Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:17][N:18]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][S:19][C:16]2[O:15][C:14]([C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=3)=[N:18][N:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2nnc(SCc3ccc(F)cc3)o2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2nnc(SCc3ccc(F)cc3)o2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
To a solution of tert-butyl[4-[5-[(4-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]-2-pyridyl]carbamate (138 mg, 0.343 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL), and the resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was alkalified with aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5-0/100), and recrystallized from methanol/chloroform/diethyl ether to give the title compound (44 mg, yield 43%) as colorless crystals.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].C1(C)C=CC=CC=1.[CH2:13]([C:18]([N:20]=[C:21]=[O:22])=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)C>[CH2:13]([C:18]([NH:20][C:21]([N:4]1[CH2:5][CH:3]1[C:1]#[N:2])=[O:22])=[O:19])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#CC1CN1
Reactant: CCCCCC(=O)N=C=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC(=O)NC(=O)N1CC1C#N

Procedure:
In a manner analogous to that described in Example 14, from 0.81 g. 2-cyanoaziridine, dissolved in 8 ml. toluene, and a solution of 1.7 g. n-pentanecarbonyl isocyanate in 17 ml. toluene, there are obtained, without purification with diethyl ether, 1.6 g. 1-(N-n-pentanecarbonyl-carbamoyl)-1-cyanoaziridine; m.p. 143°-144° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:41][C:42]4[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[O:41][C:42]5[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CCc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CN1CCN(C2CCC(n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1ccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00014 mol), N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-ethyl-1,3-benzoxazol-2-amine (0.062 g, 0.00017 mol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.00001 mol) and sodium carbonate (0.037, 0.00035 mol) in ethylene glycol dimethyl ether (3 mL) and water (1 mL) was heated at 80° C. for 16 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the residue was purified by flash column chromatography on silica using 2% aqueous ammonium hydroxide solution/5%-25% methanol/dichloromethane as a mobile phase. The solvent was removed under reduced pressure to give cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.065 g, 0.00012 mol). 1H NMR (DMSO-d6, 400 MHz) δ 11.25 (s, 1H), 8.65 (s, 1H), 8.37 (d, 2H), 8.09 (d, 2H), 7.84 (d, 1H), 7.76 (s, 1H), 7.42 (d, 1H), 5.22 (br, 1H), 3.13 (q, 2H), 2.52 (br, 7H), 2.69 (br, 4H), 2.64 (s, 3H), 2.49 (br, 21), 2.11 (br, 2H), 2.01 (br, 2H), 1.63 (t, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.3 min. MS: MH+ 552
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:16]=3)=[CH:6][N:5]2[CH:28]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH:29]1([C:32]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][C:14]([F:27])=[C:15]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:16]=4)=[CH:6][N:5]3[CH:28]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4c3)ccc2F)n(C)n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)ccc2F)n(C)n1
Yield: 61.4 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (730 mg, 1.92 mmol) in N,N-dimethylacetamide (7 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (262 μL, 2.88 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-ethanol to give the title compound (529 mg, 61%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH:12](C)[CH2:13][C:14](OC)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[Na+].Cl.[CH3:22][OH:23]>>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:22]([OH:23])=[O:19])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: COC(=O)CC(C)c1nc(-c2ccccc2)no1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCCc1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of methyl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (1.53 g, 6.21 mmole) in methanol (10 ml) was added 1N NaOH (10 mL). After stirring at room temperature for 2 hours, the reaction solution was acidified to pH=3-4 with 6N HCl under an ice bath and then extracted with ethyl acetate three times. The combined organic layers were washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the desired product (1.44 g, 99% yield) as white solid. LCMS calculated for C12H13N2O3 (M+H): 233.1. found: 233.1.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7](=[O:9])[CH3:8])[C:4]([O-:6])=[O:5].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:29](OCC)(=O)[CH3:30]>>[CH2:10]([O:1][N:2]=[C:3]([C:7](=[O:9])[CH3:8])[C:4]([O:6][CH2:29][CH3:30])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: CC(=O)C(=NO)C(=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCc1ccccc1)C(C)=O

Procedure:
A mixture of 2-hydroxyimino-3-oxobutyrate (syn isomer, 47.1 g.), benzylbromide (61.6 g.), potassium carbonate (62.2 g.), N,N-dimethylformamide (70 ml.) and ethyl acetate (70 ml.) was treated in a similar manner to that of Example A-(1) to give ethyl 2-benzyloxyimino-3-oxobutyrate (syn isomer, 70.0 g.).
Reaction SMILES: [O:1]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:18].[CH3:19][N:20](C)[OH:21].[CH3:23][Al](C)C>>[CH3:23][O:21][N:20]([CH3:19])[C:2](=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:1]
Reactant: CN(C)O
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: C[Al](C)C
Product: CON(C)C(=O)CCCCCCCCCCCCCCCO

Procedure:
More specifically, compound (I) where R1, R3, R4, R5 are methyl groups, R2 is a hydroxyl group, m=1 and n=13 can be prepared in the following manner: Oxacycloheptadecan-2-one reacts with dimethylhydroxylamine in the presence of trimethylaluminium at 0° C. and at atmospheric pressure to yield N-methoxy-N-methyl-16-hydroxyhexadecanamide. The hydroxy function of this compound is then protected in the presence of sodium hydride and benzyl bromide at −78° C. and atmospheric pressure. The resulting N-methoxy-N-methyl-16-benzyloxyhexadecanamide is subsequently treated with methyllithium at −78° C. and at atmospheric pressure to yield 17-benzyloxyheptadecan-2-one. This reacts with the vinylmagnesium to afford 18-benzyloxy-3-methyloctadec-1-en-3-ol that in the presence of trimethylhydroquinone, zinc chloride and concentrated hydrochloric acid yields 2-(15-benzyloxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol. Catalytic hydrogenation of this compound in the presence of palladium on charcoal affords 2-(15-hydroxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](OS(C)(=O)=O)[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:25]([CH:14]1[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:26]=[N-:27]
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)cyclohexanecarboxylate (11.0 g, 30 mmol) in dimethyl sulfoxide (110 mL) was added sodium azide (20 g, 300 mmol), and the mixture was stirred at 90° C. overnight under N2. The solution was cooled to ˜30° C., dissolved in ethyl acetate (˜500 mL), washed with water (500 mL×5) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1˜2:1) to thereby give the title compound (4.1 g, 44%) as an colorless oil. MS (ES+) C14H24N4O4 requires: 312, found: 213 [M+H−100]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][NH:13][OH:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:25][C:26]#[N:27].[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([N:9]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:11][CH2:12][N:13]([OH:14])[C:26]([NH2:27])=[O:25])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N#C[O-]
Reactant: Cc1cnc(N(CCCNO)C2CCCc3cccnc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(N(CCCN(O)C(N)=O)C2CCCc3cccnc32)c(C)c1

Procedure:
N-{3-[(3,5-Dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-hydroxylamine (HBr salt) (138 mg, 0.22 mmol) was dissolved in H2O (2 mL) and treated with sodium cyanate (42 mg, 0.65 mmol) for 3.5 hours. 15% aqueous NaOH solution (0.1 mL) was added and the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure to afford, after radial chromatographic purification on a silica gel plate (3% NH4OH/CH3CN) N-{3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-N-hydroxyurea (42 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[S:18][C:19]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:22])[N:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:30])[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1sc(-c2ccc(C(=O)Nc3ccc(Cl)cc3)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(=O)N(C)c3ccc(Cl)cc3)cc2)sc1C(=O)O
Yield: 72 %

Procedure:
100 mg of Ethyl 2-(4-(4-chlorophenylcarbamoyl)-phenyl)-4-methyl-5-thiazolecarboxylate produced in Example 16 was methylated with sodium hydride and methyl iodide, and hydrolyzed by a conventional process to give 69 mg of 2-(4-(N-(4-chlorophenyl)-N-methylcarbamoyl)phenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 72%).
Reaction SMILES: [N:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])=[N+:2]=[N-:3].[S:11]1C=CC=C1CC(O)=O.CCN(C(C)C)C(C)C.C1C[O:32][CH2:31][CH2:30]1>>[C:31]([S:11][CH:5]([CH2:4][N:1]=[N+:2]=[N-:3])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:32])[CH3:30]
Reactant: O=C(O)Cc1cccs1
Reactant: C1CCOC1
Reactant: COC(=O)/C=C/CN=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(CN=[N+]=[N-])SC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To the solution of (E)-Methyl 4-azidobut-2-enoate (4.00 g, 28.37 mmol) in 60 ml of THF at 0° C. was added the mixture of thiolacetic acid (3.0 ml, 42.09 mmol) and DIPEA (8.0 ml, 45.92 mmol) in 60 ml of THF in 20 min. After stirred at 0° C. for 1 hr, the mixture was stirred at RT overnight, evaporated, redissolved in CH2Cl2, washed with NaHCO3 (sat.) and 1 M NaH2PO4/NaCl (sat.), pH 4 respectively, dried over MgSO4, filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:8 to 1:4) to afford HRMS for 4.98 g (81%) of the title product. 1H NMR (CDCl3) 3.66 (m, 1H), 3.62 (s, 3H), 3.40 (dd, 1H, J=7.5, 12.7 Hz), 3.31 (m, 1H), 2.78 (m, 1H), 2.60 (m, 1H), 2.32 (s, 3H); 13C NMR (DMF-d7) 192.20, 172.48, 56.56, 53.60, 51.31, 34.58, 30.56; ESI MS m/z+ 240.0 (M+Na), 255.9 (M+K); HRMS m/Z+ (C7H11N3O3S+Na) calcd 240.0419, found 240.0415.
Reaction SMILES: [NH2:1][C:2](=[O:35])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2](=[O:35])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[C:8]2[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(/C=C/C(N)=O)cc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
To a solution of tert-butyl {[6-[(1E)-3-amino-3-oxoprop-1-en-1-yl]-2-isobutyl-4-(4-methylphenyl)-quinolin-3-yl]methyl}carbamate (250 mg, 0.53 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 5% palladium-carbon (0.10 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give tert-butyl {[6-(3-amino-3-oxopropyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (204 mg, yield 81%) as white crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.[CH:31](=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:31]([N:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1)[CH3:32]
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(n2cc(-c3cnc4ccc(Cc5nnc6ccc(C)nn56)cc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (50 mg, 0.126 mmol) in dichloromethane (3 mL) was added acetaldehyde (15 uL, 0.505 mmol). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (67 mg, 0.136) was added. After 1 hour the solution was diluted with dichloromethane (1.5 mL) and washed with sodium bicarbonate (1.5 mL). The aqueous layer was extracted further with dichloromethane (1.5 mL). The combined dichloromethane layers were washed with brine (3 mL) and dried over Na2SO4. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (4.8 mg, 9% yield). Analytical data presented in Table 2.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[S:33][C:32]=1[C:46](=O)[CH3:47]>C1(C)C=CC=CC=1.C1COCC1>[CH3:2][O:3][CH:4]=[C:46]([C:32]1[S:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:35][C:31]=1[CH3:30])[CH3:47]
Reactant: CC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.5 h

Procedure:
To a solution of (methoxymethyl)triphenyl phosphonium chloride (3.96 g, 10.76 mmole) in toluene/THF (2:1, 60 mL), is added potassium t-butoxide (1.21 g, 10.76 mmole) in one portion and stirred for 30 minutes. To the resulting ylide, is injected into a solution of 1-[3-Methyl-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethanone (1.53 g, 5.38 mmole). The reaction is stirred for 2 hours, and then concentrated on rota vapor. The residue is purified on a silica gel column, eluting with 0-10% ethyl acetate in hexane and concentrated to provide 2-(2-Methoxy-1-methyl-vinyl)-3-methyl-5-(4-trifluoromethyl-phenyl)-thiophene as brown oil. The generated vinyl ether is treated with concentrated HCl(aq) (2 mL) in THF(60 mL) at 60° C. for 2 hours. The solvents are removed on rota vapor, and the residue is purified on a silica gel column, eluting with 0-20% ethyl acetate in hexane and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O.O.CCOCC>C(N(C(C)C)CC)(C)C>[O:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:2]1([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1C=CC(O)(CCCCOc2ccccc2)C1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)OC1(CCCCOc2ccccc2)C=CC(=O)C1
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
A solution of 1.2 g (4.9 mmoles) of 4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone in 10 ml of diisopropylethylamine was cooled to 0° C. in an atmosphere of nitrogen, and 20 ml (10 mmoles) of trimethylsilyl trifluoromethanesulfonate (5 M dichloromethane solution) was added. The mixture was stirred for 20 minutes. After the reaction, water was added, and the mixture was exracted with ether. The extract was washed with water and an aqueous sodium chloride solution, and then dried. The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (n-hexane:AcOEt=10:1) to give 1.2 g (77%) of 4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH-].[Na+].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:12][C:11](=[O:27])[C:10]=1[C:28](=O)[CH2:29][CH3:30]>C(O)C>[CH2:2]([O:4][N:5]=[C:28]([C:10]1[C:11](=[O:27])[CH2:12][CH:13]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N+:23]([O-:25])=[O:24])[C:16]=2[CH3:26])[CH2:14][C:9]=1[OH:8])[CH2:29][CH3:30])[CH3:3]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Ethoxyamine hydrochloride (0.26 g; 2.7 mmole) and then sodium hydroxide (0.11 g; 2.7 mmole) were added to a solution of 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-propionylcyclohex-2-en-1-one (0.6 g; 1.8 mmole) in absolute ethanol (150 ml). The mixture was stirred at room temperature for a period of 18 hours and then the ethanol was removed by evaporation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give the product, 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)cyclohex-2-en-1-one (0.56 g; 83.2%) as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 5, Example 37.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[CH:14]=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]#[N:19]>>[CH:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:16]=[C:13]([CH:14]([OH:15])[CH2:17][C:18]#[N:19])[CH:12]=[N:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1cncc(/C=C/C2CCCCC2)c1
Product: N#CCC(O)c1cncc(/C=C/C2CCCCC2)c1

Procedure:
Addition of CH3CN to (E)-5-(2-cyclohexylvinyl)nicotinaldehyde following the method used in Example 3 gave (E)-3-(5-(2-cyclohexylvinyl)pyridin-3-yl)-3-hydroxypropanenitrile as a yellow oil. Yield (0.9 g, 95%); 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 6.42 (s, 2H), 5.05 (t, J=5.6 Hz, 1H), 2.98-2.82 (m, 2H), 2.24-2.12 (m, 1H), 1.88-1.66 (m, 5H), 1.42-1.18 (m, 5H).