Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[C:19]([S:20](=[O:22])(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CCCCNCCCC
Solvent: ClCCl
Product: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.9 g. (0.03 mole) of di-n-butylamine in 15 ml. of methylene chloride is added 2.5 g. (0.01 mole) of 4-chloro-5-chlorosulfonylbenzoic acid (J. Pharm. Pharmacol., 683 (1962), and the resulting reaction mixture allowed to stir at room temperature for 3 hrs. The solvent is removed under reduced pressure and the residue partitioned between 1N sodium hydroxide and diethyl ether. The aqueous phase is separated, acidified with 12N hydrochloric acid and the precipitated solid filtered and dried, 3.0 g., m.p. 93°-96° C. Recrystallization from ether-hexane provides the pure product, 2.5 g., m.p. 94.5°-96.5° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:37])[C@@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=O)[CH2:4][OH:5].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:35][O:34][CH2:33][C@H:32]([CH3:36])[O:31][C:16]1[CH:15]=[C:14]([C:11]2[NH:10][C:9]([C:7]3[O:5][CH2:4][C@@H:3]([C@@H:2]([OH:1])[CH3:37])[N:6]=3)=[CH:13][CH:12]=2)[CH:19]=[C:18]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH:17]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reaction time: 1 h
Yield: 66.9 %

Procedure:
N-[(1S,2S)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (1.24 g, 2.32 mmol) synthesized in Example (93a) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (0.63 g, 3.49 mmol) and triethylamine (0.97 mL, 6.97 mmol) were added at 0° C., followed by stirring for 1 hour under nitrogen atmosphere. The temperature was raised naturally, and stirring was carried out at room temperature for 2 hours, followed by stirring at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution (30 mL) was added, and the solution was separated with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired compound (800 mg, yield 67%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][N+:19]#[C-:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[K+].O>COCCOC>[CH:2]([C:1]1[O:5][CH:20]=[N:19][C:18]=1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)(=[O:16])=[O:17])([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(S(=O)(=O)c2ncoc2C(C)C)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
1.1 g (0.0103 mole) of isobutyryl chloride in 10 ml of 1,2dimethoxyethane is added rapidly at a temperature between 15° and 20° C. to a mixture of 2.1 g (0.01 mole) of 4-methoxy benzenesulfonyl methylisonitrile in 10 ml of 1,2-dimethoxyethane in the presence of 0.65 g (0.0116 mole) of potassium hydroxide. The mixture is stirred for 3 h at about 20° C., cooled in an ice bath and water is added. An oil precipitates which solidifies in the presence of a little methanol. In this manner, 0.45 g of 5-isopropyl 4-(4-methoxy benzenesulfonyl)oxazole is obtained which is recrystallized from 5 ml of isopropanol to give 0.4 g, i.e. a yield of 14.2%. M.p.: 98°-100° C.
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12].[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccc(OCc2ccccc2C(=O)O)c1)NCc1ccc(C(F)(F)F)cc1
Reaction time: 168 h
Yield: 25.1 %

Procedure:
Methyl 2-{[3-(2-oxo-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]methyl}-benzoate (82 mg, 0.18 mmol) in THF (2 ml) was cooled in an ice-bath. Lithium hydroxide (8.6 mg, 0.36 mmol) in water (1 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred for 7 days and then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and MeOH/DCM (1:99, then 2:98) as eluant gave 20 mg the desired product, yield 22.5% (two steps).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Pt].C(OC(C)C)(=O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pt]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to isopropyl acetate (400 μl). 10% Platinum on carbon (2 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). Spectroscopic data as in Example 40, Method 1.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[CH2:12]1[CH:19]2[C:15]3([C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[S:25])=[O:22])[CH2:16][CH:17]([CH2:20][CH:13]1[CH2:14]3)[CH2:18]2>>[CH3:30][O:29][CH2:28][CH2:27][N:26]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C:2]=2[S:25]/[C:24]/1=[N:23]\[C:21]([C:15]12[CH2:16][CH:17]3[CH2:20][CH:13]([CH2:12][CH:19]1[CH2:18]3)[CH2:14]2)=[O:22]
Reactant: O=C1c2ccccc2CC1Br
Reactant: COCCNC(=S)NC(=O)C12CC3CC(CC1C3)C2
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)Cc1ccccc1-2

Procedure:
Commercially available 2-bromo-indan-1-one and the product of Example 14B were processed according to the method of Example 14C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.55-1.70 (m, 4H), 1.70-1.86 (m, 4H), 2.09-2.20 (m, J=9.0, 2.5 Hz, 2H), 2.24-2.34 (m, 2H), 2.60 (t, J=6.6 Hz, 1H), 3.23 (s, 3H), 3.74-3.86 (m, 4H), 4.69 (t, J=5.4 Hz, 2H), 7.29 (td, J=7.4, 0.8 Hz, 1H), 7.39 (td, 1H), 7.58 (d, J=7.1 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H); MS (ESI+) m/z 395 (M+H)+; Anal. Calculated for C23H26N2O2S: C, 70.02; H, 6.64; N, 7.10. Found: C, 69.83; H, 6.57; N, 6.92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][C:45]([CH3:48])=[CH:46][CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)nc4)c3)c2cc1OC
Yield: 59.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (54 mg, 0.18 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (62 mg, 0.18 mmol), described in the previous step, to afford 1-(3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (59 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.26 (s, 9H), 2.53 (s, 3H), 3.98 (s, 6H), 6.37 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.36-7.43 (m, 3H), 7.54-7.55 (m, 2H), 7.83 (d, J=8.4 Hz, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 8.61 (d, J=3 Hz, 1H), 9.18 (s, 1H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([OH:18])=O)[C:5]2=1.[CH3:26][NH:27][CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([N:27]([CH3:28])[CH3:26])=[O:18])[C:5]2=1
Reactant: Cn1c2ccc(F)cc2c2c(C(=O)O)cn(-c3ccccn3)c(=O)c21
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cn(-c2ccccn2)c(=O)c2c1c1cc(F)ccc1n2C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g (7.4 mmol) of 6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 2.4 g (14.8 mmol) of N,N'-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added. The mixture is stirred for 48 h at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)#[CH:2].C([Mg]Br)C.[CH2:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]=[C:3]([C:1]#[C:2][CH2:23][OH:24])[C:9]=2[CH:10]=1
Reactant: C=O
Reactant: C#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
A solution of 13.5 g of 10-ethynyl-8-chloro-dibenzo[ b,f] thiepin in 150 ml. of absolute tetrahydrofuran is treated dropwise at room temperature with 52 ml. of a 1-M solution of ethylmagnesium bromide solution in tetrahydrofuran. After stirring the mixture for an additional hour, 1.85 g of paraformaldehyde are pyrrolyzed and led through the mixture in gaseous form. The solution, having now warmed to about 50° C., is stirred for an additional 30 minutes and then poured onto a saturated, aqueous ammonium chloride solution. By extraction with benzene and subsequent chromatography on silica gel using benzene/methanol (20:1) as the eluant, there is obtained 3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propyn-1-ol which melts at 111°-113° C. after recrystallization from ethyl acetate/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[OH2:22].O.[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C@@H:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:12])=[O:21])[C:5]([CH2:11][OH:22])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
(S)-Methyl 2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetate (135 mg, 0.368 mmol) was dissolved in a mixture of tetrahydrofuran (4.0 mL) and methanol (4.0 mL). Water (4.0 mL) was added to the mixture followed by lithium hydroxide hydrate (31.5 mg, 0.751 mmol). Reaction stirred at room temperature for 5 hours. Another 30 mg of lithium hydroxide hydrate was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 1.6 mL 1N hydrochloric acid. Organic solvents were removed from the mixture by roto-vap. Material was extracted from the remaining aqueous twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 73% yield. MS (M−H)−=355.2, 357.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:14]([O:25][CH3:26])[CH:13]=1)P(OCC)(=O)OCC.[CH:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[C:28]1=O)[CH2:34]2.P(=O)([O-])[O-].[Li]CCCC>C1COCC1>[CH3:26][O:25][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:28]2[CH:29]3[CH2:35][CH:33]4[CH2:32][CH:31]([CH2:36][CH:27]2[CH2:34]4)[CH2:30]3)[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH:15]=1
Reactant: CCOP(=O)(OCC)C(OC)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(NC(=O)C(F)(F)F)cc(OC)c1
Temperature: -68 °C
Reaction time: 0.08 h

Procedure:
Phosphonate 30, dissolved in anhydrous THF, is cooled to -68° C. under an argon atmosphere. Similarly, 2-adamantanone (1.1 eq) is dissolved in anhydrous THF and cooled to -68° C. under argon in a separate flask. To the phosphonate solution is added 2.5M nBuLi is added to complete the red color of the ylid persists. At this point, 1.2 eq nBuLi is added to complete the ylid formation and the resulting colored solution is stirred at -68° C. for 5 min. While maintaining the low temperature, 2-adamantanone in THF is slowly added to the ylid over an hour. After the final addition of ketone, the reaction mixture is stirred for 2 h while warming to room temperature. The reaction is then heated at reflux for 1 h, cooled and quenched by partitioning with EtOAc and saturated NH4Cl. The organic layer is dried over Na2SO4 and chromatographed with EtOAc/hexanes on a silica gel column to give enol ether 31.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][OH:11].CC(C)([O-])C.[K+].Cl[C:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])=[N:28][CH:27]=[CH:26][N:25]=1>CN(C=O)C>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[O:8][CH2:9][CH2:10][O:11][C:24]1[C:29]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])=[N:28][CH:27]=[CH:26][N:25]=1
Reactant: CN(C)CCOc1ccccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1ccccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 2-{2-[2-(dimethylamino)ethoxy]phenoxy}ethanol (from Step 3; 0.82 g, 3.6 mmol) in dry DMF (25 mL) was added potassium tert-butoxide (0.59 g, 5.3 mmol) and the mixture was stirred at room temperature for 10 minutes. To the mixture was added 2-chloro-3-[(2R)-2-methylpiperazin-1-yl]pyrazine* (0.70 g, 3.3 mmol) in DMF (5 mL) in one portion and the reaction mixture was stirred at 55° C. for 2 h. A small spoon of silica was added, the solvent was filtered off and the solvent was evaporated under reduced pressure. The crude product was purified on a column of silica (100 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, followed by 90:10:0.2) as eluent to give 0.80 g (60%) of the title compound as a light brown oil. HRMS m/z calcd for C21H31N5O3 (M)+ 401.2427. found 401.2414. *Reported in WO 00/76984, Example 192, Step 2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[S:26])([CH3:14])[CH3:13].Cl>>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:9][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:4]1)=[S:26])([CH3:13])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Reactant: NC1CCCC(C(F)(F)F)C1
Agent: Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=S)NC1CCCC(C(F)(F)F)C1
Reaction time: 12 h

Procedure:
16.0 g of 3-trifluoromethyl-cyclohexylamine are taken and 18.0 g of 2,6-diisopropyl-phenyl isothiocyanate are introduced whilst stirring. The reaction commences with slight evolution of heat. The mixture is left to stand for 12 hours and is then stirred with dilute hydrochloric acid. The crystalline product is filtered off, triturated with dilute methanol, filtered off and dried. The compound is obtained in the form of a stereomer mixture of melting point 67°-75° C.; yield 27 g. The elementary analysis and NMR and IR spectra agree with the assumed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]=[O:18])=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]3[O:23][CH2:22][CH2:21][O:18]3)=[C:15]([C:19]#[N:20])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: OCCO
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-n2ncc(C#N)c2C2OCCO2)c(Cl)c1OC(F)F

Procedure:
0.6 g (2.0 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3pyrazolyl)-5-formyl-4-pyrazol-carbonitrile is dissolved in 30 ml toluene and 0.14 g (2.2 mmol) ethylene glycol and a catalytic amount of p-toluene sulphonic acid are added. The mixture is heated for 2 hours on the water-separator, the cooled solution is washed with sodium chloride solution, and it is then dried and concentrated.
Reaction SMILES: [CH3:1][C:2]([NH:6][CH2:7][CH:8]1[O:12][CH:11]([CH3:13])[CH:10]([CH3:14])[O:9]1)([CH3:5])[C:3]#[CH:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>O>[CH3:5][C:2]([N:6]([CH2:7][CH:8]1[O:9][CH:10]([CH3:14])[CH:11]([CH3:13])[O:12]1)[C:29](=[O:30])[CH:28]([Br:27])[CH3:32])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)NCC1OC(C)C(C)O1
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C#CC(C)(C)N(CC1OC(C)C(C)O1)C(=O)C(C)Br

Procedure:
N-(1,1-Dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (10 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 5° to 10° C. and α-bromopropionyl chloride (7 grams) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(1,1-dimethylprop-2-ynyl)-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-α-bromopropionamide.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(1-Acetyl-4-piperidinyl)propionic acid (10.0 g) was added by portions to thionyl chloride (30 ml) at room temperature. After stirring at room temperature for 30 minutes, thionyl chloride was evaporated under reduced pressure to give the crude product of 3-(1-acetyl-4-piperidinyl)propionyl chloride. Aluminum chloride (20 g) was added by portions to a suspension of the crude product and 2,2,2-trifluoro-N-(2-methoxyphenyl)acetamide (10.0 g) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice (200 g), extracted with ethyl acetate, and washed with brine. The organic layer was, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluting solvent; ethyl acetate), and the solvent was evaporated to give the title compound as colorless crystals (8.83 g) having a melting point of 77 to 79° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ccc(N=[N+]=[N-])c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and sodium azide were dissolved in a DMF solution, followed by stirring at 50° C. for 4 hours to obtain methyl 2-(4-azido-3-cyanophenyl)isonicotinate. NMRC: 7.38 (1H, d), 7.84 (1H, dd), 8.46 (1H, d).