAc (3×80 mL). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound (1.87 g) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 3.87 (s, 3H), 4.55 (s, 2H), 7.15-7.18 (m, 1H), 7.38-7.42 (m, 1H), 7.44-7.47 (m, 2H).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=Cn3ccnc3)c3ccccc3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(Cn3ccnc3)c3ccccc3)ccc2N1

Procedure:
A solution of 390 mg of a mixture of (E) and (Z) isomers of 6-[1-phenyl-2-(imidazol-1-yl)ethenyl]-3,4-dihydrocarbostyril in 10 ml of ethanol was stirred under hydrogen in the presence of 200 mg of a 10% palladium on charcoal catalyst until the theoretical amount of hydrogen had been absorbed. The catalyst was filtered off, the solvent removed from the filtrate under reduced pressure and the residue chromatographed on silica gel eluting with 5% methanol in methylene chloride, yielding 6-[1-phenyl-2-(imidazol-1-yl)ethyl]3,4-dihydrocarbostyril, having a melting point of 87°-94° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH:27]([CH2:29][CH3:30])[CH3:28])[CH:21]=2)=[C:14]([Cl:31])[CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[OH-].[Na+]>CO.O>[CH:27]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[OH:26])[O:19][C:15]1[C:14]([Cl:31])=[CH:13][C:12]([N:6]([CH2:5][C:4]([OH:32])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:17][C:16]=1[Cl:18])([CH2:29][CH3:30])[CH3:28]
Reactant: CCOC(=O)CN(C(=O)OCC)c1cc(Cl)c(Oc2ccc(O)c(C(C)CC)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N(CC(=O)O)c1cc(Cl)c(Oc2ccc(O)c(C(C)CC)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
The ester (0.77 g, 1.5 mmol) was dissolved in MeOH (18 mL) and to it a solution of NaOH (0.19 g, 4.75 mmol) in H2O (5.6 mL) was added and it was stirred at 60° C. for 1 hr. Methanol was evaporated from the reaction mixture and H2O was added, washed with diethyl ether. Aqueous layer was acidified to pH 4 using 10% HCl solution and extracted with ethyl acetate. The organic layer was washed with H2O, brine & dried over sodium sulphate, filtered and concentrated to give 0.75 g of crude product. The crude product was purified by column chromatography (Silica gel, Chloroform Methanol) gradient elution from 95:5 to 90:10 to give pure {[4-(3-sec-Butyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-ethoxycarbonyl-amino}-acetic acid. (0.125 g, 18% yield)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[CH:7]=1)#[N:2].C([Li])CCC.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>O1CCCC1.ClCCl>[C:1]([C:3]1[C:4]([C:20]([F:23])([F:21])[F:22])=[N:5][N:6]([C:8]2[C:9]([Cl:19])=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][C:13]=2[Cl:14])[C:7]=1[Si:30]([CH3:32])([CH3:31])[CH3:29])#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.03 h

Procedure:
A stirred solution of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.5 g) in dry tetrahydrofuran cooled to -78° C. was treated with a solution of n-butyl lithium (2.6M in hexane, 1.71 ml) dropwise under nitrogen. The temperature was kept below -65° C. during the addition, and the resultant solution kept at -78° C. for 1 hour. A solution of trimethylsilyl chloride (0.56 ml) in dry tetrahydrofuran (2 ml) was then added, dropwise, during 2 minutes. The mixture was allowed to reach room temperature over 2 hours, left overnight and evaporated in vacuo to give a pale yellow solid. This was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo. The product was recrystallized from hexane to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethyl-5-trimethylsilylpyrazole as white crystals, m.p. 108°-110° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([Si](C)(C)[O:13][C@@H:14]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][N:25]([CH2:38][CH:39](OC)OC)[C:26](=[O:37])[CH2:27][NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:19][CH2:18][C:15]21[CH2:17][CH2:16]2)(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:36][C:31]1[CH:30]=[C:29]([N:28]2[CH2:39][CH2:38][N:25]([CH2:24][CH2:23][CH2:22][N:20]3[CH2:19][CH2:18][C:15]4([CH2:17][CH2:16]4)[C@H:14]([OH:13])[CH2:21]3)[C:26](=[O:37])[CH2:27]2)[CH:34]=[CH:33][C:32]=1[Cl:35]
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)C(=O)CNc1ccc(Cl)c(Cl)c1)OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(c2ccc(Cl)c(Cl)c2)CCN1CCCN1CCC2(CC2)[C@H](O)C1
Temperature: 60 °C
Yield: 17.2 %

Procedure:
Trifluoroacetic acid (1.51 g, 13.3 mmol) was added to a solution of N-{3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propyl}-2-(3,4-dichloro-phenylamino)-N-(2,2-dimethoxy-ethyl)-acetamide (142 mg, 0.24 mmol) in CH2Cl2 (1 mL) at RT, then after 3 h triethylsilane (140 mg, 1.21 mmol) was added. The solution was heated at 60° C. over 72 h, then partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc/MeOH 19:1) afforded the title compound (17 mg, 17%). Yellow gum, MS: 412.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C@H:20]([CH:29]=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:33][CH:34]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][O:36][C:35]1([CH3:45])[CH3:44]>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C@H:20]([CH2:29][N:41]3[CH2:42][CH2:43][C:38]4([CH2:37][O:36][C:35]([CH3:45])([CH3:44])[CH:34]4[OH:33])[CH2:39][CH2:40]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1(C)OCC2(CCNCC2)C1O
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COC(C)(C)C3O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This product was prepared according to the procedure described in Example 6 using (2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-tetrahydropyran-4-carbaldehyde (Description 11) and 4-hydroxy-3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane (Description 21).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:6]=[C:5]2[CH:20]=[CH2:21]>C(O)C.O1CCCC1.[C].[Pd]>[CH2:20]([C:5]1[C:4]2[C:8](=[CH:9][C:10]([NH2:11])=[C:2]([CH3:1])[CH:3]=2)[N:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:6]=1)[CH3:21]
Reactant: C=Cc1nn(C2CCCCO2)c2cc([N+](=O)[O-])c(C)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nn(C2CCCCO2)c2cc(N)c(C)cc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
The compound (3.04 g, 10.6 mmol) of step A was dissolved in an ethanol (100 ml)-tetrahydrofuran (10 ml) mixed solvent, and the mixture was stirred at room temperature. Then, 10% palladium carbon (containing water) (3.20 g) was added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the obtained solution was concentrated under reduced pressure to give the title compound (2.69 g, yield 98%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][C@@H:10]([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:18][C:12]=2[O:11][C@@H:10]([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)Cc2ncc(Cl)nc2O1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1CN(Cc2ccccc2)Cc2ncc(N3CCOCC3)nc2O1
Temperature: 100 °C
Yield: 20 %

Procedure:
A suspension of (6S)-8-benzyl-3-chloro-6-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (301 mg), morpholine (0.11 mL), Pd2(dba)3 (19 mg), XPhos (40 mg) and sodium tert-butoxide (250 mg) in toluene (5 ml) was stirred under an argon atmosphere with heating at 100° C. for 2 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 9→50% ethyl acetate/hexane) to give the title compound (70 mg, 20%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24]>C1COCC1>[Cl:1][C:2]1[C:3]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[N:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Clc1cc2[nH]cnc2cc1N1CCCC1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCn1cnc2cc(Cl)c(N3CCCC3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazole (0.443 g, 2.00 mmol) and THF (5 mL) was added NaH (96.0 mg, 60% dispersion in mineral oil, 2.40 mmol) at 0° C. After stirring the reaction mixture for 30 min at 0° C., 1-chloromethoxy-2-methoxy-ethane (0.299 g, 2.40 mmol) was added and the mixture was stirred for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-10% MeOH/DCM) to yield the titled compound as a mixture of regioisomers (0.240 g, 39%) with a purity of 90%. MS (ESI/CI): mass calcd. for C15H20ClN3O2, 309.1; m/z found, 310.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([C:26]([O:28][CH3:29])=[O:27])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1C(OCC1C=CC=CC=1)=O)[CH3:2]>CO.C(O)(=O)C.[Pd]>[CH2:1]([C:3]1([C:26]([O:28][CH3:29])=[O:27])[NH:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8]1)[CH3:2]
Reactant: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-Benzyl 4-tert-butyl 2-methyl 2-ethylpiperazine-1,2,4-tricarboxylate (1.1 g, 2.7 mmol) was dissolved in 10 mL of methanol and glacial acetic acid (2 drops) was added. Palladium on carbon (5%, 410 mg) was added, and the reaction mixture was stirred under a H2 atmosphere for 17 h at rt. The mixture was filtered through diatomaceous earth and the filter cake washed with MeOH. The combined filtrates were concentrated under reduced pressure to give 1-tert-butyl 3-methyl 3-ethylpiperazine-1,3-dicarboxylate (compound IV-JJ) as an oil. LCMS: 273.1 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[O:16][CH3:17])[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:24]3[C:23](=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:13]=2[CH3:14])[C:6]=1[O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1OC
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methoxy-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.