Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Temperature: 80 °C

Procedure:
2-methyl-4-nitrobenzoic acid methyl ester (696 mg, 3.57 mmol), azobisisbutyronitrile (58.6 mg, 0.357 mmol) and N-bromosuccinimide (785 mg, 4.46 mmol) were suspended in carbon tetrachloride (35 mL) in a sealed tube. The above mixture was flushed with nitrogen for 5 minutes and heated at 80° C. for 22 hours. After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain the crude product methyl 2-(bromomethyl)-4-nitrobenzoate as a light-brown solid, which was used for the next step without purification.
Reaction SMILES: C(OC(=O)C(NCC(C1C=CC=C(Cl)C=1)O)=C(C1N(C(OC(C)(C)C)=O)C2C=C(N3CCOCC3)C=C(C)C=2N=1)C(OCC)=O)C.[CH2:47]([O:49][C:50](=[O:86])[C:51]([O:81]S(C)(=O)=O)=[C:52]([C:58]1[N:62]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:61]2[CH:70]=[C:71]([N:75]3[CH2:80][CH2:79][O:78][CH2:77][CH2:76]3)[CH:72]=[C:73]([CH3:74])[C:60]=2[N:59]=1)[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH3:48].NC[C@H](C1C=CC=C(Cl)C=1)O>C(#N)C>[CH2:56]([O:55][C:53](=[O:54])[CH:52]([C:58]1[N:62]([C:63]([O:65][C:66]([CH3:67])([CH3:69])[CH3:68])=[O:64])[C:61]2[CH:70]=[C:71]([N:75]3[CH2:76][CH2:77][O:78][CH2:79][CH2:80]3)[CH:72]=[C:73]([CH3:74])[C:60]=2[N:59]=1)[C:51](=[O:81])[C:50]([O:49][CH2:47][CH3:48])=[O:86])[CH3:57]
Reactant: CCOC(=O)C(OS(C)(=O)=O)=C(C(=O)OCC)c1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Agent: CCOC(=O)C(NCC(O)c1cccc(Cl)c1)=C(C(=O)OCC)c1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Agent: NC[C@@H](O)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)C(=O)C(C(=O)OCC)c1nc2c(C)cc(N3CCOCC3)cc2n1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
(S)-(2E and 2Z)-2-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-but-2-enedioic acid diethyl ester: To a stirred solution of (2-E and 2Z)-2-methanesulfonyloxy-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-but-2-enedioic acid diethyl ester (0.012 g, 0.021 mmol) in acetonitrile (1 mL) was added (S)-2-amino-1-[3-chlorophenyl]ethanol (0.005 g, 0.031 mmol) and the mixture was stirred at 60° C. for 1 hour. The solvent was evaporated and the residue was purified by silica gel chromatography (50 to 75% ethyl acetate in hexane) to give the title material (0.010 g, 74%). HPLC: 97% (220 nm), LCMS (+ESI, M+H+) m/z 657; 1H NMR (400 MHz, acetone-d6) δ (ppm): 1.17-1.33 (15H, m), 2.51 (3H, br s), 3.14 (4H, m), 3.77 (6H, m), 4.24-4.34 (4H, m), 5.62 (1H, m), 6.80-7.52 (6H, m).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[CH2:14]=[C:15]1[CH2:24][CH2:23][C:18]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][CH2:16]1>>[CH3:12][C:8]1[CH:7]=[C:6]([C:5]#[C:4][C:3]2[CH2:14][C:15]3([CH2:16][CH2:17][C:18]4([CH2:19][CH2:20][CH2:21][CH2:22]4)[CH2:23][CH2:24]3)[O:1][N:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: C=C1CCC2(CCCC2)CC1
Reactant: Cc1cccc(C#CC(Cl)=NO)c1
Product: Cc1cccc(C#CC2=NOC3(CCC4(CCCC4)CC3)C2)c1

Procedure:
The title compound was prepared following the procedure described for Compound 3c, using Compound 91d instead of Compound 3b and Compound 89a instead of Compound 3a. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (ISOLERA®TM-Biotage; gradient Petroleum Ether-EtOAc from 97:3 to 9:1) to give the title compound as a white-yellowish solid. Yield: 55.8%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([S:17]([CH:20]=[CH2:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([S:17](/[CH:20]=[CH:21]/[C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S(=O)(/C=C/c1ccc2[nH]ccc2c1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 5-bromoindole (5.0 g, 25.5 mmol), phenylvinylsulfone (7.50 g, 44.64 mmol), Pd(OAc)2 (0.46 g, 2.05 mmol), tri-O-tolylphosphine (1.55 g, 5.10 mmol) and triethylamine (4.88 g, 48.46 mmol) was heated to 95-105° C. for 6-15 h in DMF. The reaction mixture was cooled to RT, diluted with dichloromethane and filtered over a bed of filter aid. The filtrate was sequentially washed with water and brine, and dried over sodium sulphate. The organic layer was concentrated under vacuum and the product precipitated from dichloromethane and hexane as a solid in about 85-90% yield.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[NH:26][C:38](=[O:39])[NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4[nH]c(=O)[nH]c4cc3-c3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
6-(4-{[4-(2-Methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.046 g, 0.094 mmol) was dissolved in 1 ml DCM and 1,1′-carbonyldiimidazole (0.017 g, 0.104 mmol) was added. After 8 h additional 1,1′-carbonyldiimidazole (0.017 g, 0.104 mmol) was added. After stirring overnight the reaction was diluted with saturated aqueous Na2CO3. The mixture was extracted 3× with DCM then 1× with iso-BuOH. Purification by flash column chromatography (95:5 to 90:10 DCM/MeOH) afforded 5-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4-5). 1H NMR (CDCl3) δ 7.69 (m, 1H), 7.55 (m, 1H), 7.27-7.16 (m, 9H), 7.08 (m, 2H), 6.76 (s, 1H), 4.12 (m, 1H), 3.34 (s, 2H), 2.96 (d, 2H), 2.61 (s, 3H), 2.52 (m, 2H), 2.27 (m, 2H), 1.79 (d, 2H, J=10.0 Hz). MS m/z (M+H)=515.16.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[C:13]=2[O:15][CH3:16])[C:8](=[O:19])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6]1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[F:18][C:11]1[CH:10]=[C:9]2[C:14](=[C:13]([O:15][CH3:16])[C:12]=1[F:17])[NH:5][CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2=[O:19]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(OC)c(F)c(F)cc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]c2c(OC)c(F)c(F)cc2c1=O
Yield: 99.9 %

Procedure:
A solution of ethyl 1-tert-butyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (4.00 g, 11.8 mmol) in CH2Cl2 (20 mL) and trifluoroacetic acid (4.0 mL) was stirred at 0° C. for 30 min. The mixture was concentrated in vacuo and poured into 500 mL of ice-water. The resulting precipitate was removed by filtration, washed with water and then dried to yield ethyl 6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (3.34 g, quant) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 100-mL round-bottom flask, was placed tert-butyl 2-(4-nitrophenoxy)acetate (2 g, 7.74 mmol, 1.00 equip, 98%), Palladium on carbon (200 mg), and methanol (50 mL). To the above hydrogen was introduced. The resulting solution was stirred for 18 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield tert-butyl 2-(4-aminophenoxy)acetate as a reddish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][N:60]=[C:59]([N:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[CH:58]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:66]3[CH2:67][CH2:68][N:63]([C:59]4[CH:58]=[C:57]([O:56][CH3:55])[CH:62]=[CH:61][N:60]=4)[CH2:64][CH2:65]3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: COc1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccnc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 2 mL DMF. 39 mg TBTU and 53 μL DIPEA were added to this solution and the mixture was stirred for a few minutes at RT. Then 24 mg 1-(4-methoxy-pyridin-2-yl)-piperazine was added. The mixture was stirred 1 h at RT. The reaction-solution was evaporated and the residue was purified by HPLC to give 30 mg of the desired compound. Rt: 1.68 (method C), (M+H)+: 491
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39])([O-:31])=[O:30].O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N+:29]([O-:31])=[O:30])(=[O:39])=[O:40])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(N)cc2CC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-amine (970 mg) in THF (34 mL) were added triethylamine (706 μL) and o-nitrobenzenesulfonyl chloride (823 mg) at 0° C., and the mixture was stirred at room temperature for 5 hr. Triethylamine (706 μL) and o-nitrobenzenesulfonyl chloride (374 mg) were further added at 0° C., and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.31 g) as a yellow gummy substance.
Reaction SMILES: NC1C=C(F)C=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[F:19][C:17]1[CH:16]=[CH:15][C:14]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:13]([NH:12][C:4]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:5])[CH:18]=1
Reactant: Nc1nccs1
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: COc1ccccc1C(=O)c1ccc(F)cc1N
Product: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nccs1
Yield: 68 %

Procedure:
(2-Amino-4-fluoro-phenyl)-(2-methoxy-phenyl)-methanone (784 mg, 32%) was prepared from 2-amino-4-fluoro-benzoic acid (1.55 g, 0.1 mol) following the general procedure S. 1-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-3-thiazol-2-yl-urea (127 mg, 68%) was prepared from (2-amino-4-fluoro-phenyl)-(2-methoxy-phenyl)-methanone (123 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C1C(=O)N([Br:21])C(=O)C1>ClC(Cl)(Cl)Cl.C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:13][C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C#N)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)c1cccc(C#N)c1CBr
Yield: 98.2 %

Procedure:
A suspension of methyl 3-cyano-2-methylbenzoate (10.6 g, 60.5 mmol), NBS (16.2 g, 90.7 mmol) and azobisisobutyronitrile (AIBN) (100 mg) in tetrachloromethane (200 mL) was refluxed under nitrogen atmosphere for 6 hours. Alternatively, the bromination step was carried out using NBS in benzene, using benzoyl peroxide as a catalyst. TLC analysis showed the complete consumption of methyl 3-cyano-2-methylbenzoate (TLC solvent: 10% ethyl acetate in hexane). The reaction mixture was filtered and washed with chloroform (3×20 mL). The combined filtrate and washings were concentrated under reduced pressure. The residue was washed through a short column of silica gel using 10% ethyl acetate in hexanes as an eluent. The eluent was concentrated and the resultant product dried under vacuum overnight to provide 15.1 g of methyl 2-bromomethyl-3-cyanobenzoate (98% yield). 1H NMR spectrum (in DMSO-d6): δ 8.15, (d, J=8.0 Hz, 1H); 8.12 (d, J=7.9 Hz, 1H); 7.67 (t, 1H); 5.04 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH2:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([NH:16][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:25][CH:26]=3)[N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: Nc1nc2c(OCc3cccc(Cl)c3)cccn2n1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5cccc(Cl)c5)cccn4n3)cc2)CC1

Procedure:
260 c) 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) was suspended in acetone (1.9 mL). 1-(bromomethyl)-3-chloro-benzene (0.184 mL, 1.40 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added and the reaction mixture was heated to 80° C. for 1 hour. Reaction mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated. Resulting oil was taken up in dichloromethane and purified via chromatography (silica gel 0-100% ethyl acetate in hexanes). 8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was isolated as an oil which solidified on standing. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.17 (d, J=6.6 Hz, 1H), 7.56 (s, 1H), 7.44-7.42 (m, 3H), 6.99 (d, J=7.9 Hz, 1H), 6.79-6.75 (m, 1H), 5.94 (bs, 2H), 5.30 (s, 2H). MS=275 (MH)+. 260 d) [8-(3-Chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-chloro-benzyloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (95.0 mg, 0.346 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (102 mg, 0.399 mmol in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.073 g, 47%). MP=135-138° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.33 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 7.58 (s, 1H), 7.51-7.44 (m, 5H), 7.09 (d, J=7.9 Hz, 1H), 6.91-6.86 (m, 3H), 5.35 (s, 2H), 3.04-3.01 (m, 4H), 2.46-2.44 (m, 4H), 2.22 (s, 3H). MS=449 (MH)+.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=N1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH3:14][C:13]1[O:15][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=1
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Reactant: CC(=O)OC(C)=O
Product: Cc1nnc(-c2ccc(Br)cn2)o1

Procedure:
In 10 ml of acetic anhydride was dissolved 1 g of 2-(5-tetrazolyl)-5-bromopyridine, followed by refluxing for 2 hours. After completion of the reaction, the same post-treatment as in Preparation Example 13 was conducted to give the title compound. 0.6 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH3:38])=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:45])[CH2:35][CH2:36][N:37]([CH2:39][CH2:40][CH2:41][N:42]([CH3:43])[CH3:44])[CH3:38])=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: COc1cc(-c2csc3c(NC(=O)CCN(C)CCCN(C)C)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)-thieno[3,2-c]pyridin-7-yl]-3-[(3-dimethylamino-propyl)methylamino]propionamide, and the procedure described in General Procedure F. m/z (M+H)+ 614.3.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6](O)(=[O:8])=[O:7].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C.O>[CH3:5][S:6]([C:17]1[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][C:16]=1[CH3:19])(=[O:8])=[O:7]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])cc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 12 %

Procedure:
Under a nitrogen atmosphere, thionylchloride (4ml, 58 mmol) and methanesulphonic acid (9 mL, 146 mmol) were refluxed for 90 min. 4-Nitrotoluene (4 g, 29 mmol) and triflouromethanesulphonic acid (200 uL, 3 mmol) were added and the mixture was allowed to stand for 48 hours at 120° C. The mixture was cooled to 0° C. and water (50 mL) was carefully added, followed by addition of ethyl acetate (150 mL). The organic phase was separated and extracted with a saturated solution of sodium hydrogencarbonate (2×50 mL) and water (2×50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethylacetate, 1:1) to give 0.75 g of 2-methylsulfonyl-1-methyl-4-nitrobenzene.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:16])[CH2:13][CH2:14]Cl)=[CH:7][CH:6]=1.C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:14][CH2:13][C:12]2=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(CCCl)Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCN1c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(4-trifluoromethylphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(4-trifluoromethylphenyl)-2-azetidinone as the residue.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[NH:9][N:8]=1.Br.Br[CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:23]([N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][CH2:19][NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[NH:9][N:8]=1)[CH3:24]
Reactant: CCN(CC)CCCBr
Reactant: Nc1n[nH]c2cccc(Cl)c12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2cccc(Cl)c12
Temperature: 80 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
To 80 ml of anhydrous N,N-dimethylformamide were added 5.04 g of 3-amino-4-chloroindazole prepared by the same method as in Example 1, 8.30 g of 3-bromopropyldiethylamine hydrobromide and 8.3 g of anhydrous potassium carbonate. The mixture was stirred for 24 hours at 80° C. and condensed under reduced pressure. The condensed residue was added with 100 ml of chloroform and 50 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 5.16 g of 3-(3-diethylaminopropylamino)-4-chloroindazole having the following analytical values in a yield of 61%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[C:17]([Si:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[C:17]([Si:21]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc([N+](=O)[O-])cc1)(c1ccccc1)c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 4-nitrobenzyl alcohol (1.00 g, 6.50 mmol) and imidazole (0.97 g, 14.10 mmol) in DMF (10.0 mL), t-butyl-diphenyl-chlorosilane (1.98 g, 1.87 mL, 7.20 mmol) was added over 10 min under nitrogen at room temperature. The reaction mixture was stirred for an additional 5 h, diluted with 75 mL Et2O, washed with H2O (5 times, 15 mL), dried (MgSO4) and evaporated under vacuum. An oil which crystallised on standing, resulted; yield: 2.54 g. After recrystallisation from EtOH 70%, 2.36 g (93%) of a white soiid is obtained mp 80-81° C. νmax /cm-1 (film): 2931. 2857 (CH2, asym., sym.), 1521. 1345 (NO2); 1H-NMR, δH : 1.06(9H, s, t-Bu), 4.92 (2H, s, CH2), 7.42-7.46 (5H, m, Ph), 7.63-7.65 (7H, m, Ph+Harom2+6), 8.23, (2H, d, J=8.23 Hz, Harom3+5); MS, (EI), (391.54); m/z: 334 (M-t-Bu, 100), 288 (M-t-Bu-NO2, 10), 256 (M-t-Bu-Ph, 20), 199 (Ph2SiOH+, 100); C23H25NO3Si.