Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]=2)=[C:11]([C:30]2[CH2:34][C:33]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[O:32][N:31]=2)[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1>[C:38]([O:37][C:36](=[O:42])[CH2:35][C:33]1([CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[O:32][N:31]=[C:30]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:20]2)[CH2:34]1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)CCN1CC=C(c2ccc(OCc3ccccc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
A mixture of tert-butyl 3-(4-(4-(benzyloxy)-2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)propanoate (245 mg), 10% Pd/C (containing about 55% water, 25 mg), and THF (3 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The obtained residue was mixed with 10% Pd/C (containing about 55% water, 50 mg) and THF (3 mL). The obtained mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The obtained residue was mixed with 10% Pd/C (containing about 55% water, 75 mg) and THF (3 mL). The obtained mixture was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (60.7 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 109.3 %

Procedure:
To a solution of [2-(4-amino-phenyl)-ethyl]-carbamicacid tert-butyl ester (10.75 g, 45.49 mmol) in pyridine (125 ml) at 0° C. 4-Isopropyl-benzenesulfonyl chloride (10.45 g, 47.76 mmol) was added. The mixture was stirred at 0° C. for 1 h and 16 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a brown oil (20.82 g, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.CCOC(C)=O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cnc(F)c2ccc(F)cc12
Temperature: 140 °C
Yield: 67 %

Procedure:
To a solution of 1-chloro-6-fluoro-4-methoxyisoquinoline (115 mg, 0.543 mmol) in DMSO (5 mL), was added CsF (165 mg, 1.087 mmol) and the reaction was heated to 140° C. for 2 h. The reaction was diluted with EtOAc and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using 20-40% DCM in hexanes. The product fractions were collected and the solvent was removed under vacuum to give 1,6-difluoro-4-methoxyisoquinoline (71 mg, 67% yield). MS m/z 196.1 (M++1).
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)/[C:5]([O:7][CH3:8])=[O:6].P(Cl)(Cl)(Cl)=O.CN([CH:22]=[O:23])C.C([O-])(=O)C.[Na+]>ClCCCl>[CH3:1][O:2]/[CH:3]=[C:4](\[N:9]1[CH:10]=[CH:11][CH:12]=[C:13]1[CH:22]=[O:23])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)n1cccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CO/C=C(/C(=O)OC)n1cccc1C=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of (Z)-methyl 3-methoxy-2-(pyrrol-1-yl)acrylate (10 g, 0.055 mol) in 1,2-dichloroethane (25 ml) was added dropwise with stirring at room temperature to the mixture resulting from adding phosphoryl chloride (5.6 ml, 0.06 mol) to DMF (4.7 ml, 0.06 mol) while cooling in ice. After stirring for 3 hours at room temperature, a saturated aqueous solution of sodium acetate (100 ml) was added and the resulting mixture was heated at reflux for 30 minutes. The mixture was cooled then extracted with dichloromethane (2×150 ml). The extracts were washed with water, dried and concentrated to give a clear oil (11.7 g, of a mixture of the 2 and 3-formylated pyrrole) which was purified by HPLC on silica gel using diethyl ether as the eluant to give (Z)-methyl 3-methoxy-2-(2-formylpyrrol-1-yl)acrylate (5.7 g, 45%) as a white crystalline solid, m.p. 58°-9° C., proton n.m.r. (CDCl3) delta: 3.74 (3) s, 3.88 (3) s, 6.35 (1) m, 6.87 (1) m, 7.04 (1) m, 7.55 (1) s, 9.30 (1) d.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: Cc1ccncc1C(O)c1cc(C)c(C)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1C(=O)c1cc(C)c(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanol (174 mg) was dissolved in chloroform (5 ml) to prepare a solution. Manganese dioxide (1.05 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was then filtered through Celite. The solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanone (151 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5]Cl.[H-].[Na+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: FC(F)(F)c1ccc(CCl)cc1Cl
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)c(Cl)c1
Yield: 67.2 %

Procedure:
Using 0.28 g of 3-chloro-4-(trifluoromethyl)benzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.25 g of 2-(3-chloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (39)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:22](=O)(OCC)[O:23]CC.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]4[CH2:19][O:20][C:22](=[O:23])[NH:21]4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Reactant: CCOC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(CC4COC(=O)N4)cc23)CC1
Temperature: 130 °C

Procedure:
A mixture of the product from step (g) (1.6 g), diethyl carbonate (0.73 ml) and potassium carbonate (0.08 g) was heated at 130° C. for 5 hours. The mixture was cooled, taken up in methanol and the insoluble potassium carbonate filtered off. The filtrate was evaporated in vacuo and the residue eluted through a silica colum using DCM/EtOH/NH4OH (30:8:1) as eluant. The eluate was evaporated in vacuo and the residue recrystallised from isopropanol/ether to give the desired product as a colourless crystalline solid (1.1 g), mp 191°-192° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[C:20]([C:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1)#[CH:21]>CCCCCCC.C(Cl)Cl>[C:22]1([C:20]#[C:21][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=Cc1ccc(C#CC2=CCCCC2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (71 mg, 68%); 1H NMR δ (CDCl3): 9.99 (s, 1H), 8.02 (d, J=8.51 Hz, 2H), 7.52 (d, J=8.60 Hz, 2H), 6.31-6.27 (m, 1H), 2.14-2.22 (m, 4H), 1.58-1.73 (m, 4H); LCMS m/z: 210.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][N:27]([C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=1)[CH:28]([CH3:30])[CH3:29])=[O:25]
Reactant: CC(C)CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-isopentyl-1H-indol-3-yl)acrylic acid (140.0 mg, 0.54 mmol), 3-fluoro-N′-isopropylbenzohydrazide (158.9 mg, 0.81 mmol) and HATU (308.0 mg, 0.81 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.81 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-3-fluoro-N′-(3-(1-isopentyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (104.0 mg, 44.2%).
Reaction SMILES: O1CCCC1.B.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](O)=[O:16])=[C:10]([I:18])[CH:9]=1.CO>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[C:10]([I:18])[CH:9]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1I
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 52.73 mmol of borane tetrahydrofuran complex (1N in tetrahydrofuran) is added dropwise to a stirred solution of 21.09 mmol of (4-chloro-2-iodo-phenyl)-acetic acid in 150 ml of dry tetrahydrofuran. The reaction mixture is stirred at room temperature for 1 hour then 20 ml of methanol are carefully added. The mixture is refluxed at 60° C. for 45 minutes, and then evaporated to dryness. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title product as a yellowish solid. Rf=0.13 (EtOAc-heptane=1:4); Rt=4.27 (gradient I).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7]=2[CH:6]=[CH:5][N:4]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[O:2]=[C:3]1[C:8]2[C:9]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)=[N:10][N:11]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7]=2[CH:6]=[CH:5][NH:4]1
Reactant: COC(=O)c1cc(-c2nn(C3CCOCC3)c3ccnc(OC)c23)cs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-(4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (146 mg) in acetonitrile (10 mL) were added sodium iodide (117 mg) and chloro(trimethyl)silane (0.396 mL)(and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (131 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=O)#[N:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.[ClH:26].CN(C)CCCN=C=NCC.[ClH:38]>CN(C)C1C=CN=CC=1>[Cl:26][CH2:1][Cl:38].[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:8])#[N:2]
Reactant: COc1cccc(N)c1
Reactant: CC(C)COc1ccc(C(=O)O)cc1C#N
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: COc1cccc(NC(=O)c2ccc(OCC(C)C)c(C#N)c2)c1
Product: ClCCl
Temperature: 25 °C
Reaction time: 21 h
Yield: 89 %

Procedure:
(20 mL) was added to a mixture of 3cyano-4-isobutyloxybenzoic acid (2.19 g, 10 mmol), m-anisidine (1.85 g, 15 mmol), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (WSC•HCl, 3.83 g, 20 mmol), and 4-(dimethylamino)pyridine (244 mg, 2.0 mmol). The resulting mixture was then stirred for 21 hours at room temperature. To the mixture was added aqueous 1M hydrochloric acid (30 mL), and the resulting mixture was extracted with ethyl acetate (40 mL). The ethyl acetate portion was washed with aqueous saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. The residue was recrystallized from toluene, to give 2.87 g (yield 89%) of the desired compound in the form of a crystalline product.
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]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]2[CH2:22][S:23][CH2:24][C:15]2=[N:14]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]2[CH2:22][S:23](=[O:33])[CH2:24][C:15]2=[N:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CSC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CS(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetamide (2) (145 mg, 0.37 mmol) in CH2Cl2 (5 mL), m-CPBA (500 mg) was added. The reaction mixture was stirred at room temperature for 30 min. and aq. NaHCO3 (10 mL) was added and the organic layer separated and washed with water (2×10 mL), dried (Na2SO4) and concentrated to obtain the title compound as a white solid. (35%); 1H NMR (CDCl3) δ 7.8 (2H, m), 4.33 and 4.46 (2H each, m), 2.12 (3H, s); MS (M+) 428.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][CH2:15][CH2:16][NH2:17].Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[N:3]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1
Reactant: CC1CCCC(C)N1Cc1cccc(OCCCN)c1
Reactant: Nc1nnc(Br)s1
Product: CC1CCCC(C)N1Cc1cccc(OCCCNc2nnc(N)s2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(2,6-dimethyl-1-piperidinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([CH3:21])=O.C(Br)C#C>C1(C)C=CC=CC=1>[CH2:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1)[C:19]#[CH:18]
Reactant: COc1ccc(O)cc1OC
Reactant: CC(C)=O
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(OC)c(OC)c1

Procedure:
Following the same procedure as in Example 1, 13.8 g (0.1 mole) of 1-hydroxy-3,4-dimethoxybenzene, 13.8 g (0.1 mole) of anhydrous potassium carbonate in ml 50 of acetone and 14.9 g (0.1 mole) of a solution of propargyl bromide in toluene (80% w/w) were reacted. After work up and evaporation of the mixture u.v. (25° C./21 mbar) a residue was obtained that was purified on silica gel column (eluant n-hexane:ethyl acetate 5:1 v/v). A thick oil that after some time solidified with low melting point (28-30° C.) (b.p.: 109-110° C./ 3 mbar) was obtained whose NMR and MS analyses corresponded to those of the aforementioned compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C:2]1([C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (308 g, 1.32 mol) in THF (1 L) cooled in an ice bath was added trimethyl(trifluoromethyl)silane (229 g, 1.61 mol) via an addition funnel over a period of 15 minutes. A 1.0 M solution of TBAF in THF (13.2 mL, 13.2 mmol) was slowly added dropwise to the mixture. After being stirred for 16 hours at ambient temperature, the mixture was charged with additional trimethyl(trifluoromethyl)silane (25.0 g, 176 mmol) and stirred for 2 hours. The mixture was concentrated to a volume of 500 mL, diluted with MeOH (3 L), cooled in an ice bath, and carefully quenched with concentrated aqueous HCl (250 mL). The mixture was removed from the ice bath, stirred for 1 hour, and concentrated in vacuo. The resulting aqueous suspension was extracted with CH2Cl2 (1 L, then 2×500 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated. The crude material was crystallized from toluene to give 357 g (89%) of product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[CH:15][CH:16]=[CH:17][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[C:33](=O)([O-])O.[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:18]([N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[CH:15][CH:16]=[CH:17][N:10]4[N:9]=3)=[CH:4][CH:3]=2)[CH:21]=[N:20]1)[CH3:33]
Reactant: O=C([O-])O
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)nn2cccc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2ccc(-c3nn4cccc4c(=O)[nH]3)cc2)cn1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A suspension of 2-(4-bromo-phenyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (58.0 mg, 0.200 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (45.8 mg, 0.22 mmol) and sodium hydrogen carbonate (20.2 mg, 0.24 mmol) in 0.4 ml DMF and 0.2 ml water is flushed with nitrogen and heated to 40° C. Then bis(triphenylphosphine)-palladium(II)-chloride (2.8 mg, 0.004 mmol) is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 18 hours. The mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off washed with water and dried under vacuum. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 2-[4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as off-white crystals; HPLC/MS 1.64 min (C), [M+H] 292;
Reaction SMILES: [S:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([OH:3])=[O:2].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21]I.[OH-].[Na+]>O.C(O)C>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][CH2:21][S:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])=[O:2]
Reactant: ICCOC1CCCCO1
Reactant: O=C(O)c1cccc(S(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(S(=O)(=O)CCOC2CCCCO2)c1
Yield: 14.8 %

Procedure:
To a solution of 3-sulfino-benzoic acid (1 g) and 2-iodoethyl tetrahydro-2H-pyran-2-yl ether (1.4 g) in water (20 ml) and ethanol (20 ml) was added NaOH solution to give a pH of 9. The resulting mixture was refluxed for 3 hours before evaporation of the ethanol. The aqueous was acidified to pH3 and the product extracted with EtOAc. The organic layer was separated, dried with MgSO4 and solvent removed by evaporation to give the sub-title compound (0.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][C:17]([OH:19])=O.[C:25]([C:29]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:30]=1[NH2:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[C:25]([C:29]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:30]=1[NH:31][C:17](=[O:19])[CH2:16][CH:15]([C:4]1[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCCCCC(CC(=O)O)c1cc(C(=O)OC)c(OC)cc1OC
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1N
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 44, but using 3-(2,4-dimethoxy-5-methoxycarbonylphenyl)octanoic acid (prepared as described in Preparation 37) and 2-t-butyl-5-carbamoylaniline (prepared as described in Preparation 38), the title compound was obtained as crystals, melting at 101-103° C. (from methylene chloride-diethyl ether).