Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21](OC)=[O:22])[CH:18]=[N:19][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)c1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a mixture of methyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate (10.70 g) and tetrahydrofuran (100 mL) was added lithium aluminum hydride (1.02 g) under ice-cooling, and the mixture was stirred at room temperature for 10 min. To the mixture was added sodium sulfate 10 hydrate (8.38 g), and the mixture was further stirred at room temperature for 30 min. The insoluble materials were removed by filtration, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (8.93 g, 91%) of [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridyl]methanol from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[N:12]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:11][C@@H:10]([C:21](OC)=[O:22])[CH2:9]1>COC1CCCC1>[C:15]1([C@H:13]([N:12]2[CH2:8][CH2:9][C@H:10]([CH2:21][OH:22])[CH2:11]2)[CH3:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC1CCCC1
Product: C[C@H](c1ccccc1)N1CC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.6 %

Procedure:
To a slurry of lithium aluminum hydride (4.55 g, 120 mmol) in cyclopentyl methyl ether (100 ml) at 0° C. under nitrogen atmosphere was added methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (14.0 g, 56.5 mmol) dropwise. The resulting mixture was stirred for 15 minutes and gradually warmed to room temperature. After one hour, the reaction was quenched by the addition saturated sodium sulfate aqueous solution at 0° C. and the resulting solid materials were removed by filtration. Concentration of the filtrate afforded {(3S)-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}methanol (6.62 g, 32 mmol, 57%). This compound was used for the next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:13][C:12]([O:25][CH3:26])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([O:25][CH3:26])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 375 mg (0.57 mmol, 57% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 162A) in 8.0 ml of 1,4-dioxane was admixed with 6.0 ml of aqueous 2M sodium hydroxide solution. The mixture was stirred at 100° C. for a further 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was admixed with 4 ml of acetonitrile and 2 ml of water, followed by 0.8 ml of trifluoroacetic acid. The resulting precipitate was filtered off and dried under reduced pressure, which gave 172 mg (65% yield, 75% purity) of product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
To mixed solution of 2M isobutylmagnesium bromide in THF (6.25 mL) and ether (50 mL), was added dropwise a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) in ether (18 mL) under N2 atmosphere. The mixture was stirred at room temperature for 45 minutes, to which was added saturated aqueous ammonium chloride solution and 1M hydrochloric acid under ice-cooling. The aqueous layer was extracted with ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated brine successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1), to give the titled compound as a yellow oil (601 mg, yield 23%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[N:20][OH:21])[CH2:10][CH2:9]1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2F)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C1CCC(c2ccccc2F)c2ccccc21

Procedure:
32 g of 4-(2-fluorophenyl)-1-tetralone in 75 ml of ethanol are treated with a solution of 9.26 g of hydroxylamine hydrochloride in 10 ml of water and then with 17 g of powdered sodium hydroxide. The mixture is heated to boiling under reflux for 5 minutes, again cooled and then poured into a mixture of ice and dilute hydrochloric acid. The mixture is extracted with ether and the extract obtained is washed with water. After evaporation of the solvent, there is obtained 4-(2-fluorophenyl)-1-tetralone oxime of melting point 120°.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([C:16]#[N:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:16]([CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])#[N:17]
Reactant: CCCCCBr
Reactant: N#CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(C#N)c1ccccc1
Yield: 82 %

Procedure:
Hexadecyltributyl phosphonium hectorite (0.050 mmol) was mixed with 2.0 ml of 50 wt % of aqueous sodium hydroxide, 1-bromopentane (5.0 mmol) and benzyl cyanide 95.0 mmol). After reaction at 50° C. for 2 hr, the emulsion was broken by centrifugation and 1-cyano-1-phenyl hexane was obtained in 82.0% yield.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[N:26]=[C:25]([CH3:27])[N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:16][CH:17]1[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+].[N:43]#[C:44]Br>CO>[CH:17]1([CH2:16][N:15]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:14]2[N:13]=[C:12]3[N:24]([CH3:28])[C:25]([CH3:27])=[N:26][C:11]3=[CH:10][C:9]=2[CH2:8][N:7]([CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=2)[C:44]#[N:43])[CH2:18][CH2:19]1
Reactant: N#CBr
Reactant: Cc1nc2cc(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 0.8 %

Procedure:
A mixture of {6-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-2,3-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl}-bis-cyclopropylmethyl-amine (0.220 g, 0.41 mol) and sodium bicarbonate (0.071 mg, 0.83 mol.) in methanol (8 mL) was stirred at 0° C. for 15 min. Cyanogen bromide (0.053 g, 0.05 mol) was added and continued to stir at room temperature for 1.5 h. Methanol was removed under reduced pressure, extracted with ethyl acetate (250 mL), washed with water (250 mL×2) and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 0.220 g of colorless gummy compound.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClN1C(=O)CCC1=O.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH:25][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][N:29]=2)[CH3:27])=[O:24])=[CH:18][CH:17]=1)([CH3:15])=[CH2:14]>>[CH3:2][C:1]1[CH2:15][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:25][C@@H:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[CH:30][N:29]=3)[CH3:27])=[O:24])=[CH:20][CH:21]=2)([CH3:14])[O:4][N:3]=1
Reactant: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Product: CC1=NOC(C)(c2ccc(CC(=O)N[C@H](C)c3ccc(OCC(F)(F)F)cn3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a solution of acetaldoxime (14.1 mg, 0.238 mmol) was added N-chlorosuccinimide (31.8 mg, 0.238 mmol). The resulting mixture was stirred at room temperature for 3 h. 2-(4-Isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (90 mg, 0.24 mmol) was added, followed by the TEA (0.099 ml, 0.71 mmol), the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was washed with saturated sodium bicarbonate solution and brine. Organics were extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. Purification by reverse phase chromatography gave 2-[4-(3,5-dimethyl-4,5-dihydro-isoxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a white solid (23.8 mg, 23%). 1H NMR (CDCl3, 400 MHz). δ 8.299 (dd, J=2.75, 5.31 Hz, 1H); 7.407 (t, J=2.93 Hz, 1H); 7.361 (dd, J=1.28 Hz, J=8.42 Hz, 4H); 7.243 (d, J=2.20 Hz, 1H); 7.222 (d, J=2.38 Hz, 1H); 5.122 (quintet, J=7.14 Hz, 1H); 4.436 (m, 2H); 3.550 (s, 2H); 3.063 (m, 2H); 1.965 (t, J=1.10 Hz, 3H); 1.684 (d, J=1.10 Hz, 2H); 1.466 (d, J=6.96 Hz, 3H); MS (ES): m/z 436.2 (M+H). FLIPR alpha1I IP=41 nM.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[C:14]3[N:15]=[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Cl[C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37][N:36]=1.CN1CCCC1=O>O1CCCC1.O>[CH3:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]([N:22]2[CH2:21][CH2:20][CH:19]([NH:18][C:16]3[S:17][C:13]4[CH2:12][CH2:11][CH2:10][CH:9]([C:3]5[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=5)[C:14]=4[N:15]=3)[CH2:24][CH2:23]2)[CH:40]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N2CCC(Nc3nc4c(s3)CCCC4c3ccccc3)CC2)ncn1

Procedure:
(4-Phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (77.3 mg, 0.2 mmol) was suspended in tetrahydrofurane (2 mL). At 0° C. N,N-diisopropylethylamine (110 1, 0.64 mmol) was added at room temperature under nitrogen and stirring. To the yellow solution 4-chloro-6-methylpyrimidine (28.9 mg, 0.22 mmol) was added and the reaction was stirred at room temperature over night. The reaction was heated to reflux over night and then heated with N-methylpyrrolidone in a microwave oven to 200° C. for 30 minutes. Water was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient from EtOAc to EtOAc/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a light yellow solid (55 mg, 68%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8][C:7]=2[CH:23]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[O:8][C:7]=2[CH:23]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Oc2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC1Cc2ccc(O)cc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A solution of ethyl (±)-10,11-dihydro-3-methoxydibenzo[b,f]oxepine-10-acetate (523 mg, 1.68 mmole) in CH2Cl2 (6.8 mL) was added dropwise to a cold solution of BBr3 in CH2Cl2 (1.0 M, 6.7 mL, 6.7 mmole) at 0° C. under argon. The reaction was stirred for 20 min, then CH3OH (7 mL) was added carefully. The mixture was concentrated and the residue was flash chromatographed on silica gel (15-20% EtOAc/hexanes) to afford the title compound (407 mg, 89%) as a pale yellow oil: MS (ES) m/e 299 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([N+:26]([O-])=O)=[CH:21][CH:22]=3)[CH2:17]2)[N:3]=1>Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH2:26])=[CH:21][CH:22]=3)[CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCc4ccc([N+](=O)[O-])cc4C3)nc(N)c2cc1OC
Agent: Cl
Product: COc1cc2nc(N3CCc4ccc(N)cc4C3)nc(N)c2cc1OC
Temperature: 0 °C

Procedure:
4-Amino-6,7-dimethoxy-2-(7-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline (2.0 g.), the product of Example 12. was slurried in 6N hydrochloric acid solution (100 ml.) and the resulting mixture was cooled with stirring to 0° C. A solution of stannous chloride (20.0 g) in 6N hydrochloric acid (20 ml.) was then added, and the reaction mixture was heated gradually to 70° C., followed by cooling to give a white solid precipitate. The latter material was collected by means of suction filtration and thereafter recrystallized from ethanol to afford 1.0 g. of pure final product as the dihydrochloride dihydrate, m.p. 265°-266° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[F:13].C1OCCOCCOCCOCCOC1.[Na+].[I-].Cl[CH2:32][CH2:33][N:34]([CH2:42][CH2:43]Cl)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:43][CH2:42][N:34]([C:35]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:41])[CH2:33][CH2:32]2)=[CH:6][C:5]=1[F:13]
Reactant: N#CCc1ccc(Cl)c(F)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 54.1 %

Procedure:
60% NaH (1.07 g, 26.7 mmol) was added in 2 portions to a 0° C. solution of 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 10.7 mmol) and 15-crown-5 (0.235 g, 1.07 mmol) in DMF (45 mL). The reaction mixture was warmed to room temperature and stirred for 35 minutes. The reaction mixture was then cooled to 0° C. NaI (1.60 g, 10.7 mmol) was added, and then a solution of freshly prepared tert-butyl bis(2-chloroethyl)carbamate (2.58 g, 10.7 mmol) in DMF (10 mL) was added by syringe. The reaction mixture was warmed to room temperature and stirred overnight (19 hours). The reaction mixture was poured into ice saturated NH4Cl, and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on silica (Biotage 40L, 9:1 hex:EtOAc until product eluted, then 6:1 hex:EtOAc to elute product) to give tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate (1.96 g, 54.2% yield) as a yellow oil. LC/MS (APCI+) m/z 239 [M-Boc+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[N+]([O-])(O)=O.O>ClCCCl.P(=O)(O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[CH:11]([OH:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: O=P(O)(O)O
Solvent: ClCCCl
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
Thereafter, 0.35 g of phosphoric acid and then a solution of 16.12 g (0.0497 mole) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) in 49.37 g of 1,2-dichloroethane were added at 20° to 25° C., and stirring was carried out at the same temperature for 20 hours. The reaction solution was decomposed with addition of 24.17 g of 20% nitric acid and 4.6 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 15.60 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conversion was 99.8%, and the composition of the product obtained was: E-form alcohol, 95.6%; saturated alcohol, 0.4%; Z-form alcohol, 3.2%; and others, 0.8%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 85.8% and (+)-isomer, 14.2%. The optical yield was 71.6%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH:26]=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 86.6 %

Procedure:
To a stirred solution of oxalyl chloride (2 mL, 22 mmol) in dry dichloromethane (50 mL) at −78° C. under argon, was added dropwise a solution of dimethylsulfoxide (3.4 mL, 44 mmol) in dichloromethane (10 mL). After 2 min, a solution of 3-[N-(t-butoxycarbonyl)piperidin-4-yl]propanol (4.86 g, 20 mmol) in dichloromethane (10 mL) was added dropwise over 5 min. After stirring an additional 15 min at −78° C., triethylamine (14 mL) was added dropwise. After 5 min, the reaction became a thick white slurry and was allowed to warm to RT and stirred for 16 h. The reaction mixture was washed with cold 1N hydrochloric acid and with brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate/hexane) to yield the title compound (4.18 g, 87%). TLC Rf 0.40 (30% ethyl acetate/hexane); 1H NMR (CDCl3) δ0.95-1.80 (7H, m), 1.48 (9H, s), 2.40-2.90 (4H, m), 4.14 (2H, br dt), 9.88 (1H, t).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:31]=[CH:30][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:32])[CH2:4]1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:31]=[CH:30][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:32])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(CCc4ccccc4)cc3)oc2c1

Procedure:
9 mg (21 μmol) 5-ethyl-6-{2-[4-styryl-phenyl]-benzoxazol-6-yl}-4,5-dihydro-2H-pyridazin-3-one are hydrogenated together with 2 mg palladium on charcoal 10% and 10 ml of methanol at RT and 3.45 bar hydrogen pressure for 80 min, then the catalyst is filtered off and the filtrate is evaporated down completely i.V. The residue is purified through silica gel (eluant: DCM/methanol) and then stirred with cyclohexane/EA.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6](N)=[CH:5][CH:4]=1.Cl.N([O-])=O.[Na+].[I-:20].[K+]>O.OS(O)(=O)=O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([I:20])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Trifluoromethylanthranilic acid (43 g, 0.21 mol) is suspended in a mixture of concentrated HCl (40 mL) and water (240 mL), cooled to 0° C. and stirred. Sodium nitrite (18 g, 0.26 mol) is dissolved in water (50 mL) and slowly added taking care to maintain the temperature of the reaction mixture below 5° C. Stirring is continued at 0° C. for 30 minutes. Potassium iodide (65 g, 0.39 mol) is dissolved in a mixture of concentrated H2SO4 (15 mL) and water (100 mL) and the solution is added dropwise to the reaction mixture while keeping the temperature below 10° C. The mixture is then heated to 100° C. and stirred for 2 hours. After cooling to room temperature, the mixture is partitioned between EtOAc (750 mL) and saturated sodium bisulfite solution (500 mL). The organic layer is washed again with saturated sodium bisulfite solution (500 mL) and then brine (500 mL), dried (MgSO4) and concentrated by rotary evaporator to give 5-trifluoromethyl-2-iodobenzoic acid (m.p. 171–172° C.).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(-n2nc(C(C)(C)C)cc2N)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)ccn1
Yield: 16.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine (496 mg, 2.2 mmol), from the previous step, and potassium carbonate (395 mg, 2.9 mmol) in anhydrous DCM (8 ml) was added dropwise phenyl chloroformate (0.83 ml, 6.6 mmol) as a solution in DCM (5 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate (130 mg, 17%). 1H NMR (300 MHz, CDCl3) δ 1.27 (s, 9H), 2.54 (s, 3H), 6.45 (s, 1H), 6.81 (d, J=8 Hz, 1H), 7.12-7.28 (m, 5H), 7.29-7.43 (m, 2H) 8.49 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:9]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[CH:15]=[CH:14][N+:13]([O-:27])=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(F)c(-c2ccnc(C#N)c2)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc[n+]([O-])c(C#N)c2)c1
Reaction time: 72 h
Yield: 77.3 %

Procedure:
A solution of 4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (which may be prepared as described in Description 111) (6.19 g, 25.55 mmol) in DCM (200 mL) was treated with mCPBA (7.56 g, 30.66 mmol) and then was reluxed under nitrogen for 3 days. The mixture was diluted with 5% sodium metabisulfite (100 ml) and DCM (200 ml) and shaken vigourously. The organic layer was then washed with sat NaHCO3 solution (200 ml) and then dried (Na2SO4) and concentrated. Purification by flash chromatography gave 4-(5-ethoxy-2-fluoro-phenyl)-1-oxido-pyridin-1-ium-2-carbonitrile (D112) (5.102 g);