Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH3:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:35])[CH:30]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(O)ccc1F
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: Cc1cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)ccc1F

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-fluoro-3-methylphenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.23–8.10 (2H, m), 7.96 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.15–6.90 (3H, m), 5.50–5.30 (1H, m), 2.32 (3H, s), 1.65–1.55 (3H, m), 1.58 (9H, s); MS (ESI) m/z 485 (M+H)+, 483 (M−H)−.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[CH:37]12[CH2:44][CH:40]([CH:41]([NH2:43])[CH2:42]1)[CH2:39][O:38]2>C(O)(CC)C>[CH:37]12[CH2:44][CH:40]([CH:41]([NH:43][C:27]3[N:26]=[C:25]([C:22]4[CH:23]=[CH:24][N:19]([C@@H:10]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=5)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:20](=[O:35])[CH:21]=4)[CH:30]=[CH:29][N:28]=3)[CH2:42]1)[CH2:39][O:38]2
Reactant: NC1CC2CC1CO2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Agent: Cl
Solvent: CCC(C)O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CC4CC3CO4)n2)cc1=O
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A microwave vial was charged with (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (100 mg, 0.190 mmol), 2-oxa-bicyclo[2.2.1]heptan-5-amine hydrochloride (53 mg, 0.47 mmol), TEA (0.50 mmol, 50 mg) and s-butanol (3.0 mL). The mixture was stirred at 130° C. under microwave irradiation for 3 hours. After completion of the reaction, the mixture was concentrated to give 4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)pyridin-2(1H)-one as an oil, which was used in the next step without further purification. LCMS (ESI) m/z: 571.3 [M+H]+.
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1)#[CH:18]>>[CH3:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2][C:18]#[C:17][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: Cc1cccc(-c2ccccc2C=CI)c1
Product: Cc1cccc(-c2ccccc2C=CC#Cc2ccc(C(=O)O)cc2)c1
Yield: 23.5 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 2.10 g (6.55 mmol) of 2-(2-iodovinyl)-3'-methylbiphenyl obtained in Example 21(b) with 1.05 g (6.55 mmol) of methyl 4-ethynylbenzoate, 520 mg (22%) of the expected compound are obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>C(O)CCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1Cl
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Solvent: CCCCO
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
A mixture of compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (3.97 g, 13.7 mmol), 3-chloro-4-methoxyaniline (2.13 g, 13.7 mmol) in butanol (30 mL) was stirred at 120° C. for 12 hours. The mixture was then cooled to temperature in the range of 20-40° C. The solid precipitated was filtered, collected, stirred in isopropanol (10 mL), filtered, and dried to give the desired compound as a white solid. Yield: 48%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:13]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(Cl)nc1
Yield: 69 %

Procedure:
6-chloropyridine-3-sulfonyl chloride (4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (150 mL) and any insoluble material filtered. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous phase was further extracted with EtOAc (1×15 mL). The combined EtOAc extractions were washed with H2O (1×50 mL) and saturated NaCl (1×50 mL), dried over Na2SO4, and concentrated in vacuo to give 6-chloropyridine-3-sulfonamide (2.58 g, 69%). MS (EI) m/z for C5H5Cl2N2O2S: 190.9 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Reaction time: 2 h
Yield: 65 %

Procedure:
13.9 g (0.1 mol) of 3-bromopropan-1-ol are mixed with 400 ml of dry dichloromethane and 45.7 ml (0.5 mol) of dihydropyran are added. While stirring and if needed cooling in an ice bath 190 mg (1 mmol) of p-toluenesulfonic acid monohydrate are added in such a way that the temperature of the reaction solution does not exceed 25° C. Subsequently the reaction mixture is left for 2 hours at room temperature and extracted with half-saturated aqueous sodium hydrogen carbonate solution, the dichloromethane phase is washed twice with water, dried with magnesium sulfate and filtered to remove the drying agent and the solvent is distilled off in vacuo. The remaining oil is fractionally distilled in vacuo via a 20 cm Vigreux column. 14.2-16.4 g (65-75%) of colorless oil are obtained, which boils at from 60° to 65° C. (0.5-1 mbar).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[CH2:11][CH2:10]1>CC(O)=O>[CH:9]1([CH2:12][NH:13][C:14]2[C:19]([I:1])=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc(NCC2CC2)n1
Solvent: CC(=O)O
Product: Nc1ncc(I)c(NCC2CC2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
N-iodosuccinimide (11.5 g, 50.9 mmol) was added to a solution of compound 237 (7.60 g, 46.3 mmol) in AcOH (90 mL). The reaction was warmed to 80° C. and stirred for 1.5 h. Solvent was removed in vacuo. The residue was taken up in dichloromethane (200 mL) and water. The aqueous layer was brought to pH 12 with 5 N NaOH and organics were sequestered. The aqueous was extracted further with dichloromethane (2×100 mL). The combined organics were treated with solid sodium thiosulfate, dried with MgSO4 and concentrated in vacuo. Silica gel chromatography (gradient elution 10 to 75% ethyl acetate in hexanes) afforded compound 238 (8.0 g, 60% yield).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12].C(O)(=O)C>ClCCl>[CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[N:16]1[CH2:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH2:9]1)([CH3:23])[CH3:22]
Reactant: O=Cc1ccccc1C=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1N1Cc2ccccc2C1

Procedure:
0.5 g of o-phthalaldehyde and 0.661 g of 2,6-diisopropylaniline were dissolved in 20 ml of dichloromethane, 1 ml of acetic acid was added thereto, and the mixture was reacted at room temperature for 25 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1C(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (9 ml) was added to a solution of 2-amino-N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (2.2 g; prepared in a similar manner to that described above) in dichloromethane (50 ml) and the mixture stirred at ambient temperature for 1 hour. The solvent was removed in vacuo to give crude 2-amino-N-(4-piperidylmethyl)pyridine-3-carboxamide trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]([OH:34])([CH3:35])[CH3:33])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:3]=[C:2]([NH:1][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)cn1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCC(C)(C)O)c4)ccc32)c1
Yield: 33.6 %

Procedure:
The compound was prepared from 4-(4-(1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (88 mg, 0.185 mmol) using the procedure of Example 2(b) and ethanesulfonyl chloride (28.6 mg, 0.370 mmol, 1.2 eq.) to give the product in 33.6% yield (35 mg)1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.92 (s, 1H), 8.30 (s, 1H), 8.01-7.97 (d, 2H), 7.69 (m, 3H), 7.59 (d, 2H), 7.56 (m, 2H), 7.32 (m, 1H), 4.30 (m, 2H), 3.31-3.28 (m, 4H), 1.8 (m, 2H), 1.28-1.24 (t, 3H), 1.15 (s, 6H), Calculated mass: 565.63; Observed mass: 566.2 [M+H]+ (rt: 1.40 min).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:33]1COCO[CH2:34]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([CH2:34][OH:33])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1OCOCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
1 M of titanium tetrachloride in DCM (43 mL) was added to a solution of intermediate (7b) (12.7 g, 41 mmol) in DCM (150 mL) at 0° C. under nitrogen. After 20 minutes, DIPEA (7.9 mL, 45.2 mmol) was added dropwise at 0° C. After 80 minutes, 1,3,5-trioxane (4.1 g, 45.2 mmol) in DCM (30 mL) was added, followed by a second equivalent of 1 M titanium tetrachloride in DCM after 10 minutes. After 2.5 hours at 0° C., the mixture was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with water (100 mL) and DCM (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7c), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13]([OH:20])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH3:14])[CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][O:20][C:13]([CH3:14])([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: CC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of N-[4-bromo-2-(1-hydroxy-1-thien-2-ylethyl)phenyl]-2-chloroacetamide (1.29 g, 3.44 mmol) in anhydrous THF (20 mL) was added at 0° under nitrogen sodium hydride (60% in mineral oil, 0.38 g, 9.5 mmol). After addition, the reaction mixture was stirred for 3 h, treated with an aqueous saturated ammonium chloride solution (30 mL). Ethyl acetate (50 mL) was added and organic layer separated, dried (Mg2SO4), and concentrated to yield the title compound as a white solid (1.1 g, 96%). 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.57 (dd, J=5.0, 1.0 Hz, 1H), 7.47 (dd, J=8.6, 1.4 Hz, 1H), 7.39 (d, J=1.67 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.00 (m, 1H), 6.88 (dd, J=2.6, 0.9 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 4.03 (d, J=16.3 Hz, 1H), 1.99 (s, 3H). MS (ES) m/z 338/340 ([M +H]+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15])=[O:24]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(-c2ccccc2)cc1O
Product: O=C(Nc1ccc(-c2ccccc2)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and 2-bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56%).EI-MS m/z 383(M+H)+
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.C[O:10][C:11]([C:13]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=O>>[CH3:2][N:3]1[N:7]=[C:6]([NH:8][C:11]([C:13]2[CH:23]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=3[CH:14]=2)=[O:10])[CH:5]=[N:4]1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)cc2)c2c(c1)OC(C)(C)C2
Reactant: Cn1ncc(N)n1
Agent: Cl
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (533 mg, 1.78 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (130 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1 H) 8.07 (s, 1 H) 7.62 (d, J=8.59 Hz, 2 H) 7.09 (d, J=10.36 Hz, 2 H) 7.02 (d, J=8.59 Hz, 2 H) 4.07 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H19N5O3 m/z 390.20 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:14].CCO>CO>[ClH:14].[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: c1ccc(CC2CCCCN2)cc1
Reaction time: 5 h
Yield: 94 %

Procedure:
A solution of 2-benzylpyridine (2.0 g, 12 mmol) in MeOH (50 mL) containing conc. HCl (1 mL) was hydrogenated in a Parr apparatus over Pt (PtO2, 30 mg) at 25° C. The reaction was allowed to proceed at 22 psi for 5 h, 45 psi for 4 h, then overnight at 22 to 12 psi. The catalyst was removed by filtration and the solvent was removed in vacuo to give a syrup. Absolute EtOH (50 mL) was added and then evaporated in vacuo. This was repeated to give a near colorless solid. The solid was triturated with ether (2×20 mL) and dried in vacuo to give a colorless powder (2.36 g, 94% yield); mp 128-131° C., lit. 125-130° C. (vide supra); 1H NMR (D2O) 1.45-2.05 (m, 6H), 2.80-3.05 (m, 3H), 3.27-3.45 (m, 2H) 7.26-7.46 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.[C:14]([N:16]=[CH:17]OCC)#[N:15]>C(O)C>[C:14]([NH:16][CH:17]=[N:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=2)=[CH:8][CH:9]=1)#[N:15]
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]1
Reactant: CCOC=NC#N
Solvent: CCO
Product: Cc1nc(-c2ccc(N=CNC#N)cc2)c[nH]1
Yield: 77.9 %

Procedure:
A solution of 2-methyl-4-(4-amino-phenyl)-1H-imidazole (15 g) and ethyl N-cyanoformimidate (9.35 g) in ethanol (150 ml) was stirred at room temperature overnight. The product which crystallized out was collected by filtration, washed with cold ethanol and dried to give 15.2 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:11]3[C:12](=[O:21])[O:13][C@H:14]([CH2:15]CS([O-])(=O)=O)[C@@H:10]3[CH2:9][O:8][C:7]=2[CH:22]=1)#[N:2].[K].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>>[O:29]=[C:27]1[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24](=[O:34])[N:28]1[CH2:15][C@H:14]1[C@H:10]2[N:11]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=3[O:8][CH2:9]2)[C:12](=[O:21])[O:13]1
Reactant: N#Cc1ccc2c(c1)OC[C@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: N#Cc1ccc2c(c1)OC[C@H]1[C@H](CN3C(=O)c4ccccc4C3=O)OC(=O)N21
Yield: 79.6 %

Procedure:
Using compound ((3R,3aS)-7-cyano-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (0.31 g, 0.957 mmol) and phthalimide potassium (0.266 g, 1.435 mmol) as starting materials, preparation following the method as described in Example 1(d) afforded white solid 0.286 g, yield: 79.71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:16]([S:19][C:20]([F:23])([F:21])[F:22])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 28.6 %

Procedure:
To the solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole (7.00 g, 16.6 mmol) and pyridine (4.91 g, 62.1 mmol) in 1,2-dichloroethane at room temperature was added trimethylacetyl chloride (4.37 g, 36.2 mmol) dropwise. Ice bath was used to maintain the temperature of the reaction. After 20 hr at room temperature, the organic layer was washed five times with aqueous KHSO4 till the aqueous solution was at pH 1. The organic layer was then dried (MgSO4) and concentrated to give a solid residue. Upon chromatographic purification via silica gel column of the solid residue, after trituration with pentane, a off-white solid (2.403 g, 28.6% yield, 97.0% HPLC purity) was provided as the desired product, m. p. 82-83 C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]1([CH2:14]Cl)[CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][CH2:10][C:11]1([CH2:14][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][O:12]1
Reactant: ClCC1(CCl)CO1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCC1(COc2ccc(Cl)cc2)CO1
Yield: 32.6 %

Procedure:
12.85 g (0.1 mol) of 4-chlorophenol in 50 ml of acetone are added dropwise to a mixture of 14.1 g (0.1 mol) of 2,2-di(chloromethyl)-oxirane and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of acetone. The mixture is heated under reflux for 18 hours, left to cool and filtered. The filtrate is concentrated in vacuo, the residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and concentrated. Purification of the residue by distillation gives 7.6 g (32.5% of theory) of 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane of boiling point 150° C./0.5 mbar.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:9][CH:10]([CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(N)C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(NCc1ccccc1)C1CCOCC1

Procedure:
0.53 ml (4.5 mmol) benzylbromide, 0.85 g (4.5 mmol) ethyl (rac)-amino-(tetrahydropyran-4-yl)-acetate and 1.9 g (13.7 mmol) potassium carbonate in 10 mL DMF were stirred for 2 h at 100° C. After cooling the mixture was mixed with water and extracted three times with ethyl acetate. The combined organic phases were extracted with saturated, aqueous saline solution, three times with 0.5 M hydrochloric acid and once more with saturated saline solution. The combined aqueous phases were adjusted to pH 9 with conc. aqueous ammonia solution and extracted three times with dichloromethane. The combined organic phases were washed with saturated saline solution, dried and concentrated by rotary evaporation.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)=[N:14][C:15]([NH:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)=[CH:16]2
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-Hydroxy-phenyl)-acetamide and (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine to give N-{4-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 390(MH+).