Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[F:14][C:15]([F:40])([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([F:39])=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH2:26][OH:27])[C:21]([Cl:24])=[CH:22][CH:23]=1>C(Cl)Cl>[F:40][C:15]([F:14])([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([F:39])=[CH:31][CH:30]=1)[CH2:16][NH:17][C:18]1[C:19]([F:28])=[C:20]([CH2:25][CH:26]=[O:27])[C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: OCCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
To a solution of DMSO (470 mg, 6.0 mmol), DIEA (823 μL, 4.74 mmol) and 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)ethanol (723 mg, 1.82 mmol), as prepared in the preceding step, in DCM (55 mL) in an ice-bath was added sulfur trioxide pyridine complex (754 mg, 4.74 mmol). After stirring for 3.5 hours the reaction mixture was diluted with DCM (110 mL). The organic layer was separated, and the aqueous layer extracted with DCM (100 mL). The organic layers were combined, washed with 10% citric acid (3 times), H2O, and brine, dried over Na2SO4, and concentrated to give the title compound (722 mg, quantitative yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 9.69 (d, J=1.1 Hz, 1H), 8.22-8.18 (m, 2H), 7.67-7.60 (m, 3H), 7.14 (t, J=9.2 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (t, J=8.7 Hz, 1H), 4.20 (bs, 1H), 4.00 (dt, J=13.3, 6.7 Hz, 2H), 3.83 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[CH:5]=[C:4]([CH3:10])[C:3]=1[OH:11].[N+]([O-])(O)=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[CH:5][C:6](=[O:13])[C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)c(C)c(C)c1O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
17.0 g (0.1 mole) of 2,3,6-trimethyl-4-chlorophenol obtained in Example 1 (A) was dissolved in 100 g of acetic acid, and 10 g of concentrated nitric acid was added dropwise thereto in 30 minutes under stirring. The reaction proceeded immediately. After stirring for another 30 minutes, the reaction solution was subjected to steam distillation. The same treatment as in Example 1 was conducted to obtain 13.8 g of 2,3,6-trimethyl-p-benzoquinone (92.0 percent in yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@@H:19]([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[O:11])[CH2:17][CH2:16]2)[CH2:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperidine-4-carboxamide (150 mg) and benzaldehyde (0.04 mL) in dichloromethane was added sodium triacetoxyborohydride (103 mg). The reaction mixture was stirred at room temperature for 18 hours. The reaction was incomplete so sodium triacetoxyborohydride (50 mg) was added and the mixture was stirred for 48 hours. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (28 mg, 15%)
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][CH2:11][C:12]#[CH:13].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: C#CCBr
Reactant: CCOC(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (11 g; 70.41 mmol) in ethyl acetate (60 mL) was added dropwise at room temperature to a mixture of 3-bromoprop-1-yne (15.2 mL; 141 mmol), sodium bicarbonate (11.95 g; 141 mmol), ethyl acetate (400 mL), and water (4 mL). The mixture was stirred at room temperature for 24 h and the solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to give 14.38 g (87%) of ethyl 5-(bromomethyl)isoxazole-3-carboxylate as a white solid.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:31])[C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][CH:20]=3)[CH2:13]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][C@H:18]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][CH:20]=2)[OH:31])[CH2:13]1
Reactant: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CN)C3)c2n1
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of phenylmethyl[((3S)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.24 g, 0.56 mmole) in MeOH (50 mL) was added Pd(OH)2 (100 mg). The reaction contents were placed under a balloon of H2 and stirred for 18 hours. The reaction contents were filtered through Celite (MeOH) and concentrated under vacuum to give the title compound (0.16 g, 98%) as a light yellow oil: LC-MS (ES) m/e 303 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]2)[CH:21]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:18][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:28]3[CH:29]=[CH:30][N:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:27]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[C:15]([F:17])[C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(-c2cccnc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cccnc2)n1
Yield: 98.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.050 g, 0.179 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.034 g, 0.179 mmol), DIPEA (0.094 ml, 0.538 mmol 1), HOBt hydrate (0.041 g, 0.269 mmol) and EDCI (0.052 g, 0.269 mmol) using the method of Example 274 affording 0.079 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.38 (m, 2H), 4.49 (m, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.59 (m, 1H), 7.88 (m, 3H), 8.30 (m, 1H), 8.35 (d, 1H), 8.59 (d, 1H), 8.65 (d, 1H), 9.18 (d, 1H).
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[Li]CCCC.[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37].O>C1COCC1>[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)CC=Cc2ccc3c(c2)OCO3)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 6.3 mL, 10.0 mmol, 1.0 equiv.) at 0° C., the dark red suspension was stirred at 0° C. for 10 min. 3-(3-Isopropylphenyl)butanal (1.90 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 0° C.→25° C. for 16 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes and MTBE, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 4:1) to yield 2.35 g (75%) of the title compound as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Br:20])=[CH:14][C:10]=1[NH:11][CH:12]=[O:13])C1C=CC=CC=1>CO.[C].[Pd]>[Br:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:9]([OH:8])=[C:10]([CH:14]=1)[NH:11][CH:12]=[O:13]
Reactant: O=CNc1cc(CCBr)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=CNc1cc(CCBr)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a solution of 2′-benzyloxy-5′-(2-bromoethyl)formanilide (510 mg) in methanol (8 ml) was added 10% palladium carbon (wet, 50% water) (100 mg), and the mixture was stirred for 45 minutes at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the solvent of the filtrate was removed under reduced pressure. Purification of the residue by flash column chromatography on silica gel (eluent:methanol/dichloromethane/diethyl ether=1/10/10) gave 5′-(2-bromoethyl)-2′-hydroxyformanilide (339 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH3:30])[C:9]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:21]([NH2:22])=[CH:20][C:19]([CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][N:17]=2)=[N:10][CH:11]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:7]=[C:8]([CH3:30])[C:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:16]3=[N:17][CH:18]=[C:19]([CH2:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:20]=[C:21]3[N:22]=[N:1]2)=[N:10][CH:11]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Br)cnc1CCCn1nnc2cc(Cc3cccnc3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Sodium nitrite solution (1.02 g in 50 ml water) was added dropwise over 25 minutes to a stirred and cooled solution of 2-[3-(5-bromo-3-methylpyrid-2-yl)-propylamino]-3-amino-5-(pyrid-3-ylmethyl)pyridine (4.7 g) in sulphuric acid (molar, 200 ml) keeping the temperature at 4° C. Reaction was stirred at 4° C. for a further hour and was then left in the fridge overnight and then warmed to room temperature. The reaction mixture was basified to pH 13 with sodium hydroxide solution (10 M). Chloroform extraction of the reaction mixture gave the crude product which was then chromatographed on silica in methanol/chloroform 1:19 and then recrystallised from acetonitrile to give the title compound (2.75 g), m.p. 109°-110° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C([Li])CCC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[N:19][CH:20]=1.[CH:22](N1CCCCC1)=[O:23]>C1COCC1>[Br:14][C:15]1[CH:16]=[C:17]([CH:22]=[O:23])[C:18]([F:21])=[N:19][CH:20]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=CN1CCCCC1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cnc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to −78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at −78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at −78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at −78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10% (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52% yield) as pale beige flaky crystals. 1H-NMR (500 MHz, d6-DMSO) δ10.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa+], 204, 206 [MH+], 176, 178 [MH-CO+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:27][N:28]1[CH2:35][CH:34]2[CH:30]([CH2:31][CH2:32][CH2:33]2)[CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:27][N:28]3[CH2:35][CH:34]4[CH2:33][CH2:32][CH2:31][CH:30]4[CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: NN1CC2CCCC2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CC4CCCC4C3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[C:13]1([C:12]2[C:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][NH:9][N:8]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Yield: 54.4 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)propenoate (300 mg), 5% palladium-carbon (600 mg), formic acid (3 ml), and ethanol (10 ml) was refluxed for 2 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (120 mg, yield: 55%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][CH:21]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:26]([Mg]Br)#[CH:27]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:25]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([C:22]([OH:24])([C:26]#[CH:27])[CH3:23])[CH:19]=[CH:20][CH:21]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Yield: 6.4 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.261 g (0.79 mmol) of 1-{3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]phenyl}ethanone obtained in stage 4.1, in solution in 10 ml of tetrahydrofuran, followed by addition of 4.74 ml (2.37 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and dichloromethane (1/9), 0.018 g (6%) of the expected product is obtained in the fowl of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.C([NH2:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[O:9])[NH:16][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1
Reactant: NC=O
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A mixture of 4-methoxyphthalic anhydride (27.8 g, 0.16 mol) and formamide (175 ml) was stirred and held at 210° C. for 5 hours and was then allowed to cool to room temperature overnight. The solid material was filtered off, washed sequentially with water (100 ml), 50% aqueous acetone (50 ml) and diethyl ether (200 ml) and sucked dry under reduced pressure to afford 4-methoxyphthalimide (21.3 g, 77%) as a pale yellow solid. 1H NMR (DMSO-d6) 11.15 (1H, br s), 7.74 (1H, d), 7.33-7.28 (2H, m), 3.92 (3H, s).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:23])([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[S:9][C:10]=1[CH2:11][CH3:12])[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:5][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=2)[S:9][C:10]=1[CH2:11][CH3:12])([CH3:23])[CH2:3][OH:2]
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)CO
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid methyl ester (14.5 g, 40.6 mmol) in THF (100 mL) is added a solution of lithium aluminum hydride in THF (1.0 M, 41 mL) at 0° C. After 2 hrs, the reaction is quenched by water and sodium hydroxide, filtered, concentrated. Chromatography on silica gel yields 2-Methyl-2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (12.3 g).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(N2CCN(CCCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1

Procedure:
This ester is then dissolved in 200 ml of ethanol. To this solution, a solution of 4.7 g of sodium hydroxide in 20 ml of water is added, and this is followed by reflux with heating for 30 minutes. After the completion of the reaction, the solvent is distilled off, and the residue, after dilution with water, is adjusted to pH 5 with hydrochloric acid. The crystals precipitated are collected by filtration and further recrystallized from methanol-isopropyl ether to give 14 g of 4-oxo-4-[4-(4-(4-(3-methylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid having a melting point of 199° to 201° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17]O)=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH2:17][Br:48])=[CH:11][CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)NC1CCc2ccc(CCO)cc2C1Cc1cccc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(CCBr)cc2C1Cc1cccc(Cl)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of [1-(3-chloro-benzyl)-7-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-yl]-carbamic acid ethyl ester (554 mg, 1.428 mmol) in 15 ml dry CH2Cl2 cooled to 0° C. was added triphenylphosphine (562 mg, 2.142 mmol) and carbon tetrabromide (0.208 ml, 2.142 mmol). The mixture was stirred for 1 h, after which solvents were evaporated. The residue was purified by chromatography to obtain 277 mg of product as a white solid.
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH3:2][C:1](=[O:5])[CH2:3][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OO
Solvent: Cc1ccccc1
Solvent: C=CCCCCCC
Product: CCCCCCC(C)=O
Reaction time: 4 h

Procedure:
3 cc of 80% tert-butyl hydroperoxide (23 mmoles), 1 cc of 1-octene (6.5 mmoles), 2 cc of toluene, and 25.4 mg of PPA (0.1 mmole) prepared according to Example 1, are introduced into a heat-insulated glass reactor. An argon atmosphere is applied and stirring is performed at a temperature of 50° C. After 4 hours, it is found that 55% of 1-octene is converted and that 2-octanone is formed with a molar selectivity of 76% with respect to the converted 1-octene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:16]([CH3:38])[C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[C@@H:26]([CH3:37])[CH2:25]4)=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([N:16]([CH3:38])[C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:37])[CH2:25]4)=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(-c4cccc(F)c4)nc3)cc2)CCN1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[{[6-(3-fluorophenyl)-3-pyridinyl]carbonyl}(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D60) (0.127 g, 0.245 mmol) was stirred in DCM (10 mL) and TFA (2.5 mL) was added drop-wise. The reaction mixture was stirred for ˜1 h, then concentrated in vacuo and re-diluted with DCM and water. The separated aqueous layer was basified to pH14 with concentrated NaOH solution, then extracted with DCM which was dried (Na2SO4) and concentrated to yield the title compound as a yellow oil (0.091 g). δH (CDCl3, 400 MHz) 8.52 (1H, d), 7.75 (1H, dd), 7.67 (2H, m), 7.54 (1H, d), 7.40 (1H, m), 7.25 (2H, d), 7.09 (1H, m), 7.03 (2H, d), 3.53 (3H, s), 3.41 (2H, s), 2.83 (3H, m), 2.66 (2H, d), 1.96 (1H, td), 1.62 (1H, m), 1.55 (br.s), 0.97 (3H, d), NH not observed. MS (ES): MH+ 419.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([CH3:17])[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccccn2)=CC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.4 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.1 g, 9.9 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). The reaction solution was stirred at room temperature for 2 days. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown solid. The residue was purified by chromatography (silica gel, pet. ether/ethyl acetate) to yield yellow crystals (1.6 g, 75% yield), m.p. 87.5°-89.0° C.